The singles spun on the Great are now on the skein winder. I'm 2-plying them using the new Navajo spindle.

 

 This is the Great wheel (also called a Walking Wheel or Wool Wheel) that came from the Athearn family on Martha's Vineyard. The wheel was found in the farmhouse attic. It was missing the spinning head, but Harriet had a spare Minor's head to lend. Notice the wheel has 4 legs instead of the usual 3.

 With a little bit of tweaking, the wheel spins wonderfully.  I'll be asking the Athearn family about the wheel, so far I've hear about memories of a grandmother fussing because she couldn't spin because a part was missing (I assume the spinning head). And I hope to get into the attic this came from to look for other fiber processing tools that went with it.  See the last photo for the "matching" skein winder.

The axle is wooden, which may mean the wheel is older, since most Greats have metal axles. (Ignore the yellow on the left, that is just a spacer we put in to make the wheel work.) There are no maker's marks anywhere, that I can find. The wheel is pegged instead of nailed. Below are photos of the peg that holds up the post that holds the wheel.

The bench is decorated with scalloped indents, which also match the scalloping on the ends of the skeiner.

Below is the tensioner.

And here is the very worn skeiner found with the wheel. It will get its own set of pictures!

 

 

Last week's CT scan, seven weeks after I started on Sutent, showed that I had stable disease; no new lesions and the extant lesions had not changed in size (within image mensuration error). While I have been described as having stable disease before, the increase over two months has never been this close to zero. So, I expect to be around at least another six months. What is particularly pleasant about this is that I am experiencing no side effects from the drug. I did have some minor side effects, mainly tiredness, for the first week or so, but that has completely cleared up. So, stable disease, no side effects, and having to go in to Boston only once a month and overnight only every other month -- what more could one possibly ask?

What is different about Sutent that it works on me? There is no definitive answer, but I can speculate. In contrast to the other drugs I have been on that regulate a very specific cellular pathway or process, Sutent targets multiple cell surface receptor tyrosine kinases (RTK). Of particular interest in my case is that it inhibits the RTK KIT. The drug that Dr. Hodi first proposed when my metastases were detected was Gleevec, which is also a KIT inhibitor. However, tests at that time concluded that while I did have KIT changes, they were not the mutations that Gleevec addresses. Sutent has broader KIT inhibitory effect. Sutent also inhibits most receptors for platelet derived growth factor as well as VEGF (Vascular Endothelial Growth Factor) receptors. By inhibiting VEGF, which is necessary for the formation of new blood vessels that tumors need to feed their growth, tumor growth is fully or partially stopped. It appears that when VEGF is inhibited the immune system is stimulated, which is a good thing. So, although Sutent is composed if a single chemical entity, Sunitinib (1,1-dimethylbiguanide - if anyone cares), it attacks a tumor several different ways simultaneously. For that reason I can hope that it will continue to work on me for a longer time than some of the single pathway inhibitors we have previously tried. Given the current discussions of health care in Washington, I feel obliged to mention that were it not for the excellent drug coverage provided by my former employer, I could not afford Sutent, whose actual price significantly exceeds my total income from all sources -- it costs an astounding (one might say obscene) $8259.11 a month!

This calm time is my opportunity to talk about some peripheral issues and perceptions. Possibly the most interesting one is what causes some people's tumors to grow rapidly and other people's slowly. The bare outline of a study to address this question is presented below the break.

There are, in addition, two personal observations that are appropriate in this Rumination. One is a consequence of its date of publication falling very near to my 80th birthday. When I was a teenager, 65 years ago, I found it unfair that I was born just a few years to soon; I anticipated a life expectancy of less than 70 years and would therefore miss the millennium. I certainly never expected to see 80. Two years ago, when the liver metastases were first discovered, I was reliably (and reasonably) informed that I would be symptomatic within a few months and, by implication, gone within a year. Again, little, if any, chance of reaching 80. Yet, here I am. An amusing sidelight is that 30 or so years ago I decided that I would declare myself to be middle aged half way between whatever my present age was and 65. Xeno's paradox to the contrary not withstanding, I became 65 (and middle aged) after all. I then decided that I would consider myself 'old' halfway between my present age and 80. Unfortunately, Xeno didn't help that one either and here I am, about to become 'old'. Ah, well, I don't feel any different, and that is a good thing. As my birthday present to me, I promise myself more postprandial naps.

The other observation is to reassure any of my readers who may be the reluctant owners of a chronic disease, their caregivers, and their family, by making explicit what we all know implicitly but often forget or ignore. Anytime we feel a twinge or catch a bug or a cold, we inevitably worry whether it is related to the chronic condition and whether it suggests a relapse or exacerbation. This suspicion is perfectly natural but can easily get out of hand and interfere with getting on with life. Since everyone is subject to such twinges and bugs, it can easily drive individuals with a natural inclination to worry to distraction. I think the best remedy is to constantly remind oneself that such symptoms are not related to the chronic disease unless the relationship is proven. Innocent until proven guilty is the way to go - Kathy and Katherine, please take note.

***********************************************************************************************

It should come as no surprise that I am fascinated by the question of what mechanisms modulate the aggressiveness of cancer. So the question that immediately occurred to me is what is the statistical distribution of survival times. (Is it random – flip of a coin, or is there a consistent pattern). While my access to literature is somewhat limited, I am discouraged by the fact that while I found that considerable effort has gone into surrogate predictive models and measures such as five year survival statistics, Kaplan-Meier survival curves, progression-free survival, and time to progression, I could find no information regarding the statistical distribution within any of these measures of survival - are they normally distributed, skewed, bimodal, or ...? Because it is not possible to know exactly when a metastases first developed (it can be weeks, months, or years between that point in time and when it is detected) directly determining the underlying distribution is a daunting problem; however, the distribution of the surrogates can reasonably be expected to reflect the distribution of the underlying reality, sufficient at least to explore the general shape of the distribution. I could not find any data on the distribution.

What follows, although cast as a broad outline of a study, is really a plea to start now to collect the specimens and relevant patient data so that as large a specimen library as possible be readily available when cost effective technology is ready for the task. The study that I am outlining is best carried out in an institution with a large population of cancer patients, such as Dana-Farber, Sloan-Kettering, etc. Although it will not be able to be carried out for a few years until genomic, epigenomic, and proteonomic testing of biopsy specimens becomes cheaper and routine, that time is close enough [e.g., S.P. Shay et al., Mutation of FOXL2 in Granuloma-cell Tumors of the Ovary. NEJM 360: 2719-2729 (June 25, 2009) and J. Shendure and C.J. stewart, Cancer genome on a Shoestring Budget, NEJM 360: 2781-2783 (June 25, 2009)] that now is the time to begin the collection of data and specimens.

Consider the totality of the cancer patient population, excluding those who had successful resections of their tumors and sufficient time has elapsed to consider them cancer-free. For each of the commonly accepted classifications of cancer (prostate, pancreatic, colon, GIST, HER-2 positive breast, etc.) data on individual survival is available. That some patients progress quickly and others slowly is well known. From the patients in each classification, select the top and bottom quartiles or quintiles of survival time as the study population. Of course, the time spans involved will differ markedly with the cancer involved; none the less, for each tumor there are patients who progress very quickly and those who progress very slowly (relative to the mean). Consider this subset of the total population as the subjects of the study whose underlying hypothesis is that there are detectable differences between the fast and slow progressors (FPs an SPs). The task is to define and quantify the similarities and differences among clusters of FPs and SPs. Equally important is to determine the cluster characteristics that best characterize / classify / group cancers.

I am using the term 'cluster' in the statistical sense of a group that segregates a property. Each study subject is a member of many clusters. (As a specific example, I cluster with males, melanoma, mucosal melanoma, 75-85 year age group, married, hepatic metastases, c-KIT replication positive, etc., etc.) Of course, many of the possible clusters are irrelevant to the study at hand and others will turn out to be so.

The first task of the study is to define as many potentially relevant clusters of the whole study population, FPs and SPs combined. I would expect these clusters to include ( and also to include many others) primary tumor site, common clinical and lab characteristics, specific aberrant cellular pathways, genomic anomalies, specific protein excess and insufficiency, which drugs have been tried with what results, etc. It is important to note that these clusters contain both SPs and FPs and that each cluster includes tumors from all organs and tissues that fall within the cluster definition. E.g., the c-KIT positive cluster includes all organ and tissue types that are c-KIT positive. It may well be desirable to define several different c-KIT positive clusters to separate out different alleles or mutations and replication. (Cluster compactness and correlation analysis will reduce the number of clusters that are retained.)

