Archive for October, 2021

FROM NORTH AMERICA SYNDICATE, 300 W 57th STREET, 15th FLOOR, NEW YORK, NY 10019

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TO YOUR GOOD HEALTH #TFB20211018

FOR RELEASE WEEK OF OCT. 18, 2021 (COL. 1)

BYLINE: By Keith Roach, M.D.

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DEAR DR. ROACH: I am a 71-year-old female in very good health. I have been taking a thyroid replacement since I was 12 years old. I currently take 125 mcg of thyroxine once daily, as well as 60 mg of Cymbalta. Other than arthritis and obesity, I have no health problems. My question is regarding my lab results. My TSH is 0.04 (the normal range is 0.30-5.5); my T3 and T4 are in the normal range. My physician assures me that as long as my T3 and T4 are normal, the TSH is of no concern. I cannot lose weight, no matter what I try. Would you suggest I see an endocrinologist, or is my primary doctor correct? -- D.A.

ANSWER: The thyroid stimulating hormone is a signal from the pituitary gland to the thyroid to "tell" the thyroid to make more hormone. Since your TSH level is low, it suggests that the dose of replacement thyroid hormone is too high. This is despite the fact that the T3 (the active form of thyroid hormone) and T4 (thyroxine, the major thyroid hormone, which T3 is made from) are normal, and despite the fact that you report no symptoms. The range of normal for T3 and T4 is very broad, and the low TSH is good evidence that those levels are too high for you.

Excess thyroid hormone can cause bone disease and predispose to heart problems, such as atrial fibrillation. I think an endocrinologist is likely to say that your dose of thyroxine should be decreased.

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DEAR DR. ROACH: I have a history of C. diff. I had the shingles vaccine, and developed severe diarrhea, which has lasted eight weeks. Could the vaccine have instigated this? I'm now on vancomycin, and it is helping. -- M.G.

ANSWER: Clostridioides difficile is most commonly associated with antibiotic use, but can be acquired in a hospital or other nursing facility or even out in the community. I have never heard of C. diff as a complication of a vaccine, so I did a search on the VAERS database of vaccine side effects. I found no reported cases of C. diff with the shingles vaccine. I really didn't expect to.

Vaccines are a powerful public health tool, and like all medicines, they have the potential for side effects. It is human nature, when presented with a health change, to ascribe it to any new event, such as a new medicine or vaccine. Sometimes they are linked, but sometimes they are not. In this case, I think they most likely are not.

DEAR DR. ROACH: I had my first pneumonia injection (PCV13) in October 2015 and the second injection (PPSV23) in October 2016. My primary care physician sends me reminders that my pneumonia shot is past due. The head nurse at the same primary care clinic reviewed my medical files and says I do not need additional pneumonia shots for the rest of my life. I have asked my cardiologist, urologist and gastroenterologist if I need to update my pneumonia injections, but they avoid answering me. I am 72 years old and have health problems. Since the COVID virus affects the lungs and many suffer from pneumonia, I am concerned about my protection, although I have both Moderna vaccinations. Should I get a pneumonia shot? -- C.V.

ANSWER: Your nurse is correct, you are not recommended for any additional pneumonia vaccines at this time. These pneumonia vaccines protect against only one bacterium, Streptococcus pneumoniae, with no protection against COVID-19. You should get your third dose of Moderna when it's recommended (expected at the time of this writing to be eight months after your second dose). That is, unless the recommendations have changed by then -- this is a fast-moving area!

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Dr. Roach regrets that he is unable to answer individual letters, but will incorporate them in the column whenever possible. Readers may email questions to ToYourGoodHealth@med.cornell.edu or send mail to 628 Virginia Dr., Orlando, FL 32803.

(c) 2021 North America Syndicate Inc.

All Rights Reserved

More here:
TSH tells thyroid gland to make more hormone - New Castle News

Introduction

Polymyalgia rheumatica (PMR) and remitting seronegative symmetrical synovitis with pitting edema syndrome (RS3PE syndrome) are diseases of unknown etiology that affect elderly persons. They are characterized by pain of sudden onset that continues and elevated erythrocyte sedimentation rate and C-reactive protein levels.1 Once the symptoms develop, they greatly impair patients quality of life. With the aging of the population, an increase in the number of such patients has been reported from the UK.2 The incidence of PMR has been found to be higher in individuals of Scandinavian background, lower in Southern European countries, and unknown in Japan.3,4 Although the symptoms improve markedly with glucocorticoid (GC) treatment, prudent tapering of GC is required.5 Although GC could be decreased from the initial dose in all PMR patients, it is difficult to stop GC treatment, as has been previously reported.6 Past studies reported that relapse has been variably associated with female sex, longer duration of morning stiffness, peripheral arthritis, higher erythrocyte sedimentation rate at diagnosis, persistent elevations of C-reactive protein, interleukin-6 levels, and soluble interleukin-6 receptor levels, larger initial doses of prednisone, and a faster rate of tapering.7 Furthermore, reports of GC continuation and risk factors for relapse in Japanese PMR patients are few.4 To better estimate GC treatment duration, the percentage of patients who could stop GC treatment and the baseline variables associated with inability to withdraw GC after the time when the GC continuation rate stopped decreasing were examined. In particular, sex differences were examined.

A total of 105 patients (64 women) who were started on GC treatment for PMR and/or RS3PE syndrome at Ikeda City Hospital from July 2004 to December 2019 were evaluated. Birds criteria8 were used up to 2014, and the EULAR/ACR polymyalgia rheumatica interim standard of classification9 was used between 2015 and 2019 for PMR diagnosis. Patients who showed pitting edema of both hands and both lower extremities and did not fulfill the diagnostic criteria of rheumatoid arthritis,10 spondyloarthropathy,11 or other diseases were diagnosed as having RS3PE syndrome. Both PMR and RS3PE syndrome were diagnosed in patients with PMR who showed pitting edema of both hands and both lower extremities without other cause.