Once the clusters and their members have been selected, the next task is to identify dissimilarities between the SPs and FPs in each of the clusters identified in the first step. Of course the same database can be used for other analyzes such as the relationship of cluster characteristics to drug response. At this time, what is important is the establishment of a sample and data repository. The details of any study proposed now will certainly be significantly modified by the ongoing flood of experimental results and their interpretation.

If nothing else, I suggest that any serious contemplation of a study of this kind will go a long way to removing the blinders resulting from the organ based tumor classification and treatment (particularly chemotherapy) that is a consequence of historical imperatives that focus on organs but may be of marginal significance in the light of current oncological science. The painfully slow pace of testing and approving Sutent for KIT positive tumors other than renal cell carcinoma and gastrointestinal stromal tumors (GIST) is a worthwhile case study this issue.


The collected Ruminations may be found at http://upislandeggs.com/Ruminations.htm
and my e-mail address at the bottom of the page at http://upislandeggs.com/

Last week's CT scan, seven weeks after I started on Sutent, showed that I had stable disease; no new lesions and the extant lesions had not changed in size (within image mensuration error). While I have been described as having stable disease before, the increase over two months has never been this close to zero. So, I expect to be around at least another six months. What is particularly pleasant about this is that I am experiencing no side effects from the drug. I did have some minor side effects, mainly tiredness, for the first week or so, but that has completely cleared up. So, stable disease, no side effects, and having to go in to Boston only once a month and overnight only every other month -- what more could one possibly ask?

What is different about Sutent that it works on me? There is no definitive answer, but I can speculate. In contrast to the other drugs I have been on that regulate a very specific cellular pathway or process, Sutent targets multiple cell surface receptor tyrosine kinases (RTK). Of particular interest in my case is that it inhibits the RTK KIT. The drug that Dr. Hodi first proposed when my metastases were detected was Gleevec, which is also a KIT inhibitor. However, tests at that time concluded that while I did have KIT changes, they were not the mutations that Gleevec addresses. Sutent has broader KIT inhibitory effect. Sutent also inhibits most receptors for platelet derived growth factor as well as VEGF (Vascular Endothelial Growth Factor) receptors. By inhibiting VEGF, which is necessary for the formation of new blood vessels that tumors need to feed their growth, tumor growth is fully or partially stopped. It appears that when VEGF is inhibited the immune system is stimulated, which is a good thing. So, although Sutent is composed if a single chemical entity, Sunitinib (1,1-dimethylbiguanide - if anyone cares), it attacks a tumor several different ways simultaneously. For that reason I can hope that it will continue to work on me for a longer time than some of the single pathway inhibitors we have previously tried. Given the current discussions of health care in Washington, I feel obliged to mention that were it not for the excellent drug coverage provided by my former employer, I could not afford Sutent, whose actual price significantly exceeds my total income from all sources -- it costs an astounding (one might say obscene) $8259.11 a month!

This calm time is my opportunity to talk about some peripheral issues and perceptions. Possibly the most interesting one is what causes some people's tumors to grow rapidly and other people's slowly. The bare outline of a study to address this question is presented below the break.

There are, in addition, two personal observations that are appropriate in this Rumination. One is a consequence of its date of publication falling very near to my 80th birthday. When I was a teenager, 65 years ago, I found it unfair that I was born just a few years to soon; I anticipated a life expectancy of less than 70 years and would therefore miss the millennium. I certainly never expected to see 80. Two years ago, when the liver metastases were first discovered, I was reliably (and reasonably) informed that I would be symptomatic within a few months and, by implication, gone within a year. Again, little, if any, chance of reaching 80. Yet, here I am. An amusing sidelight is that 30 or so years ago I decided that I would declare myself to be middle aged half way between whatever my present age was and 65. Xeno's paradox to the contrary not withstanding, I became 65 (and middle aged) after all. I then decided that I would consider myself 'old' halfway between my present age and 80. Unfortunately, Xeno didn't help that one either and here I am, about to become 'old'. Ah, well, I don't feel any different, and that is a good thing. As my birthday present to me, I promise myself more postprandial naps.

The other observation is to reassure any of my readers who may be the reluctant owners of a chronic disease, their caregivers, and their family, by making explicit what we all know implicitly but often forget or ignore. Anytime we feel a twinge or catch a bug or a cold, we inevitably worry whether it is related to the chronic condition and whether it suggests a relapse or exacerbation. This suspicion is perfectly natural but can easily get out of hand and interfere with getting on with life. Since everyone is subject to such twinges and bugs, it can easily drive individuals with a natural inclination to worry to distraction. I think the best remedy is to constantly remind oneself that such symptoms are not related to the chronic disease unless the relationship is proven. Innocent until proven guilty is the way to go - Kathy and Katherine, please take note.

***********************************************************************************************

It should come as no surprise that I am fascinated by the question of what mechanisms modulate the aggressiveness of cancer. So the question that immediately occurred to me is what is the statistical distribution of survival times. (Is it random – flip of a coin, or is there a consistent pattern). While my access to literature is somewhat limited, I am discouraged by the fact that while I found that considerable effort has gone into surrogate predictive models and measures such as five year survival statistics, Kaplan-Meier survival curves, progression-free survival, and time to progression, I could find no information regarding the statistical distribution within any of these measures of survival - are they normally distributed, skewed, bimodal, or ...? Because it is not possible to know exactly when a metastases first developed (it can be weeks, months, or years between that point in time and when it is detected) directly determining the underlying distribution is a daunting problem; however, the distribution of the surrogates can reasonably be expected to reflect the distribution of the underlying reality, sufficient at least to explore the general shape of the distribution. I could not find any data on the distribution.

What follows, although cast as a broad outline of a study, is really a plea to start now to collect the specimens and relevant patient data so that as large a specimen library as possible be readily available when cost effective technology is ready for the task. The study that I am outlining is best carried out in an institution with a large population of cancer patients, such as Dana-Farber, Sloan-Kettering, etc. Although it will not be able to be carried out for a few years until genomic, epigenomic, and proteonomic testing of biopsy specimens becomes cheaper and routine, that time is close enough [e.g., S.P. Shay et al., Mutation of FOXL2 in Granuloma-cell Tumors of the Ovary. NEJM 360: 2719-2729 (June 25, 2009) and J. Shendure and C.J. stewart, Cancer genome on a Shoestring Budget, NEJM 360: 2781-2783 (June 25, 2009)] that now is the time to begin the collection of data and specimens.

Consider the totality of the cancer patient population, excluding those who had successful resections of their tumors and sufficient time has elapsed to consider them cancer-free. For each of the commonly accepted classifications of cancer (prostate, pancreatic, colon, GIST, HER-2 positive breast, etc.) data on individual survival is available. That some patients progress quickly and others slowly is well known. From the patients in each classification, select the top and bottom quartiles or quintiles of survival time as the study population. Of course, the time spans involved will differ markedly with the cancer involved; none the less, for each tumor there are patients who progress very quickly and those who progress very slowly (relative to the mean). Consider this subset of the total population as the subjects of the study whose underlying hypothesis is that there are detectable differences between the fast and slow progressors (FPs an SPs). The task is to define and quantify the similarities and differences among clusters of FPs and SPs. Equally important is to determine the cluster characteristics that best characterize / classify / group cancers.

I am using the term 'cluster' in the statistical sense of a group that segregates a property. Each study subject is a member of many clusters. (As a specific example, I cluster with males, melanoma, mucosal melanoma, 75-85 year age group, married, hepatic metastases, c-KIT replication positive, etc., etc.) Of course, many of the possible clusters are irrelevant to the study at hand and others will turn out to be so.

The first task of the study is to define as many potentially relevant clusters of the whole study population, FPs and SPs combined. I would expect these clusters to include ( and also to include many others) primary tumor site, common clinical and lab characteristics, specific aberrant cellular pathways, genomic anomalies, specific protein excess and insufficiency, which drugs have been tried with what results, etc. It is important to note that these clusters contain both SPs and FPs and that each cluster includes tumors from all organs and tissues that fall within the cluster definition. E.g., the c-KIT positive cluster includes all organ and tissue types that are c-KIT positive. It may well be desirable to define several different c-KIT positive clusters to separate out different alleles or mutations and replication. (Cluster compactness and correlation analysis will reduce the number of clusters that are retained.)

Once the clusters and their members have been selected, the next task is to identify dissimilarities between the SPs and FPs in each of the clusters identified in the first step. Of course the same database can be used for other analyzes such as the relationship of cluster characteristics to drug response. At this time, what is important is the establishment of a sample and data repository. The details of any study proposed now will certainly be significantly modified by the ongoing flood of experimental results and their interpretation.

If nothing else, I suggest that any serious contemplation of a study of this kind will go a long way to removing the blinders resulting from the organ based tumor classification and treatment (particularly chemotherapy) that is a consequence of historical imperatives that focus on organs but may be of marginal significance in the light of current oncological science. The painfully slow pace of testing and approving Sutent for KIT positive tumors other than renal cell carcinoma and gastrointestinal stromal tumors (GIST) is a worthwhile case study this issue.


The collected Ruminations may be found at http://upislandeggs.com/Ruminations.htm
and my e-mail address at the bottom of the page at http://upislandeggs.com/

                      Rumination 21. Experimental design 101
                                                         By
                                           Thomas P. Vogl
                                             March 5, 2009

I have just spent a week in Boston, arriving late Tuesday 2/25 and finally getting home on Tuesday, 3/3 because the Nor'easter on Monday canceled both buses and planes (I spent six hours at the airport after which Cape Air canceled the delayed flight.) Wednesday and Thursday were devoted to scans - ECHO cardiogram, CT scan, and two PET scans, one with FDG and the other with FLT. The FDG is the usual pet scan using glucose with a radioactive tagged fluorine atom attached; the FLT is a fluorothymidine with a tagged fluorine atom that identifies high thymidine kinase-1 activity. FDG allows visualization of glucose metabolism which indicates how active the cell is; FLT allows visualization of DNA turnover, a measure of cell division (proliferation). If you think of cells as rabbits, FDG PET tells you how much they are running around and FLT PET tells you how fast they are breeding. FDG PET is a recognized and approved procedure; FLT is still experimental and it looks like it is more useful for blood cancers, such as the lymphomas, than for solid tumors like carcinomas, melanomas, etc. On Friday I had the first infusion of the new drug, AUY922, an Hsp90 inhibitor and endless hourly EKGs, (I suspect the plethora of EKGs are the contribution of the lawyers who may have had more input into the experimental design than the scientists.) The only side effect was a tolerable level of diarrhea.

The scans showed that in the five weeks since my previous scan the size of my metastases had increased only slightly despite the fact that there had been no treatment during that time and that the treatment in the previous three to six weeks had been ineffective. Looking back over my shoulder at the whole sequence of events since my initial surgery in July of 2005, it is clear that my mucosal melanoma is exceptionally indolent considering that mucosal melanoma is known to be especially aggressive and fast growing, even compared to dermal melanoma. Now, whether this is due to particular strengths in my immune system, or a genetic peculiarity of my melanoma, or the effect of some combination of the Celebrex and fish and flax oils, all of which actively reduce inflammation, is not known and cannot be determined. However, I'll take what I can get. The reason it cannot be determined is relevant to the primary topic of this rumination.

An obvious experiment would be for me to stop taking the Celebrex and fish/flax oils for four to six weeks and see if the disease progress has increased; then, as a check, resume the three 'drugs' (technically the oils are not drugs) and see if the progression again slows down. What is wrong with this scenario? There are three possible outcomes: (1) progression increases when the drugs are withdrawn and decreases when they are resumed; (2) progression increases when the drugs are withdrawn and continues to increase when they are resumed; (3) progression does not change throughout. In case 1, the conclusion that the drugs are of benefit is reasonable; in case 3, the conclusion that the drug is of no benefit is reasonable; but in case 2 the conclusion that the drug is of no benefit is not reasonable because the increase while the drugs were withdrawn may have overwhelmed the immune system and that the drugs, while effective before, are no longer up to the task. So, in that case, we have learned nothing. Consequently, it is a poorly designed experiment because it is a fundamental principle of experimental design that a well designed experiment yields useful information irrespective of the outcome of the experiment. It is a dictum as fundamental to experimental design as 'Above all do no harm' is to medicine.

So, in that spirit, let us examine the design of clinical trials. To make the discussion concrete, consider an (imaginary) drug, TPV001, that in animal experiments has been shown to produce an effective treatment (of some disease) at a dose of 60 U(nits).

The first step is to clearly state the objectives of the experiment. I submit that the appropriate objective is 'Is this drug effective in humans without producing unacceptable side effects'. Put more formally, can we disprove the statement (null hypothesis) that TPV001 is ineffective or that it causes unacceptable side effects. Let us further suppose that we can afford to test the drug on 40 individuals and that this is a sufficient number to satisfy the statistical requirements.

What the drug companies have elected to do is to divorce the primary objective (does it work) from the secondary objective (and can it do so without unacceptable side effects) and give primacy to the secondary objective. In fact, they ignore the primary objective until they have established whether the secondary objective can be met. This is called a phase I dose escalation trial. So, they take their 40 patients and give the drug to the first 10 patients at a dose of 15U. These patients exhibit no side effects and no therapeutic benefit. What has been learned from this experiment? Essentially nothing -- no side effects (that's nice), no therapeutic benefit (not a surprise at this dose). If the drug companies were honest with these patients they would have told them from the beginning that the chance of this dose doing them any good at all was minimal.

The next group of 10 patients get 30 U. Of the 10, two have mild side effects, say one has fatigue lasting less than 48 hours and the other mild diarrhea lasting less than a day. One of these patients showed a slight therapeutic benefit. What does this experiment show? Not much. It suggests that the drug may work on people and that at this dosage the side effects are mild and the therapeutic effect, milder.

The next group of 10 get 45 U. Four have mild side effects, one had more severe but still acceptable side effects, and one has severe enough side effects to cause concern. Three patients demonstrate some therapeutic benefit, say lack of progression. While some information can be gleaned from knowing whether it is the patients who had the side effects were the ones who benefited from the treatment, the most likely (and usual) result is that some of the patients who benefited had no side effects.

Undaunted, because the FDA has approved the protocol and it is, therefore, set in concrete, they forge ahead to a dose of 60U for the last group of 10 patients. Now there are 4 severe and 4 moderate side effects and some therapeutic response in 6 patients. They conclude that four severe reactions is too much and go on to the phase II trial (therapeutic efficacy) at 45 U.

At 45 U, the phase II trial fails to show adequate efficacy in a sufficient number of patients and the drug is abandoned. This is the fate of about 80% or more of the drugs entering phase I trials. What an incredible waste of time and money. All that has really been shown is the well known fact that people differ greatly in response to drugs and that the average response of a group of ten patients totally fails to capture the extent of the variation.

With the same number of subject, there is a much better way, i.e., a way that yields far more information without any added danger to the patients. In fact, when compared to the current system, it diminishes the danger to the most at risk group (the last ten subjects) and an enhances the likelihood of benefits to the group least likely to benefit under the current system (the first ten subjects).

As before, start the first ten patients at 15U. If they show no adverse reaction, escalate the dose to 30U for each of those patients, Continue the dose escalation on each patient until the criteria used before to establish the unacceptability of side effects is reached, but on each patient individually. Note that this does not subject any patient to more risk that they would be exposed to if they had been part of the 40 patient group described above (much less risk for the last 10). But it has huge advantages: It immediately relates the dose, side effects,and therapeutic efficacy for each individual patient; it assures each patient that if there is therapeutic potential for him/her, then it will be reached; and it allows an immediate initial quantitative determination of not only the average maximum tolerable dose (MTD) but also of its variance.

Assume that from this first group of 10, it is determined that the MTD is 42 +/- 16 U. Then the next group of 10 patients can be started at, say, 41-16 (1 SD below the mean) at 26 U and the dose escalation might be in 10U steps instead of 15U steps as it was in the first group.

By the time all four groups of 10 have been through this study, so much more will be known: the MTD for all 40 subjects individually and its variance; the therapeutic response of each of the 40 to their individualized MTD; the side effects of each individual at their MTD and whether it is correlated with therapeutic efficacy, and even dose-response curves. Last, but not least, each of the 40 patients will have had the same optimal opportunity to benefit from the trial. Little, if any, of such data are available from Phase I studies as currently carried out.

The pharmaceutical companies are not incompetent and they have highly skilled scientists and statisticians in their employ. The same can be said about the FDA, possibly not quite as enthusiastically. Consequently, I find it difficult to believe that the current system is the result of negligence or stupidity. That leaves the question of how the current state of affairs came about and why it continues. It is a mystery. As the detectives would have it, cui bono? I cannot figure it out. Maybe a reader can enlighten me. I will appreciate it.

The collected Ruminations may be found at http://upislandeggs.com/Ruminations.htm
and my e-mail address at the bottom of the page at http://upislandeggs.com/

I'm stuffing the croissant dough this time. The experiments have either white chocolate or Tom's very dense Oxford-style marmalade or leftover gremolata (a parsley, minced lemon peel and minced garlic mix). And the scraps will be bread sticks dusted with my Parm. We will see!

Tom and I have stuck our toes in the waters of Facebook - so you can "friend" us if you like. Most of his family and some of mine are already on it and I've reconnected with several old friends from high school and college.