The GC dose was left to the discretion of the attending physician. The initial dose of prednisolone is generally 10 to 16 mg/day, and the aim is to discontinue it by 24 years. The dose was actually reduced by 2.5 mg/day every 24 weeks in patients treated with >10 mg/day, and by 1 mg/day every 24 weeks in patients treated with 10 mg/day.7 When symptoms returned with GC reduction, the attending physician increased the dose promptly. GC was continued when it was resumed for disease recurrence once it had been stopped.

The days from GC initiation to GC withdrawal were calculated. If GC could not be stopped, the last observation day was used. The GC continuation rate during the observation period was then estimated by the KaplanMeier method, creating KaplanMeier curves by sex.

Furthermore, cases that had stopped GC (withdrawal group) and cases that had continued GC for 7.5 years (continuation group) were identified, and the following were compared between them: Age at time of starting GC treatment; sex; type (PMR and/or RS3PE syndrome); erythrocyte sedimentation rate, C-reactive protein, hemoglobin, ferritin, aspartate aminotransferase, and alanine aminotransferase levels before starting GC; days from onset of symptoms to GC initiation; GC maximum dose; GC dose half a year after it was started; presence of relapse (GC restarting or increasing due to deterioration of symptoms); and the presence of concomitant malignant disease. Cases belonging to neither the withdrawal group nor the continuation group constituted the intermediate group. Patients with malignant diseases were counted when they were diagnosed with them within 6 months since GC was started for PMR or RS3PE syndrome. It was thought that cases in the intermediate group included cases that would be reclassified to the withdrawal group or the continuation group if they were observed for a longer time. It was expected that the parameters associated with GC continuation in the intermediate group would be between those of the withdrawal group and the continuation group and totaled the parameters in the intermediate group.

This survey was based on a chart review, but a telephone poll of patients whose charts could not be reviewed was conducted.

Statistical analyses were performed with IBM SPSS Statistics, version 27. KaplanMeier curves were compared using the Log rank test. Comparisons between the withdrawal group and the continuation group were made with Students t-test for independent continuous variables, and the chi-squared test was used to compare categorical data between groups.

This investigation protocol adopted the ethical guidelines of the 1975 Declaration of Helsinki and was approved by the Ikeda City Hospital Ethics Committee (approval number A20010). The data accessed from the medical records were de-identified in this report. Because this report contains no individual persons data, and this investigation was observational and noninterventional, the Ikeda City Hospital Ethics Committee waived the need for patient consent.

There were 58 cases diagnosed by Birds criteria, 43 cases diagnosed by the EULAR/ACR polymyalgia rheumatica interim standard of classification, and 4 cases with pure RS3PE syndrome. There were 32 cases in the withdrawal group and 17 cases in the continuation group.

The dose of GC could be reduced from the initial dose in all patients.

The duration from the onset of symptoms to GC therapy starting was 79.579.6 days (meanSD) in all patients.

The GC continuation rate 7.5 years after starting GC was 52.5% in all patients, 69.2% in women, and 27.1% in men. The rates remained unchanged for 15 years (Figures 1 and 2). The GC continuation rate was significantly higher in women (Log rank test). No patients were prescribed immunosuppressants.

Figure 1 Glucocorticoid continuation rate of all cases (KaplanMeier method).

Figure 2 Glucocorticoid continuation rate by sex (KaplanMeier method). The glucocorticoid continuation rate is higher in women (P=0.020).

P values by Students t-test or the chi-squared test are shown in the table for the other survey items, including numbers of cases, with data displayed as mean standard deviation (Table 1). Since there was a case with suspected temporal arteritis at the beginning in the withdrawal group that was treated with prednisolone 50 mg/day, this case was excluded as an abnormal value for the GC maximum dose and the GC dose half a year after its initiation. In the withdrawal group, there were few women (P=0.016). In all patients, hemoglobin levels (mean SD) before starting GC were lower (10.51.6 g/dL) in women than in men (11.41.8 g/dL) (P=0.014). In the withdrawal group, they were 10.91.5 g/dL in women and 11.91.6 g/dL in men. In the continuation group, they were 10.41.9 g/dL in women and 10.02.8 g/dL in men. Relapses were fewer in the withdrawal group than in the continuation group (P=0.0003).

Table 1 Clinical Features of the 105 Patients

In this study, the duration of GC treatment for PMR and RS3PE syndrome in Japanese patients was longer than in previous reports in English.12 GC treatment was needed for a longer time in women than in previous reports, and it was difficult to stop GC treatment in cases with severe anemia.

Although it has been reported that female sex is a risk factor for long-term GC treatment by Narvez et al13 and Cimmino et al,14 there has been no English-language report from Japan. Aoki et al reported the GC treatment duration of Japanese PMR patients, and they found no difference between men and women.12 They classified their patients into two groups by whether they had stopped GC therapy as of 24 months. Therefore, their observation period was shorter than in the present study. Two important factors causing sex-based disparities are genetics and sex hormones.15 Estrogen enhances B cell differentiation and immunoglobulin production.16 Several studies reported an immunosuppressive role of testosterone on different components of the immune system.15 Furthermore, the small number of GC receptors or low GC receptor affinity in woman may have an effect.14

In the present study, although the GC continuation rate fell to 55.6% at 7 years and 5 months, it did not fall further. The necessity for continuing GC differed among reports. Aoki et al reported that the median time of remission was 16 months.12 Cimmino et al reported that about 26% of the patients required GC treatment for 6 years or more.14 Shbeeb et al reported that the median GC treatment period was 5.95 years.17 Although the present study found a longer GC treatment period than previous reports, a prudent approach to GC dose reduction may have been one reason, given the report of a certain rate of disease recurrence in the report by Aoki et al.12 In 17 patients in the continuation group, three patients have not relapsed. This may show that our treatment is sometimes passive with respect to reducing the GC dose. Although there may have been a bias among certain institutions for longer GC treatment, the bias among institutions cannot explain the sex difference. There sometimes were newly suspected patients who received no GC treatment while waiting for spontaneous resolution. This study included no spontaneously resolved patients. The duration from the onset of symptoms to the start of GC therapy in all patients was over 2 months. This might be one reason for the long GC continuation in this study, and it might be a characteristic of Japanese/Asian people.