The latest small bread project has been real croissants.

This is the third try, and though the first two were edible, these are pretty close to the way they should be. I used the recipe from the King Arthur Flour Baker's Companion and the only thing I did differently was to use a cultured unsalted butter. I bought a new, huge rolling pin for the recipe and it worked beautifully.

I've been debating about whether a big pastry board is worth the cost in both terms of money and storage space. The croissants are rolled out into a big rectangle and only one countertop in the kitchen - which usually has the plastic wrap holder, thermo sealer and electric grill on it - is big enough. Fantes has a wooden one I've been eyeing,  28" X 22.5", and a silicone one as well, though I sent the small silicone pastry mat I had to the Dumptique because everything stuck to it. I suspect I'll stick with the counter, though Tom thinks I ought to ask the guys at Krug & Ryan who made our lovely cutting board to make one for us.

The chickens are doing fine and laying tons of eggs. The zebra finches are having a batch of babies every week or so. We have no idea how many zeebs are in the sunroom, but they don't look crowded. They are, however, eating vast quantities of finch food which has become very hard to get on island, at least in big sacks. Either the feed store doesn't have a big enough order to put in with the bird food company, or, when they do order, the company is backordered on the food we need. Kaytee Forti-Diet Finch food is their favorite, but they will eat whatever finch food we can find!

Spring is here - Tom needs to show me some plumbing stuff in case the flapper valve on the toilet breaks while he is in Boston for a week for his new treatment (he leaves Tuesday afternoon.) 

 

I've gotten drop biscuits, cut-out biscuits and English muffins figured out. Now on to scones! My first try was of the Cook's Illustrated version of oatmeal scones. I think they will need a bit of practice and maybe combining with the King Arthur version .  Send me your scone recipes! And savory scones are sounding wonderful!

Tom was asked for his latest bread recipe - the one that started out as the New York Time's No-Knead Bread . And here is his reply:

Unfortunately, a simple question has a complicated answer.  The reason for this is that I have merged King Arthur's sourdough bread recipe with the handling/baking technique of the original no-knead bread as modified by some suggestions in Cook's Illustrated . Consequently, it is no longer no-knead. However, everyone thinks the results are so good that it is worth the effort.

Bye 2008! Hi 2009!

2008 was amazingly good to and for both of us. Tom is stable and feeling fine, the chickens are doing well, Katherine has learned to knit cables, and the island is wonderful.

Tom spent a good deal of time going to Boston for treatments, though that has calmed down to once every three weeks. (You can find all the details about his medical journey as they happen in his Ruminations on this blog or the collected version on our web site upislandeggs.com/Ruminations.htm

We borrowed broody hens and let them hatch out eggs for us. Out of that batch came a truly amazing rooster who battles the crows who swoop down trying to grab the chicken treat. Our suspicion to one of the tricks to having a well-behaved non-aggressive-to-people rooster is to have a mixed breed rooster with lots of Dorking and Brahma in his background and let a very friendly gentle hen raise him. This seems to work better than using pure-breed roosters and us doing the raising.

It is hard to resist taking a hand in the raising though, particularly when the chicken is willing to help Katherine play World of Warcraft (Zaw, 80, Echo Isles).

The summer and fall were full of our traditional weaving & spinning demos at the Fair, helping the Ag Society to get a barn built by the Amish, and a wonderful trip to New York City. Our cooking took one of those occasional leaps forward – Tom adapted the famous no-knead bread recipe to perfection, Katherine mastered English muffins, and we realized that the Swiss style cheeses we make are some of our best. So we have started tweaking them and came up with very memorable Saffron Swiss and Caraway-Cumin Swiss (there is a Dill Swiss aging now – we have high hopes!)

And the ever present conundrum on what to take to parties and picnics in 2008 was solved by skewered stuff – we must have made 6 or 8 skewery things, sometimes with shrimp, sometimes with steak. The Solstice party was held in the middle of an impressive snow storm but Island folk are a hearty bunch and can, mostly, drive in snow so the party went on and was one of our better efforts.

2008 kept the guest bedroom filled up with friends and family – nice visits and new perspectives. Katherine turned out lots of chemo hats and in doing so finally learned to knit regular and bi-color cables (lace knitting is still unconquered territory.) Tom is weaving linen chenille hand towels on his big loom and goes curling twice a week when schedule permits. This time of year Tom is doing interviews of lower Cape and Island kids applying to Columbia.

As for 2009, in January we will celebrate out 30^th anniversary! Wishing you a glorious New Year!

With the kind permission of Dan Waters, here is the poem he read on Dec 9, 2008 at the West Tisbury town party. 

West Tisbury Town Party

When beetlebungs stand bare of bough
And winter stings the air,
And woodsmoke hangs on Brandy Brow
Like wisps of thinning hair,
We waken hungry for a bite
Like some gigantic beast
And tie our kitchen aprons tight
And cook a town-wide feast.

It's quite the neighborly affair -
Warm kisses, mug to mug,
No lack of pies or news to share
With mothball-perfumed hug.
We fill our ears and stuff our face
With casserole and rumor,
And loosen belts for breathing space
To laugh at Skipper's humor.

And what's the potluck's main appeal?
Well, often it's a tossup:
Part cheap night out, part home-cooked meal,
Part good old-fashioned gossip.
We chew the fat; we laugh, complain -
It's almost like Town Meeting,
Except that here the stomach pain
Is caused by too much eating.

At last, when all's been said and chewed,
We end the night's adventure
And take a peaceful interlude
To rest both tongue and denture
Before we launch the second round
With palates hale and hearty
At Tom and Katherine's world-renowned
Hibernal Solstice Party!

© Daniel Waters

We are starting to seriously get ready for our annual Winter Solstice Party, Sunday, Dec 21 from noon to eight. (You are invited!)

The menu is pretty much the same as always

Whole poached salmon decorated to look vaguely like striped bass

Big ham

Chili with all the fixings

Ham and Bean Soup

Wild rice salad

Corn pudding (this is new this year)

Saurkraut and weisswurst (new last year and very popular)

People will bring desserts and finger food.

The weather is always iffy - it may be raining Sunday, the reports are still mixed about whether it will/won't rain/sleet/snow.

I'm off to go make dashi to poach the salmon in and to chop and toast the nuts for the wild rice salad.

 

Rumination 19. Waiting for Godot

Curried Chickpeas And Kale

2 Tbsp ghee or vegetable oil
2 lg onions, chopped
6 garlic cloves, minced
2 tsp cumin seeds
1 bunch kale, deveined and chopped
1 1/2 Tbsp curry powder
1 lg knob ginger, finely chopped
2 tsp coriander, ground
2 cups dry vermouth or chicken or vegetable broth
2 cans chickpeas
1 1/2 cup tomatoes
salt

In a 2-quart saucepan, heat the ghee or oil over medium-high heat. Add the onions, garlic, cumin and ginger. Cook stirring until softened, about 5 minutes.
Add the kale; cook, stirring, until softened, about 3 minutes.
Stir in the curry powder and coriander until absorbed.
Stir in the liquid and bring to a boil. Add the chickpeas, tomatoes, and salt.
Simmer, uncovered until kale is cooked, about 20 minutes.
This recipe yields 6 servings.

Variation: Substitute Swiss chard or a 10-ounce package frozen chopped
spinach for the kale.
Comments: This is a mild curry. If you like yours spicy, stir in some ground
red pepper when you add the curry powder.

 

---

I've been knitting little bear ornaments. Here are the first efforts.

The one on the left is very close to the original pattern .   But then I remembered all the chenille we have left from weaving and that is perfect for the bears!

 

Ten of us will sit down this afternoon and feast on:

A standing rib roast with Yorkshire pudding and horseradish cream on the side

Asparagus with Hollandaise

Classic sweet potatoes with marshmallows

Roast potatoes

Biscuits

Maple glazed carrots

Corn pudding

Fruit salad that is almost a cold fruit soup (Tom thinks it is the best one I've made)

Starters are boiled shrimp with cocktail sauce, smoked bluefish and one of our cheeses and crackers

Desserts are pie and whatever shows up 

Rumination 18. Glad Tidings

By

Thomas P. Vogl

November 1, 2008

 

The news is all good.  Three weeks ago I had another infusion of the Cdk-inhibitor at half the original dose and with additional fluid support. No serious side effects and it took me just four days to fully recover, for my white count to return to normal, and the tiredness to go away, nor was there any loss of smell or taste. This week we did repeat PET and CT scans that showed not only solid stability (no new spots in my liver) but an observable response to the drug in that the avidity of some of the old lesions had decreased (less dense, i.e., less metabolic activity).  Things are definitely looking up!

 

With these radiology results (which Andrew, ever thoughtful and considerate, gave me over the phone the same day!), I had the third infusion on Wednesday, again half dose and fluid support. This time the side effects were even less than before.  While still a little shaky  the evening of the infusion, by the next morning (Thursday) I felt fine – no nausea, no diarrhea, and only the slightest of headaches. By Friday morning I felt so well that both Katherine and I were amazed. I was so surprised I went over to the hospital and had them run my chemistry.  My white count was back to normal and while the anemia is still there it clearly is bothering me much less. I can only surmise that my body is getting acclimated to the drug and handling it much better.  This suggests that we could increase the dosage without any major consequences in terms of side effects.

 

Next infusion in three weeks.

 

It is clear that I am not the only one disgusted with the current status of clinical trials. The cover of the 10 October 2008 issue of Science features "Clinical Trials and Tribulations" and a 14 page Special Section with 5 articles bemoans the current state of affairs. Even with all that, the section does not come close to discussing the entire spectrum of clinical trial problems. None the less it is worthwhile reading.

 

Nothing like a brief upbeat Rumination, is there?

Tom and I had a wonderful whirlwind visit to New York City - left Saturday and back Monday.  Even though we had the noblest of intentions to culture ourselves at MOMA and the Whitney , we ended up eating our way through the Lower East Side and Spanish Harlem, puddleducking (looking in all the windows and people watching) along the way. It was splendid!

The cab picked us up at 5:30 AM Saturday, we caught the 6:00 ferry to Woods Hole and the 7:00 bus to Boston and then the train left at 9:40 to New York at about 2:00. It was a very pleasant trip - much nicer than driving or flying. We stayed with friends, Olivia and Anna, in Spanish Harlem. They have darling apartment - much bigger than we expected for that part of the world, and were very close to subways stops. 

One thing we really wanted to do was eat outstanding Thai, and they knew just the place -  Sripraphai in Queens! It had my favorite ever dish Mo Grop (spelling?) which is a crispy pork in chili and basil (on their menu it is C18). Also incredible was item A5, crispy fried Chinese watercress salad with shrimp, squid and chicken. This is now officially my favorite restaurant and it alone is worth a trip to the city.

On the way back we stopped by Olivia's favorite pastry shop to get croissants and a little pine nut tart for breakfast. Chef Samba at Samba Bakery Cafe in East Harlem is experimenting with serving a Moroccan meal once a month or so, and it sounds so very very good!   

Sunday we headed out for a walk through China Town, admiring all the fresh produce and fish of kinds we just don't get on island. Side walk vendors were selling abalone!  Our cooking would take a whole other turn for the better if we could get these kinds of ingredients!  And, at a cooking supply place, we confirmed that no rack for a 16" wok exists, found some little dishes to match a set we are slowly filling in of the rice pattern ware, and found my little rolling pin.  (I am going to learn to make tortillas from scratch and have been asking everyone who knows of tortilla making about a palote - a short, thin rolling pin.  And everyone says to use a sawed off broom handle or sawed off [unused] toilet bowl plunger handle) Apparently Chinese dumpling makers need the same thing, and I found the perfect one. Then it was time for lunch and we met Anna's mom for dim sum at Delight 28 Restaurant (aka Hee Win Lai). We enjoyed the meal very much, and were pleased at how well our own favorite Boston dim sum place, Chau Chow City , stood up to New York.  The real treasure of the meal was Anna's mom, who is even more of a foodie than we are!

We wandered around after lunch, and officially decided we would rather wander around than go to museums.  In Little Italy we discussed cheeses with Lou Di Palo at Di Palo Selects . We stopped somewhere for gelato and ate it while watching Chinese dancers at a street fair.

 Then, for dinner (not that anyone was all that hungry but we certainly weren't going to miss the chance at another incredible meal) we went to El Paso Taqueria in Spanish Harlem. The Quesadillas de la Abuela with home made tortillas, Oaxaca cheese, chicharon, epazote, chilis, and squash blossom was super good. We also had a drink (which is popular but we'd never heard of it and I'm blocking on the name) made of dark Mexican beer, hot sauce and lime juice.

Much science and medicine and food were discussed the whole trip, I turned a heel on a sock and am ready to turn a second one, the chickens did just fine under Glenn and Rosemary's expert care, and we loved looking at all the mosaics in the subway!

A wonderful mini-vacation - and we are almost caught up with our mail, I've made a batch of English muffins for lunch, and need to do a load of laundry.

 

Rumination 17. Dear Diary

By

Thomas P. Vogl

October 5, 2008

 

 

Since so much has happened so fast, and despite the fact that I dislike reading (and writing) diaries, it seems that the best way to describe it is chronologically. At the end of this piece is a discussion of significant changes in cancer research that are just over the horizon and that offer hope to the next generation of cancer patients.

 

Sunday, September 28. This is the first time in two weeks that, with the help of a few Tylenol, I feel collected enough to write. There is no way around it; it has been a rough time during which I aged at least ten years and was fighting to get the decade back one year at a time. (Which I did in 10 days.)

 

It started innocently enough on Monday, September 15, with a late afternoon meeting with Dr. Geoff Shapiro and Dr. Bruno Bastos (Geoff’s charming new associate) to go over the protocol for the SCH 717965 study, sign the consent forms, and review the expected side effects, which, it was clear, are significant and unpleasant but, because of the short half-life (1.5 – 2 hours) of the drug were expected to last at most a day or two. I went into this with my eyes open and expecting nothing too awful, and it turned out worse than any of us expected.

 

Tuesday morning I had a biopsy of the malignant lymph node in my neck to provide a 'before treatment'' specimen. The rest of Tuesday and Wednesday passed uneventfully with PET and CT scans (except for being knocked down by a panel van backing into a parking space while crossing the street to spend some free time at the MFA – minimal damage done and a great show of Art Nouveau jewelry).

 

Thursday the serious part began. I arrived at the CRC (Clinical Research Center) at 7:00 am, and after some preliminary labs the eight hour infusion began around 8:00 using both lumens of my port, one for the drug and the other for a large assortment of meds including anti-diarrhea, anti-nausea, and antibiotic (the drug is known to drop white counts precipitously albeit briefly).  A scopolamine patch behind my ear (the experimental drug crosses the blood-brain barrier and is known to produce vertigo) and an IV in my arm for blood samples completed the getup.

 

Things went very well indeed most of the day with no discomfort or nausea. I had a egg salad sandwich and a fruit cup for lunch and was feeling quite chipper, although I knew that the problems would show up near or after the end of the infusion (even though the pharmacokinetics suggest that by then half of the infused drug had already cleared the system). The changes it instigated in a large number of pathways obviously are much longer lasting.

 

Near the end of the infusion (at least that’s when I think it was because I don’t remember an IV pole in the bathroom with me although I am so used to them that I may be misremembering) the diarrhea hit and with it, much to my surprise, the classic symptoms of shock – a cold sweat and light headedness.  When I came out of the bathroom my blood pressure was down to 70/40 that the prompt administration of two liters of saline (one through each lumen, running wide open) soon fixed.  I am still puzzled by the hypovolemic shock. The diarrhea was not that large a volume and I was neither bloated nor was there any obvious swelling of the extremities. Even after the two liters of saline, my urine output was still negligible. Into what compartment did all that water vanish?

This may be the right point say how impressed I have been over the past year with the astounding competence, caring, dedication, and compassion of everyone connected with the CRC – Cheryl the receptionist, the women who take your vital signs and escort you into the CRC, the entire nursing staff of whom I single out Susan Aikey only because she is my nurse and I have spent the most time with her – every last one of them are amazingly wonderful and competent people as is obvious from having watched them deal with their patients.  If every ICU in the country were staffed and run like the DFCI CRC, medical care would be of much higher quality.

 

I stayed in the CRC, in my very comfortable recliner, for another hour or so, to recuperate and get my blood pressure to stabilize. In anticipation of this kind of reaction to the drug, I had elected to stay at the Best Western motel that is immediately adjacent to DFCI and is accessible with only a few steps across a courtyard from the hospital complex. I’m glad I did because it took me more than half an hour, with rests in chairs thoughtfully provided by DFCI, for the trip of usually five minutes, picking up a container of wonton soup for my dinner on the way through the food court. I slept like a log.

 

The next morning, Friday, I went back to the CRC for blood work and vital signs and to make sure my blood pressure had returned to normal. It had. None the less, I felt tired, weak, and unsteady, rather like the morning after major surgery (except for the absence of pain). I had aged 10 years in 24 hours and was very glad to be home after five days in Boston.

 

I really expected to bounce back by Monday, but it did not happen. To add injury to insult, I noticed that my sense of taste and smell had disappeared. I could not tell whether a patty was beef or lamb! Everything else I could live with, but not that! No cliffhangers – taste did come back two weeks later.