There are many more female than male patients. In Ikeda City, in which our hospital is located, the population aged 60 years and over as of March 31, 2020, included 18,880 women and 14,506 men.18 Therefore, it cannot be said that the incidence is higher among women than men.

Since PMR and the RS3PE syndrome often merged, they were considered together in one group.1,19 Since there are few pure RS3PE syndrome cases, whether there are differences between PMR and RS3PE syndrome in GC continuation and by sex is unknown. Aoki et al observed peripheral edema in 41 of 93 PMR patients.12 Such cases would be considered combined PMR and RS3PE syndrome cases according to the definition used in the present study.

Origuchi et al reported that GC dose and CRP 1 year after starting therapy were high in men with RS3PE syndrome.20 In the report by Origuchi et al, the observation period was 1 year, shorter than in other reports.20 In the present study, the womens continuation rate was also not high until 1.4 years after starting.

The present data showed severe anemia in the GC continuation group. Narvez et al reported that hemoglobin levels were low in women with PMR.13 They considered that anemia reflects intense inflammation. The range of ferritin was large for every case, and the difference between the withdrawal group and the continuation group was not clear. Ferritin levels were high in all groups, reflecting the impaired iron utilization in these diseases.

As a limitation of the present investigation, the number of patients was insufficient for a multivariable statistical analysis of the GC continuation rate and anemia. In addition, because some of the patients were interviewed by telephone, recall bias may have occurred. Because this study was retrospective, sex hormone levels were not measured before treatment; it is a future task to measure them in order to identify causes of the sex difference.

When considering the future treatment strategy for PMR and RS3PE syndrome in Japan, it is important to note that it is difficult to stop GC treatment for women and for those with severe anemia.

It is difficult to stop GC for PMR and/or RS3PE syndrome in women in Japan, especially in cases with severe anemia.

All authors have no conflicts of interest that should be declared. All authors take full responsibility for the content of this paper.

1. Mimori A. Polymyalgia rheumatica/PMR & remitting seronegative symmetrical synovitis with pitting edema/RS3PE (in Japanese). In: Mimori A. Physicians Notes on Rheumatology: The Process of Clinical Consideration. 4th ed. Tokyo, Japan: Japan medical journal; 2019:413426.

2. Partington RJ, Muller S, Helliwell T, Mallen CD, Sultan AA. Incidence, prevalence and treatment burden of polymyalgia rheumatica in the UK over two decades: a population-based study. Ann Rheum Dis. 2018;77(12):17501756. doi:10.1136/annrheumdis-2018-213883

3. Gonzalez-Gay MA, Vazquez-Rodriguez TR, Lopez-Diaz MJ, et al. Epidemiology of giant cell arteritis and polymyalgia rheumatica. Arthritis Care Res. 2009;61(10):14541461. doi:10.1002/art.24459

4. Nishioka K, Tanaka T. [Rheumatology: Progress in diagnosis and treatments. topics: III. Rheumatoid arthritis and allied conditions; 2. Allied conditions. 2) polymyalgia rheumatica]. Nihon Naika Gakkai Zasshi. 2014;103(10):24402448. Japanese. doi:10.2169/naika.103.2440

5. Hernndez-Rodrguez J, Cid MC, Lpez-Soto A, Espigol-Frigol G, Bosch X. Treatment of polymyalgia rheumatica: a systematic review. Arch Intern Med. 2009;169(20):18391850. doi:10.1001/archinternmed.2009.352

6. Muratore F, Pipitone N, Hunder GG, Salvarani C. Discontinuation of therapies in polymyalgia rheumatica and giant cell arteritis. Clin Exp Rheumatol. 2013;31(4 Suppl 78):S86S92.

7. Docken WP. Treatment of polymyalgia rheumatica [homepage on the Internet]. Wolters Kluwer; 2018 [Updated September 7, 2018]. Available from: https://www.uptodate.com/. Accessed February 21, 2020.

8. Bird H, Esselinckx W, Dixon AS, Mowat A, Wood P. An evaluation of criteria for polymyalgia rheumatica. Ann Rheum Dis. 1979;38(5):434439. doi:10.1136/ard.38.5.434

9. Dasgupta B, Cimmino MA, Kremers HM, et al. 2012 provisional classification criteria for polymyalgia rheumatica: a European league against rheumatism/American College of Rheumatology collaborative initiative. Arthritis Rheum. 2012;64(4):943954. doi:10.1002/art.34356

10. Arnett FC, Edworthy SM, Bloch DA, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheumatism. 1988;31(3):315324. doi:10.1002/art.1780310302

11. Dougados M, Linden SVD, Juhlin R, et al. The European Spondylarthropathy Study Group preliminary criteria for the classification of spondylarthropathy. Arthritis Rheumatism. 1991;34(10):12181227. doi:10.1002/art.1780341003

12. Aoki A, Kobayashi H, Yamaguchi Y. Predictors of long-term therapy with glucocorticoid in polymyalgia rheumatica. Modern Rheumatol. 2020;31(2):417426. doi:10.1080/14397595.2020.1777680

13. Narvez J, Nolla-Sol JM, Valverde-Garca J, Roig-Escofet D. Sex differences in temporal arteritis and polymyalgia rheumatica. J Rheumatol. 2002;29(2):321325.

14. Cimmino MA, Parodi M, Caporali R, Montecucco C. Is the course of steroidtreated polymyalgia rheumatica more severe in women? Ann N Y Acad Sci. 2006;1069(1):315321. doi:10.1196/annals.1351.030

15. Trigunaite A, Dimo J, Jrgensen TN. Suppressive effects of androgens on the immune system. Cell Immunol. 2015;294(2):8794. doi:10.1016/j.cellimm.2015.02.004

16. Moulton VR. Sex hormones in acquired immunity and autoimmune disease. Front Immunol. 2018;9:2279. doi:10.3389/fimmu.2018.02279

17. Shbeeb I, Challah D, Raheel S, Crowson CS, Matteson EL. Comparable rates of glucocorticoid-associated adverse events in patients with polymyalgia rheumatica and comorbidities in the general population. Arthritis Care Res. 2018;70(4):643647. doi:10.1002/acr.23320

18. Ikeda City Office [homepage on the Internet]. Populations in Ikeda city by age and sex (in Japanese); April 2, 2020. Available from: http://www.city.ikeda.osaka.jp/material/files/group/4/020331_nenreibetu.pdf. Accessed July 25, 2020.