 

Having gone through all this, I did hope that it had done me some good and the following Thursday (September 25), still very tired and shaky, I went back to Boston for a repeat PET scan. After the scan I met with Andrew who had already reviewed the scan with the radiologist. Andrew was surprised that I was not recovering faster since all my labs, except for white count, had returned to near normal, to which all I could say was “so am I”.  (The temporary abnormalities in the labs, from white count to liver function were pretty amazing – quite a drug.)The results of the PET scan were not encouraging. What we had expected to find was that the ‘avidity’ (the metabolic activity) of the metastatic hot spots had decreased significantly. But, no decrease could be found. I arrived home at 8:30 in the evening, having gotten up at 4:15 am, so tired that I just fell into bed.

 

Friday morning I awoke feeling tired and shaky as usual but mid-morning, like flipping a switch, I suddenly got back at least eight of the ten years, with only a slight headache, easily treated with Tylenol, as a reminder of what I had been through.  Today, Sunday, the headache is less but still there and the other residual symptoms are fading fast. On Thursday I will go back to Boston to meet with Dr. Shapiro and decide where we go from here.

 

Tuesday, September 30. Andrew called in the morning to give me surprising news. The drug company (Bristol-Meyers-Squib) that makes the anti-CLA4 antibody, Ipilimumab (my son-in-law, Bill Colbert, tells me that ipilimumab is a Swahili word meaning "my stomach hurts") last Thursday informed all the clinical trail centers that any patient not on the drug by the next day (last Friday) will not be allowed in a trial because of "manufacturing problems". This was the drug I was planning to go on if the Cdk-inhibitor did not work. I am reliably informed that drug companies have pulled this stunt before. My disgust knows no bounds and there is no recourse. Free enterprise, Republican version, in action. Is it not time for NIH and FDA to define, run, and publish the drug trials, combining drugs from different companies as suggested by research and patient needs (at drug company expense)?

 

Friday, October 3. Yesterday, I went up to Boston on the 6:00 am boat, as usual, to meet with Dr. Shapiro to decide what to do next. That morning's lab results showed that I was as back to normal, as I felt. We had an extended and very fruitful conversation reviewing the options now that Ipi is no longer available. There are basically two options. One is to start on one of three currently available Hsp90 inhibitors, one of which, by Schering, had demonstrated efficacy against canine mucosal melanoma. We agreed that if, note the big if, we knew that my melanoma had one of the aberrant pathways that Hsp90 modulates then it would certainly be worth trying. The reason that study is not permitted is as pathetic as it is insulting: For a biopsy tissue sample to be analyzed/sequenced, the patient must sign an IRB approved release. One of the main reasons to do the analysis is not just for the patient but for the generation of a database of cancer cell characteristics (see below). At this point which characteristics will turn out to be important are unknown. If they were known, there would be no need to do the research. But the IRB insists that a patient cannot sign a blanket release, for example, "I allow the pencil tip size piece of tissue taken from me to be used for any legitimate research purpose that does not identify me without my explicit permission" is deemed unacceptably broad by IRBs that require the specific end purpose(s) to be explicitly stated. Talk about a catch 22! Joseph Heller would be proud.

 

It also turns out that the PET scan last week that showed no decrease in avidity is a very poor predictor of the drug's efficacy. It was expected to be, but it turned out not to be; that's the nature of research. But the patient must still go through the two hour procedure anyhow, because it was written into the protocol approved by the FDA and that remains cast in concrete. The straightjackets imposed by the FDA and the IRBs are clearly counterproductive to patient safety and comfort, optimal care, and cost containment.

 

So, what we decided, since the drug certainly was having effect on me (the disappearance of my dermatitis and my hair loss both demonstrate effects on rapidly dividing cells) was to continue as we had planned for the current cycle but at half the drug dose. The next infusion will be next Thursday. Then, as originally planned, three weeks later another infusion and a repeat biopsy and definitive PET and CT scans that will give a realistic reading on whether the drug works on me or not. I am very comfortable with this plan. At half the dose, I expect to recover from the side effects far more rapidly.

 

***************************************************************************************************

 

It should not come as a surprise that I have been contemplating the state of cancer research and cancer drug research, different but interrelated subjects. I was therefore utterly delighted with the editorial in Nature (Nature 455: 138, 11 September 2008) which starts:

"Beneath cancer's daunting complexity lies a simplicity that gives grounds for hope.

"For several years now, large-scale cancer-genome studies have made it increasingly clear that a tumour cell is a genetic disaster area littered with mutations that differ not only from one type of cancer to the next, but from one patient to the next. Pharmaceutical companies have had to accept that Gleevec, a drug that treats a form of leukaemia by targeting a specific gene product, is almost certainly going to be a rare exception in the therapeutic arsenal; most cancers are far too complex to yield to such a magic bullet.

"That message was hammered home with new statistical power in three studies released last week."

The three studies focused on three different solid tumors. To make a long story short, the results are that

"The studies took a more comprehensive approach than previous large cancer-genomics studies, by simultaneously analysing genetic sequences, copy-number variations, expression arrays and other forms of data. The Johns Hopkins team looked at all the active genes in tumours from a few dozen patients; the Genome Atlas team looked at selected genes in tumours from 206 patients. Taken together, their results show that no single mutated gene lies at the heart of any of these tumours. The pancreatic tumour samples, for example, showed an average of 63 genetic mutations each — with considerable variation from one sample to the next."

Shortly thereafter, the New England Journal of Medicine (NEJM 359: 1367-1380, 25 September 2008) published a review article on the molecular origins of cancer, focusing on non-small-cell lung cancers, about 85% of all lung cancers. By comparing the rate of genetic abnormalities among the two types of non-small cell cancer (Squamous cell and Adenocarcenoma) and small cell cancer, they found that except for abnormalities in p53 which appeared in 50 – 75% of all the tumors, almost all of the other mutations occurred less than 20% of the time. These low percentages strongly suggest to me that we are not aggregating the data in the right way.

Taken together, these results lead to some obvious and far more interesting less obvious conclusions. The obvious ones, mentioned in my previous Rumination, is the demise (the sooner the better) of the block buster model of pharmaceutical research and with it, the demise of the one-drug-company-sponsored, one-drug-at-a-time clinical trial.

 

The less obvious ones deal with how the data are being analyzed, a problem that has its roots in the organization of medical education and practice, which is organized almost entirely along organ system lines. Consequently, I propose asking the question (which I have not yet seen in print but expect to momentarily): Given the poor data aggregation displayed above, does it make really sense to sort cancers primarily by organ and secondarily by cell type (as all four of these studies have done), or does it make more sense to cluster by molecular profiles? I submit, as a testable hypothesis, that the initiating processes responsible all cancers, only secondarily modulated by organ system or cell type, will be a well defined subset of mutations and epigenetic events or precursors out of the broad spectrum of genetic and epigenetic changes that have been recorded to date.

 

Put another way, cells throughout the body are more alike than they are different, particularly when it comes to the cell's internal reproductive mechanisms and controls, which are what goes awry in cancer. I therefore suggest that the research effort focus on obtaining a sufficiently large number of genetic, epigenetic, copy number, and proteonomic profiles of individual cancers of all types and from all organs so that the statistical power of cluster analysis and other statistical techniques (see the 4 September 2008 issue of Nature for a focus on "Science in the petabyte age") can be brought to bear on the question of which cancers are similar by virtue of their molecular profiles, not by virtue of the organs or cells involved. My prediction is that the number of these clusters will be far fewer than current pessimistic estimates.

 

This, in turn, leads to the currently unpalatable conclusion that clinical oncology as well as cancer research needs to be reorganized by molecular profiles rather than organ systems and that drug companies must develop mechanisms for cooperation on drug development and trials that focus on multi-drug treatment of the (soon to be identified) common constellations of molecular profiles.

 

One organization that agrees with this analysis was recently founded by my friends Dr. Jennifer Carter and June Kinoshita. They call it N-of-One. If you are interested in what they are doing and planning, their website is N-of-One.com. Because the website is still under development you will need to go to the 'REGISTER' tab in the upper right hand corner and enter a password: newvisitor – no further registration or identification is needed. [Publication of the password in this blog has been authorized by Dr. Carter.]

 

Note added in proof: I urge you to read the Commentary by Heng in the current issue of J. of the American Medical Assoc. [H. H. Q. Heng, The Conflict Between Complex Systems and Reductionism, JAMA 300:156-1581 (October 1, 2008)]. He concludes (but do read the whole article):

 

"The unpredictable nature of the [genetic and epigenetic] heterogeneity will force the consideration of the significance of clinical exceptions, because complex disease results in highly diverse responses that include many exceptions to the general rules. Furthermore, heterogeneity is not simply "noise" but a key component of evolution directly related to the human disease conditions and must also be considered when designing interventions such as cancer therapies. Clinical therapies must be individualized, balancing the parts of the system and the response of the patient as a whole. Clinical research on pharmaceutical agents needs to focus more on the differential responses within diverse patient populations."

 

The paper is two pages long and I would have included it here, but it is copyrighted, so I can only provide copies upon request to individuals, under the fair use exception. (Of course, you, the tax payer, probably paid for its writing, and undoubtedly its thinking, under an NIH grant, However, the law, in its wisdom, requires you to pay to read what you have already paid for.)

Nation is Terry Pratchett's "latest" YA novel though it doesn't take place in Discworld or any of his other worlds. Nation is set on a world more-or-less parallel to ours in something like the late 1800s. Two story lines about disasters - a tsunami in one line and a flu epidemic in another, bring two vastly different adolescents together on a deserted island. The islander boy and proper British girl have little in common except trying to survive, and then to build a nation out of what the sea washes up on the shore. This is very different from Pterry's other works (more like the Bromiliad Triology than anything else), though the footnotes he is famous for are sprinkled throughout the book.

Pratchett fans have been wondering if his early-onset-Alzheimer's has effected his writing. Judging by this book, it most certainly has not. This is one of the best books he has written lately - certainly the best for YA - and, though more could be written about this world, it is a stand-alone. It is delightful that Pratchett can write so wonderfully without all the beloved underpinnings and folklore of the Discworld. (Speaking of folklore, I've just started Folklore of the Discworld , co-written by Pratchett and Jacqueline Simpson. No opinion yet.) The book is out now in the UK and releases in the US in a couple of days.

Flora's Dare is the sequel to Flora Segunda , by Ysabeau Wilce. Tom and I loved the first Flora, and love the second just as much. You really need to read these in order, since the second book explains various of the questions Segunda left up in the air. Just wait till you meet Tiny Doom!

 

Chalice is what I've just finished reading this afternoon. It is by Newberry Medal winner Robin McKinley (The Hero and the Crown ).  I re-read Hero and the Crown and its sequel at least once a year, but haven't been grabbed by any of her other books - they were OK but not moving. Chalice changes that. It is grand! It invents its own fantasy mythology, which is refreshing, about a young woman who inherits the position of tying the land to the rulers by means of what she mixes in cup for the rituals that bind wordds to deeds to land. Also lots about bees and a word that has something to do with milk that I'm trying to track down. Anyone know what hilliehoolie might be? After I finish the blog I've go to drag down the OED and try to find it. Anyhow, a splendid book that is too short, but I hope for a sequel.

 

Magic Thief by Sarah Prineas is a more typical wizard-and-his-humble-apprentice-in-somewhere-like-London. But it is well illustrated and well written and its characters bump the boundaries of their stereotypes. It is for a younger audience than the others, but I enjoyed it.

The crew got an earlier boat than expected last Monday and we scrambled to get lunch ready. They arrived about noon, had ham sandwiches, coleslaw, biscuits, bread and fixingings and plum cake and were on the job by 2:00.  While the women and children got organized in the houses, the men started putting up the uprights on the already prepared foundation.

The lumber had all been pre-cut and drilled, bundled and labeled by the crew in Pennsylvania so it was like watching a huge 3-D jigsaw go together.

 

This photo is after they were at work a few hours on Monday. You can see the massive framework is well underway. The beams are notched and slotted into the uprights - Tom says it is mortised &pegged, post & beam.

 

And this is what it looked like just after daylight on Tuesday morning. All the posts are up, the cross beams are being lifted up by the crane operator that works with this crew, and even some siding is on. 

 Here is one of the cross beams coming down.

 

And this is the barn by Wednesday dusk. The door was hung, windows put in, roof was shingled and all was finished by Thursday lunch (except for the side shingles that will happen in two weeks or so.) Amazing!  

The new barn fits nicely right beside the old animal barn. It is about the same size as the old one and, once the shingles have weathered, it will just blend into the landscape.

Here is a closeup of the inside of another barn built by the same crew.

Rumination 16. Bad News, Good News

By

Thomas P. Vogl

September 10, 2008

 

I’ll dispose of the bad news first. My scans on 8/26 showed definite disease progression, particularly in the liver. Let me hasten to add that my liver function tests are still normal and my liver is not enlarged. So, I have been kicked off the trial, which is probably a good thing since it is statistically unlikely that it was doing me much good. I had very positive conversations with both Dr. Shapiro and Dr. Hodi and we agreed that there are two ongoing studies that make sense for me. One is Dr. Hodi’s  ongoing trial of our old friend MDX-010 (aka Ipilimumab) which is now available without the addition of dacabazine and is a CTLA-4 immune system enhancer. The other is a trial of a cyclin-dependent kinase inhibitor, Cdk-inhibitor, run by Dr. Shapiro, one of a new class of drugs that, at least theoretically, has a great deal of promise and has had success with melanoma in early trials. I wrote to both Dr. Shapiro and Dr. Hoi that my preference is to participate in the Cdk-inhibitor trial first, since we would find out whether it is working in six to twelve weeks whereas it will take 20 weeks or longer to see if Ipi is effective on me. It has done wonders for two friends of mine with metastatic melanoma. (I wrote most of this Rumination on 8/29 at which time I did not know which trial it will be. I must admit that the uncertainty was seriously discomforting and an e-mail from an amazing guy, Andrew Wolanski, Dr. Shapiro’s nurse practitioner and right hand man, was remarkably reassuring and calming.)

 

In the process of deciding on possible studies, I ran across a review paper on Cdk inhibitors [I. M. Chu et al, The Cdk inhibitor p27 in human cancer: prognostic potential and relevance to anti-cancer therapy, Nature Reviews, Cancer 8: 253-267 (April 2008)]. Looking at this paper reminded me why immunology and intracellular signaling pathways have always made my head spin and made me wonder whether I am sorry never to have paid much attention to those subjects or whether I am glad I didn’t.

 

{Added September 9: On September 8 I was told that I would be accepted into the Cdk inhibitor trial. SCH727965 is a novel pyrazolo[1,5-a]pyrimidine which potently and selectively inhibits the cyclin- dependent kinases CDK1, CDK2, CDK5 and CDK9. The most common treatment-emergent adverse events are nausea/vomiting, diarrhea, neutropenia, and fatigue.  However, SCH 727965 is rapidly eliminated with a terminal half-life of 1.5 to 3 hours, so that recovery from side effects is rapid. A good response has been observed in other melanoma patients in the study. I expect to start the study next week.}

 

The good news is that, at long last, someone has had the courage to announce that, as far as clinical trials of cancer drugs is concerned, the emperor is hardly wearing any clothes. M.K.B. Pamar et al, from the MRC Clinical trials Unit in London, UK, wrote ‘Speeding Up the Evaluation of New Agents in Cancer, J.N.C.I. 100: 1204-1214 ( September 3, 2008) available on-line as DOI: 10.1093/jnci/djn267. The abstract reads:

 

Despite both the increase in basic biologic knowledge and the fact that many new agents have reached various stages of development during the last 10 years, the number of new treatments that have been approved for patients has not increased as expected. We propose the multi-arm, multi-stage trial design as a way to evaluate treatments faster and more efficiently than current standard trial designs. By using intermediate outcomes and testing a number of new agents (and combinations) simultaneously, the new design requires fewer patients. Three trials using this methodology are presented.

 

Hurray for our side!

 

While I am at it, I might as well get another pet peeve off my chest. What is it about cancer that makes people talk in terms of ‘cancer survivor’ and battles and courage. We never hear of people ‘surviving’ COPD, or heart disease, or strokes, or AIDS if they live with the disease for more than a couple of years. Nor have I ever read ‘She died after a long, heroic struggle with multiple heart attacks’. Middle ear infections in children (that can lead to brain damage or death) often re-occur; when have you heard anyone say “My Johnny is a middle ear infection survivor”? Cancer is a disease like any other, sometimes fatal, sometimes not. It can re-occur. It is true that two generations ago, cancer was a mystery and its cause unknown. It was commonly undetected until symptoms appeared by which time the patient was terminal. I remember a time when even physicians would not say the word, but use ‘CA’ as a euphemism. People, its 60 years later – we know what causes cancer. Can we please stop the bullshit! I cannot say it better than Colleen Shaddox, a writer in Hamden Conn. did in the Washington Post on June 2, 2007 (page A13):

 

It's Cancer, Not a Moral Crucible

 

"You're so brave," people would say. "You're a real hero."