19. Cantini F, Salvarani C, Olivieri I, et al. Remitting seronegative symmetrical synovitis with pitting oedema (RS3PE) syndrome: a prospective follow up and magnetic resonance imaging study. Ann Rheum Dis. 1999;58(4):230236. doi:10.1136/ard.58.4.230

20. Origuchi T, Arima K, Umeda M, et al. Clinical outcomes in the first year of remitting seronegative symmetrical synovitis with pitting edema (RS3PE) syndrome. Modern Rheumatol. 2017;27(1):150154. doi:10.1080/14397595.2016.1192744

Read more:
Glucocorticoid therapy withdrawal in polymyalgia rheumatica | IJGM - Dove Medical Press

Komal Jhaveri, MD, discussed the case of a 63-year-old patient with HER2-positive metastatic breast cancer during a Targeted Oncology Case-Base Roundtable event.

During a Targeted OncologyTM Case-Based Roundtable event, Komal Jhaveri, MD, the section head of the Endocrine Therapy Research Program, clinical director, of Early Drug Development Service, and a medical oncologist at Memorial Sloan Kettering Cancer Center in New York, NY, discussed the case of a 63-year-old patient with HER2-positive metastatic breast cancer.

Targeted OncologyTM: How typical is the presentation of this patient in your clinical practice, and what data are most relevant to you in choosing a treatment approach?

JHAVERI: According to the recently updated NCCN [National Comprehensive Cancer Network] guidelines in systemic therapy options for recurrent stage IV disease, we use a taxane with a dual HER2 blockade, which is trastuzumab and pertuzumab in the first line.1 This is obviously based on the unprecedented progression-free survival [PFS] and overall survival [OS] benefit in the CLEOPATRA trial [NCT00567190].2 The paclitaxel was based out of a phase 2 trial that was conducted by my colleague, Chau Dang, MD, here at Memorial Sloan Kettering Cancer Center, and we did not see any febrile neutropenia with the paclitaxel, so that has really become our go-to regimen in the first line.3

What data support treatment options in the second-line setting?

In the second-line setting, we have data from the EMILIA trial (NCT00829166), which led to T-DM1, or ado-trastuzumab emtansine, an antibody-drug conjugate [ADC], the first one for breast cancer.4 This is despite this trial not having patients progressing on trastuzumab, but in clinic this is our contemporary choice...for our patients. Additionally, we have a plethora of options that patients can receive on the third line and beyond. These include tucatinib [Tukysa] plus trastuzumab plus capecitabine [Xeloda] and fam-trastuzumab deruxtecan-nxki [Enhertu].1 We also have other chemotherapies with trastuzumab, such as capecitabine with trastuzumab and capecitabine with other TKIs [tyrosine kinase inhibitors]. There are targeted therapies, including a recent approval for margetuximab-cmkb [Margenza], an Fc-optimized antibody that was approved for use with chemotherapy in this last year.5

We have these many options, but what we do not know is the optimal sequence for third-line therapy and beyond.

Now, what is interesting here is that the triplet of tucatinib plus trastuzumab plus capecitabine, per the NCCN guidelines, is preferred in patients with both systemic and CNS progression on ado-trastuzumab emtansine.1 However, it may be given even in the second-line setting. Fam-trastuzumab deruxtecan is preferred in patients with visceral metastases [if there is disease] progression on ado-trastuzumab emtansine. [However, it is] contraindicated for patients with known pneumonitis or interstitial lung disease.

What makes this ADC special? Why is it distinct from T-DM1?

I think there are a few key attributes that we might want to think of [in] T-DXd [trastuzumab deruxtecan]. One is that the drug-to-antibody ratio [DAR] is 8 molecules of chemotherapy that can be delivered. Now, to put this into context when we think of T-DM1 therapy, that DAR is 3.5. So we are delivering more chemotherapy to the tumor cell. The payload itself is a topoisomerase I inhibitor, which we do not regularly use for our HER2- positive patients.

It is a highly potent payload, which the patients have not seen...in their regimens, and it has a very short half-life, so the free payload has a very short half-life, which is great. The linker is stable, and it is a tumor selective cleavable linker. Once this is delivered to the tumor, it is the pepsin in the tumor that makes the linker cleave and then deliver the payload. It is very tumor selective, so one can potentially expect less off-target toxicity.

And another important attribute to keep in mind is the bystander effect. It has membrane permeability, and so this payload can be membrane permeable and go to the neighboring cells, which might not necessarily be HER2 overexpressing. But that is why we have also seen activity in what we now call HER2 low, which is HER2 IHC 1+ and 2+ patients who have shortened benefit with T-DXd and other novel inhibitors that are also being developed and have this bystander effect. Of note, T-DM1 does not have that. And as we know, we do not utilize T-DM1 for patients who do not have HER2-amplified or HER2- expressive tumors.

Please discuss how the DESTINY-Breast01 trial [NCT03248492] has affected decisions for this patient.

[These data that] led to the approval of trastuzumab deruxtecan [were from] an open-label, multicenter, phase 2 trial [that enrolled] patients 18 [years] or older with unresectable metastatic breast cancer who had centrally confirmed HER2-positive disease and who had prior T-DM1.6,7 Patients with a history of interstitial lung disease were excluded.

This was because [of what] we had already learned from an adjudication committee that was put in place with the phase 1 experience of this agent. And stable, treated brain metastases were allowed to enroll on this trial. These patients were then enrolled in 2 parts. Part 1 included a PK [pharmacokinetic] stage and a dose-finding stage. In the PK stage, we studied 3 doses of which two, 5.4 mg/kg and the 6.4 mg/kg, moved on to the dose-finding stage. Based on the PK data and the safety data, the 5.4 mg/kg [dose] was selected to move forward and is the current recommended and approved dose.

This was the dose that moved into the continuation stage, where most of the patients had TDM-1 resistant disease. There were 4 patients who had TDM-1 intolerance, for a total of 184 patients [who] were treated with this dose, 5.4 mg/kg, with a primary end point of ORR [overall response rate]. One thing that I would like to highlight is that these patients have received up to 6 prior lines of therapy, and [approximately] two-thirds received prior pertuzumab therapy.

Additional baseline characteristics [also should be considered]. Median age was [approximately] 55 years. These were patients predominantly with a good performance state. [Approximately] 50% of these patients were hormone receptor positive. [Approximately] 84% had HER2 positivity by IHC 3+ expression. The remaining were IHC 2+ or 1+ or ISH [in situ hybridization] positive. Visceral disease was present in 92% of patients, of whom 57% had lung metastases. This is important to remember for the discussion of our case. Liver metastases were present in 30%, and the rest also had bone disease. There were 24 [13%] of these patients enrolled in the trial who also had stable, treated brain metastases.

How do the updated data from the DESTINY-Breast01 trial affect treatment decisions?

In the updated DESTINY-Breast01 trial data from June 2020, all but 4 patients had tumor shrinkage.8 The overall response rate, despite this [population being] heavily treated with a median of 6 prior lines of therapy, was 61.4%, including patients who had a complete response. The median duration of response, which is also very important to understand for our patients who are heavily pretreated, was 21 months in this phase 2 trial. And this response was seen rather early: time to response was 1.6 months. So if you are really worried about somebody with extensive disease or burdened disease, this was a quick response with this drug.

The median PFS in DESTINY-Breast01 was 19.4 months. This is rather impressive for such a heavily pretreated population. Just to put this into context and into perspective, when we think of other trials in the third line and beyond, whether it was the TH3RESA trial [NCT01419197] that studied TDM-1 with physician choice therapy, the NALA study [NCT01808573], the HER2CLIMB study [NCT02614794], or the SOPHIA trial [NCT02492711], the median PFS for the patient population [in the] third line [was approximately] 7 to 8 months.9-12 The PFS [in DESTINY-Breast02] of 19.4 monthsin such a heavily pretreated population, I think it is really unprecedented.8 The median OS data at 21 months was 25 months, but what I would really like to highlight here is that this is just 35% maturity of data, and we really need follow-up maturity now to understand the implications. [Approximately] 119 patients were already censored, and 17 were thought to have events at month 2, so at 18 months we had 74% alive, but [these are] still immature data.

Did these data show progression of disease in other areas?

A subgroup analysis for the 24 patients [13%] in the CNS subgroup was presented at ASCO [American Society of Clinical Oncology Annual Meeting] this year.13 Seventeen patients had brain lesions at baseline, and the data [were] available to evaluate responses in the brain for 15 of the 17. Though this was a small subgroup, it was important that there were responses seen in patients with stable brain metastases; 41% had a partial response and another 41% had disease stabilization in the brain. Again, this subgroup also had median of 6 lines of therapy, the same as the total population. Median follow-up here was 11 months, and...in the CNS subgroup, the ORR, PFS, and duration of response were comparable to those in the total patient population treated at the same dose. The median PFS in this population with brain metastases was 18 months [95% CI, 6.7-18.1]. There was also an additional case report where we saw 55% regression of a metastatic brain lesion.

The most common sites when we looked at progression were the liver, lung, and lymph nodes, which was similar in all patients total and the CNS subgroup. Meaning, once you were in the CNS subgroup or the total patient population and then you progressed, the common types of progression were within the liver, lungs, and lymph nodes. Progression in the brain was not as common. There were only 4 of 48 patients who had progressed in the brain, including 2 out of the 8 patients with baseline CNS metastases.

What is the safety profile of T-DXd?

I think the most common adverse events [AEs] that we see, and that were seen in more than 10% of the patients in the study, were nausea, vomiting, alopecia, fatigue, and neutropenia.14 But an important AE that we want to keep in mind is the drug-related ILD [interstitial lung disease] or pneumonitis. The ILD incidence that was reported initially with the August 2019 data cutoff was 25 patients [13%] who developed ILD or pneumonitis. The majority had grade 1 or grade 2 ILD or pneumonitis; however, there were 4 fatal events. The median time to developing ILD was 4.1 months. At the additional 1-year cutoff, and overall median cutoff, there were 3 additional ILD cases determined by the independent adjudication committee.

ILD events were seen mostly within the first 12 months, and after the 12-month mark, only 1 patient developed ILD, perhaps suggesting that ILD is not a cumulative AE. But this is something that we really must be aware of, and not just us, but also our frontline nursing staff who are fielding the calls when the patient calls in. [If there are symptoms that may indicate ILD or pneumonitis,] whether they have shortness of breath, a new cough, extreme fatigue, [we need] to quickly interrupt therapy, get pulmonology involved, and give patients steroids. [There are] patients who are asymptomatic, [so we have] to keep a very close eye on this to make sure that we are not missing anything.

We have become more trained look for these [potential AEs] given that there are so many classic agents with breast cancer that cause pneumonitis: checkpoint inhibitors and everolimus, and [also] CDK4/6 inhibitors....I think we all have become a little more vigilant about keeping a close eye on symptoms for our patients and for also for keeping an eye on the scans to make sure that we are not missing the so-called ground glass opacities for which we might want to interrupt or discontinue therapy. Fortunately, the heart events or cardiac events were very low, including left ventricular ejection fraction decreases or cardiac failure, as is seen with trastuzumab.

What was the design of the HER2CLIMB phase 2 trial?

[Lets move on] then to the phase 2 HER2CLIMB trial of tucatinib [Tukysa] and capecitabine and trastuzumab, which studied patients with HER2-positive metastatic disease who had prior treatment with trastuzumab, pertuzumab, and T-DM1.15 What was key in the study was that active brain metastases not needing local therapy were allowed, but they were not required. So you could have had treated, stable brain metastases, but you were also allowed to have active brain metastases. What is important to remember here is that these are patients with small tumors, less than 2-cm tumors, who do not have symptoms warranting local therapy. They did not require immediate radiation and they were [still] considered eligible.