 

I used to get that a lot after my hair fell out. The effects of chemotherapy made me look like some plucky child protagonist in a movie of the week. Volunteering to have cancer to spare someone else the pain of it would have been heroic. But I was no volunteer.

 

"I'm not brave," I would say, "I'm just unlucky."

 

This made people uncomfortable. But I would rather do that than accept unearned praise or, worse, listen to comments that, to me, dishonor those who have died of cancer.

 

During the 10 years I've been a cancer survivor, my marriage has grown stronger, my bouncing baby has blossomed into a gorgeous virtuoso of sarcasm, and my career has taken flight. I am grateful for this life every day.

 

It's tough being a cancer patient. Surgery, chemotherapy, radiation and the prospect of painful, premature death are quite enough for one person to shoulder. The additional burden of sainthood is simply too much.

 

When strangers would observe bald little me doing something normal -- grocery shopping, for example -- they would beam like proud parents. "You are so brave!" they would exclaim.

 

Of course, grocery shopping is a necessary act, even for people with cancer, and not terribly dangerous. But my admirers persisted, as though I were suddenly extraordinary. "I could never be as brave as you!"

 

That oft-repeated line is telling. After all, if cancer is a disease for extraordinary people, the average Joe or Jane doesn't have to worry. Even in the psyches of the healthy, fear of cancer is enormous. Consciously or not, making cancer patients the saintly "other" helps make that fear manageable.

 

When I battled breast cancer, I was frequently told that God would not take a person as good and loving as I. It might be a nice thing to believe: I was a churchgoer. I'd worked in a soup kitchen, collected for Toys for Tots. I was not Mother Teresa, but then virtue doesn't make one immortal; Mother Teresa died, just like everyone else.

 

When I expressed skepticism that my character could supercharge my immune system, I was often treated to impromptu sermons about keeping a positive attitude. Consider the logic: When you have the flu, people say, "I'm sorry. Hope you feel better." When you have cancer, people expect you to maintain a positive outlook and remember that you'll come out on top. People I barely knew would quote lines such as Bernie Siegel's "There are no incurable diseases, only incurable people."

 

Ultimately, stressing the importance of positive thinking is a way of managing fear. It makes cancer controllable -- for the patients, yes, but especially for the healthy. But linking virtue, resilience and survival dishonors those who do not survive.

 

I remember watching a television segment on an athlete who'd had cancer. "Cancer really picked on the wrong person," one of those interviewed said in explaining the man's determination and ultimate recovery. So, are there right people for cancer to pick on?

 

I kept my sanity during treatment through the help of a support group. Half of these women have died. Those who did not make it had cancers with high mortality rates or cancers that were quite advanced when they were detected. The women were strong, smart and caring -- such terrific ladies that they almost made me believe the myth of cancer sainthood. But they also got parking tickets and forgot appointments, just like everybody else. They were human, and I loved them for it.

 

My friends were failed by their cells, not by their will. The horror of cancer is that it descends on irreplaceable mothers, brothers, children and friends. Some of them will die, no matter what we or they do. As we strive to honor those who had and those who are still fighting the disease, it's important to remember whom exactly our words are meant to comfort -- the people speaking, or the people in need of support.

 

********************************************************

 

I also want to recommend an exceptionally readable book, that both of us enjoyed reading, by Meredith Norton, ‘Lopsided. How having breast cancer can be really distracting. A memoir.”  Viking Press, ISBN 978-0-670-01928-1 (2008). Available from Amazon at

http://www.amazon.com/Lopsided-Having-Breast-Cancer-Distracting/dp/0670019283/ref=pd_bbs_sr_1?ie=UTF8&s=books&qid=1220102157&sr=1-1

or

http://tinyurl.com/6mx4xe

So the next big thing is the barn that the Ag Society is having an Amish construction group from Lancaster County, PA build. I'm helping find houses for the group to stay in and arranging food, transport and other "necessaries". It has been more than a little confusing -both on our end and on theirs about what is expected. We had thought that the work crew could stay in peoples' guest bedrooms, and that is how I first got involved when we volunteered our guest bedroom.  Then I was asked to coordinate the housing end of things and, when I talked to the head of the construction group, I found out that staying in peoples' homes was unacceptable. The group (35 or so including families) needed to be in separate houses.  That is a little difficult because a lot of the guest houses on the island are still rented out - those in the know know that Sept is a very nice time to be on island.

But I've rounded up 5 houses and have been promised another 2 or 3 (and have an apartment in reserve). The single men can't stay in a house, I gather, with women they aren't related to, so one house will be bachelor quarters. Another fairly large one will house the main family of 10 or 11, and the rest get scattered around. The idea is to find houses as close to the Ag Hall as possible, since the Amish do not drive and will have to be transported around. We are trying to find vans and van drivers to bring the workmen to the job site and the wives to the Ag Hall at least twice a day to feed the men. I won't go into details here, but if you are in a similar situation, email me and I will tell you what is and isn't working for us.

The group arrives on Monday (leaves on Saturday) and several of us involved in the non-construction end of the project are well into a quiet panic. I think housing is OK (but without a firm head count of bodies - and their ages and genders and religion [some Mennonites are coming to drive the Amish group down and operate the crane and truck down the construction supplies and those people I think need separate housing]) I'm not sure. Transportation is uncertain - even if there are enough vans, finding people who are willing to drive around up island at dawn and pick people up and deliver them to the Ag Hall is iffy (cabs have been suggested if the Ag Society is willing to pay for them). And the whole food/feeding thing is not quite settled. 

I think the group will have a light breakfast before dawn in the houses, then mid-morning the wives come with egg sandwiches. Not sure about lunch. Then in mid-afternoon the wives come with submarine sandwiches/pizza. Then dinner around 7. The Ag folks are trying to arrange with the Slow Food folks to fix a traditional New England shellfish dinner for Wednesday. And maybe hot dogs and marshmallows on the beach on Friday.  I plan to have a light lunch of ham, biscuits and coleslaw waiting when they get in on Monday and stuff for the light breakfast in the houses for Tuesday, since they won't have had time to shop and we won't have had time to transport them to the grocery store. The food thing has me worried, though one of the guest houses I found has a small but splendid commercial kitchen on the ground floor, and of course the Ag Hall has a kitchen, though it has nothing in the way of cooking pots, utensils or supplies.

 Everyone tells me it is all going to work out, but some of the details are just going to have to be worked out when the time comes. 

 

Sunday is the last day of the Fair. It has gone very well so far, we think in large part due to the nice weather.  We are tired but not exhausted. Have not gotten many pictures taken, but the ones below were taken by a friend who is an outstanding photographer.

Many kids were dissapointed that Tom wasn't teaching weaving, but many more (and their dads) were delighted to ask him endless questions about the loom. Tom's line this year is, "you can't wear thread, it won't keep you warm, you have to turn it into cloth."

 

Wendy's drum carder has been a huge hit. She has done wool washing and dyeing and spinning, but it is the drum carder that holds everyone's attention. Fortunately, she brought a lot to card and the rest of us had stuff that needed a pass as well. (I'm just about convinced I need a small drum carder.)

And I've been spinning and sort of re-inventing the long draw technique.

Tom's daughter Wendy came down from Buffalo for the Fair. We set up yesterday, Tom's loom needed much adjustment.

We watched the oxen practicing - including a pair of calves yoked together and learning to walk around the pen, more or less.

The next day the oxen pull shows what these calves are training for.

Wendy set up a wool processing demo, going from raw wool, to washed wool, to carding to dying roving to spinning. The drum carder was the big surprise hit.

And I spun miles of black Shetland roving.

The weather is cool, breezy and clear. Perfect Fair weather and everyone is in an unusually good mood. Hope it lasts!

 

 We had a great time at the pig roast on Saturday. Here is Tom inserting the skewers of shrimp and tomatoes/hearts of palm into half of a red cabbage. We took this and skewers of tomatoes and our cheese for appetizers.

 This is the pig getting its final flip. Brian cooked it in one of the best ways we have seen. The pig was butterflied open (head removed) and the body sandwiched between two grills. The grills were bolted together and the whole thing placed over the coals. The pig cooked more evenly than the spit or buried/baked ones and had gloriously crispy skin.

 

 This is Brian and Gary deciding how to carve the pig. The pig roast brought together Brian and his friends from high school. All live (or plan to live) on the Vineyard and have kept up with each other all these years. 

 Perhaps the happiest at the pig roast were the dogs who stood under the carving table to catch the drippings!

We are going to try to sell the yarn we had spun from Anne Hopkin's sheep. It is bulky weight 3 ply, not a weaving wool and not the size yarn I usually knit with. But I knit this hat (An Unoriginal Hat by The Yarn Harlot)as a demo model and am thinking that the yarn would make a nice warm vest.