[More than] 600 patients were enrolled410 in the tucatinib arm and 202 in the placebo arm.15 And they were well-balanced groups with a median age of [approximately] 55 years, all with predominantly good performance status; 60% were hormone receptor positive; overall, they had received 4 prior lines of therapy. Forty-eight percent had a history of brain metastasis. Of these 48%, 60% [of the brain metastases] were stable and treated. The remaining were what was called active, which could be untreated brain metastases. Untreated [meant] no local therapy or systemic therapy or [that they had been] treated in the past with some kind of local therapy but [were] progressing again. Even though they are progressing again, they are not symptomatic enough to warrant additional local therapy.

REFERENCES:

1. NCCN. Clinical Practice Guidelines in Oncology. Breast cancer, version 7.2021. Accessed August 20, 2021. https://bit.ly/2Y4zXiQ

2. Swain SM, Miles D, Kim SB, et al. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA): end-of-study results from a double-blind, randomised, placebo-controlled, phase 3 study. Lancet Oncol. 2020;21(4):519-530. doi:10.1016/S1470-2045(19)30863-0

3. Dang C, Iyengar N, Datko F, et al. Phase II study of paclitaxel given once per week along with trastuzumab and pertuzumab in patients with human epidermal growth factor receptor 2positive metastatic breast cancer. J Clin Oncol. 2014;33(5):442-447. doi:10.1200/JCO.2014.57.1745

4. Diras V, Miles D, Verma S, et al. Trastuzumab emtansine vs capecitabine plus lapatinib in patients with previously treated HER2-positive advanced breast cancer (EMILIA): a descriptive analysis of final overall survival results from a randomised, open-label, phase 3 trial. Lancet Oncol. 2017;18(6):732-742. doi:10.1016/ S1470-2045(17)30312-1

5. FDA approves margetuximab for metastatic HER2-positive breast cancer. News release. FDA. December 17, 2020. Accessed August 20, 2021. https://www.fda.gov/drugs/resources-information-approved-drugs/ fda-approves-margetuximab-metastatic-her2-positive-breast-cancer

6. Krop IE, Saura C, Yamashita T, et al. [Fam-] trastuzumab deruxtecan (T-DXd; DS-8201a) in subjects with HER2-positive metastatic breast cancer previously treated with T-DM1: a phase 2, multicenter, open-label study (DESTINY-Breast01). Abstract presented at: San Antonio Breast Cancer Symposium; December 10-14, 2019; San Antonio, TX. Accessed August 20, 2021. https://www.abstractsonline.com/ pp8/#!/7946/presentation/2039

7. Modi S, Saura C, Yamashita T, et al. Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. N Engl J Med. 2020;382(7):610-621. doi:10.1056/ NEJMoa1914510

8. Modi S, Saura C, Yamashita T, et al. Updated results from DESTINY-breast01, a phase 2 trial of trastuzumab deruxtecan (T-DXd) in HER2 positive metastatic breast cancer. Abstract presented at: San Antonio Breast Cancer Symposium; December 8-11, 2020; virtual. Accessed August 20, 2021. https://www. sabcs.org/Portals/SABCS2016/2020%20SABCS/ALL%20ABSTRACTS%202-9. pdf?ver=2020-12-09-104626-337

9. Krop IE, Kim SB, Martin AG, et al. Trastuzumab emtansine vs treatment of physicians choice in patients with previously treated HER2-positive metastatic breast cancer (TH3RESA): final overall survival results from a randomised open-label phase 3 trial. Lancet Oncol. 2017;18(6):743-754. doi:10.1016/S1470-2045(17)30313-3

10. Saura C, Oliveira M, Feng YH, et al. Neratinib plus capecitabine vs lapatinib plus capecitabine in HER2-Positive metastatic breast cancer previously treated with 2 HER2-directed regimens: phase III NALA trial. J Clin Oncol. 2020;38(27):3138-3149. doi:10.1200/JCO.20.00147

11. Murthy RK, Loi S, Okines A, et al. Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer. N Engl J Med. 2020;382(7):597-609. doi:10.1056/NEJMoa1914609

12. Rugo HS, Im SA, Cardoso F, et al. Efficacy of margetuximab vs trastuzumab in patients with pretreated ERBB2-positive advanced breast cancer: a phase 3 randomized clinical trial. JAMA Oncol. 2021;7(4):573-584. doi:10.1001/jamaoncol.2020.7932

13. Jerusalem GHM, Park YH, Yamashita T, et al. Trastuzumab deruxtecan (T-DXd) in patients with HER2+ metastatic breast cancer with brain metastases: a subgroup analysis of the DESTINY-Breast01 trial. J Clin Oncol. 2021;39(suppl 15):526. doi:10.1200/ JCO.2021.39.15_suppl.526

14. Jerusalem GHM, Park YH, Yamashita T, et al. CNS metastases in HER2-positive metastatic breast cancer treated with trastuzumab deruxtecan: DESTINY-Breast01 subgroup analyses. Ann of Oncol. 2020;31(suppl 2):S63-S64. doi:10.1016/j. annonc.2020.03.239

15. Enhertu. Prescribing information. Daiichi Sankyo, Inc; 2021. Accessed August 20, 2021. https://bit.ly/3hkf3mN

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Focus on These Data When Making Treatment Decisions in Breast Cancer - Targeted Oncology

Aspirin-induced asthma (AIA) is a condition where asthma symptoms can develop after taking aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs). Its also known as aspirin-exacerbated respiratory disease (AERD) or Samters Triad.

The American Academy of Allergy, Asthma, and Immunology (AAAAI) estimates that 9 percent of adults have asthma and that 30 percent of adults who have asthma and nasal polyps may also have AERD.

Read on to learn more about the underlying causes and risk factors of AIA as well as how this condition may be treated.

Acetylsalicylic acid (aspirin) is a type of NSAID used to relieve pain, inflammation, and fever. Similar medications include ibuprofen (Advil) and naproxen (Aleve).

Aspirin and other NSAIDs interact with an enzyme known as cyclooxygenase-1 (COX-1). While the exact triggers are unknown, its thought that people with AIA have a sensitivity to the way these medications inhibit this enzyme.

You may be more prone to AIA if you have all three of these conditions:

A doctor may still recommend aspirin for the treatment of other conditions, such as preventing heart attacks or strokes, in cases where a person may have already experienced one of these conditions and when the benefits outweigh the risks of triggering asthma symptoms.

Symptoms of AIA tend to develop shortly after taking aspirin or other NSAIDs often within minutes or hours after exposure.

While its important to address any suspected symptoms of AIA with a doctor, heres a breakdown of mild symptoms as well as more severe symptoms that require immediate medical attention.

Mild symptoms of AIA may include:

More severe symptoms of AIA can make it harder to breathe even if you take a rescue inhaler. Although rare, these acute symptoms can be life threatening.

Seek emergency medical help if you experience the following:

People who develop AIA are usually between ages 20 and 50 years old and likely have a combination of:

You may also be more susceptible if you experience the following on a recurring basis:

Age is another consideration. You more generally can become more vulnerable to side effects from NSAIDs as you age past your 50s.

Its also possible that reactions to aspirin could be induced by drug allergies. Besides NSAIDs, other common drug allergies include:

Symptoms of AIA may also be further exacerbated if you also drink alcohol. The AAAAI estimates that 75 percent of people with the condition may experience symptoms after drinking alcohol along with aspirin use.

AIA is typically diagnosed with the help of an asthma specialist, such as an allergist, pulmonologist, or immunologist.

Theres not just one test that can diagnose AIA. Instead, a diagnosis is made with a combination of the following factors:

A doctor may also recommend ordering a test called an aspirin challenge to rule out drug allergies. This involves taking aspirin either in the doctors office or at the hospital while under medical supervision. Any reactions you have to taking aspirin can then be identified and treated.

Along with avoiding NSAIDs, treatment for AIA involves managing symptoms of asthma, sinusitis, and nasal polyps.

You can also talk with a doctor about the following options.

Home treatments can include:

A doctor may recommend one or more of the following medical treatments:

Besides exacerbated asthma symptoms, complications of AIA may include hives (urticaria). The AAAAI estimates that between 20 and 40 percent of people who have chronic hives may have worsening symptoms if they also experience AIA. A type of swelling called angioedema can also occur.

Its also important to consider long-term side effects of taking aspirin and other NSAIDs, especially when taken for longer than recommended. These include:

Avoid mixing aspirin with the following, too:

Aspirin is a type of NSAID primarily used to relieve pain. But be careful using aspirin if you have a history of asthma, sinusitis, and nasal polyps. These underlying conditions may put you at a higher risk of developing AIA.

Talk with a doctor if youre concerned about the risks or side effects of taking NSAIDs or if you have a history of side effects after taking these types of medications. They can help diagnose and treat potential AIA along with related medical conditions.

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What Is Aspirin-Induced Asthma? Causes, Symptoms & More - Healthline

Leading clinicians at Allegheny General Hospital support first islet cell transplant to treat chronic pancreatitis.

PITTSBURGH (PRWEB) October 05, 2021

Allegheny Health Network (AHN) today announced a groundbreaking new capability for treating patients who suffer from chronic pancreatitis, an inflammation of the pancreas that occurs over many years and, in severe cases, can be life-threatening. Every year, more than 80,000 people are diagnosed with the disease, according to the National Pancreas Foundation.

Surgeons at Allegheny General Hospital (AGH) have joined a select group around the country performing islet cell transplantation to restore the functions of a diseased pancreas. AGHs Institute of Cellular Therapeutics, is one of just a few in the nation that specializes in islet cell isolation, a highly sophisticated process in which islet cells, such as those that produce insulin, are extracted from the patients removed pancreas and transplanted back into the body. For the past six years, the institutes Islet Cell Isolation Laboratory has extracted and processed these life-saving cells to assist in the care of patients at select islet cell transplant centers around the country. With the launch of its own transplant program, AHN becomes one of just a few medical centers in the nation able to provide the comprehensive therapy from start to finish.

Pancreatic islets are tiny clusters of cells scattered throughout the pancreas. Included among these islets are beta cells, which produce the hormone insulin that helps the body absorb glucose from the bloodstream and use it for energy. Diabetes develops when the pancreas does not make enough insulin, the bodys cells do not effectively use insulin, or a combination of both. Massimo Trucco, MD, Director of AHNs Institute of Cellular Therapeutics and an internationally preeminent diabetes researcher, leads the islet cell extraction team at the hospital.

The islet cell transplant is critical for patients with immense pain and have failed other therapies. Dr. Trucco and his staff collaborate with AHNs gastroenterology, abdominal transplant, endocrinology, psychology and social services teams to complete the procedure and provide wrap-around patient support.

Chronic pancreatitis is a debilitating disease that can lead to frequent hospitalizations, higher use of narcotic pain medication and a lower quality of life, said Abhijit Kulkarni, MD, FASGE, an AHN gastroenterologist who evaluates patients for the islet cell transplant procedure. This treatment really represents the pinnacle of pain management for pancreatitis care and can be a true lifeline for the most critically ill patients.

According to Rita Bottino, PHD, from AHNs Institute of Cellular Therapeutics, the poor condition of the pancreas can make extraction of islet cells challenging. We sometimes have to be a little creative in finding a way to inject enzymes into the organ that will break the matrix that holds the cells together. By injecting enzymes, clusters of cells or single cells will be released from the organ and those are the kind of insulin-producing cells that we ultimately want to transplant back to the patient.

Once the islet cells are extracted and ready for transplant, AHN surgeons Harry Williams, MD, Ngoc Thai, MD, PhD, and Tadahiro Uemura, MD, PhD, transplant the cells into the patients own liver through the portal vein. Called an autologous islet cell transplant (TPAIT), the cells continue to produce insulin to control blood sugar levels in the body, eliminating the risk of becoming diabetic.

So we remove the diseased organ, which is causing debilitating symptoms for the patient, while creating a new pathway for insulin production in the body. And the advantage of a smaller time interval between extraction and transplant of these cells is significant and we believe will result in even better outcomes for our patients, said Dr. Williams.

Thus far, AHN has completed one TPAIT procedure and prepared more than 100 islets for regional hospitals including UPMC and The Cleveland Clinic. In addition to treating patients, AHN supplies research donor islets to Mt. Sinai Hospital, Stanford University Medical Center, Vanderbilt University Medical Center, and the universities of Pennsylvania, Miami and San Francisco, among others.

Our ultimate goal when starting our islet cell isolation lab several years ago was to ultimately develop the transplant capabilities and become one of the few one stop shops for this highly specialized care in the country, said Dr. Thai, Director of AHNs Center for Abdominal Transplantation. Having some of the worlds foremost experts in this field at our institution, like Dr. Trucco and his team, has afforded us with an extraordinary opportunity to build an internationally leading program.

To learn more about AHNs Cellular Therapeutics Institute or Transplant program, please visit http://www.AHN.org.

About the Allegheny Health Network: Allegheny Health Network (AHN.org), a Highmark Health company, is an integrated healthcare delivery system serving the greater Western Pennsylvania region. The Network is composed of 13 hospitals, ambulatory surgery centers, Health + Wellness Pavilions, an employed physician organization, home and community based health services, a research institute, and a group purchasing organization. The Network provides patients with access to a complete spectrum of advanced medical services, including nationally recognized programs for primary and emergency care, trauma care, cardiovascular disease, organ transplantation, cancer care, orthopedic surgery, neurology and neurosurgery, womens health, diabetes, autoimmune disease and more. AHN employs approximately 21,000 people, has more than 2,500 physicians on its medical staff and serves as a clinical campus for Drexel University College of Medicine and the Lake Erie College of Osteopathic Medicine.

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AHN Performs Its First Islet Cell Transplants to Treat Chronic Pancreatitis - PR Web

Otto Warburg probably would have been sent to a concentration camp if the Nazis werent hoping he could cure cancer.

Warburg was a Jewish gay man living openly in Berlin with his partner as Hitler rose to power. Warburg was also a biochemist, as brilliant as he was arrogant. In the 1920s, he discovered a hallmark of cancer, now called the Warburg effect. Malignant cells are ravenous for glucose, or blood sugar, consuming 10 times more than healthy cells. He dedicated his career to studying this strange metabolic anomaly because he believed it was the root cause of cancer.

He won the 1931 Nobel Prize for his work. But it was mostly forgotten by the 1950s, eclipsed by the molecular genetics revolution that set off a search for mutated, cancer-causing genes. He died in 1970 at age 86.

The rise, fall, and recent resurgence of research into cellular metabolism is the subject of Ravenous: Otto Warburg, the Nazis, and the Search for the Cancer-Diet Connection. Author Sam Apple, a journalist based in the Philadelphia suburb of Wyndmoor, weaves together this complex narrative in a way that makes arcane science accessible and fascinating.

The book is also thought-provoking for anyone interested in avoiding cancer and who isnt?

Its not obvious to me that there would be a breakthrough cancer therapy if Warburgs focus on cellular metabolism had not been shunted aside, Apple said in a recent interview. More likely, there would have been more attention to the relationship between our diets and the metabolism of the whole body and cancer. I think this could have had a dramatic impact on cancer prevention. But the link is still is not widely appreciated.

Otto Warburg was related to a wealthy German Jewish clan of bankers, scholars, and influencers. He was groomed for scientific greatness by his father, Emil Warburg, a leading physicist of the time.

The pinnacle of Otto Warburgs career happened to coincide with the rise of the Third Reich. When Warburg refused to sign a declaration of Aryan descent, the Nazi customs official tasked with asking Warburg to lie endeavored to get him punished by the Kaiser Wilhelm Society, the parent organization of Warburgs scientific institute.

Warburg not only managed to get off scot free, but he asked the Wilhelm Society president to ask the Reich Ministry of Finance to rewrite racial decrees so that non-Aryan institute directors would be treated like Aryan directors.

In 1934, at a moment when Hitler had already begun sending Germans to concentration camps, Otto Warburg, a gay man of Jewish descent, wanted Nazi laws rewritten according to his personal needs, Apple writes in the book.

As the author explains, cancer rates were inexplicably rising in Germany and other developed countries, and the Nazis fear of the disease ran almost as deep as their antisemitism and homophobia They despised Warburg, but needed his scientific genius.

Warburg invented several new tools to study the metabolism of cells, including the manometer, an instrument used to measure the force exerted by a gas or liquid.

He knew that in a healthy cell, blood glucose was normally converted to energy in a process using oxygen. This process, which involves enzymes that Warburg spent years identifying, occurs in the cells power stations, now known as mitochondria.

He discovered, to his amazement, that cancer cells broke all the metabolic norms. In addition to overconsuming glucose, the cells turned it into energy using an inefficient process that did not require oxygen even though plenty of oxygen was available.

The cancer cells were chopping glucose molecules in half and spitting the fragments right back out of the cell, Apple writes in an elegantly simple description of anaerobic glycolysis, or fermentation, the biochemical process that also gives us beer and wine. Cancer cells, Warburg realized, were fermenting glucose just as simple organisms like yeast and bacteria do.

But why? Warburg hypothesized more like proclaimed that cancer cells mitochondria were somehow defective, so the cells had to resort to a backup power generator, namely fermentation.

Today, while the search for answers continues, the evidence suggests that fermentation is not a response to a defect. Rather, it gives malignant cells an advantage as they turn into uncontrollable, immortal renegades.

Glucose molecules are the building blocks that cancer needs to create daughter cells, Apple boiled it down during the interview. The most influential scientists now think its about the cancer cells bioenergetic needs.

Following the 1953 discovery of the structure of DNA the genetic instructions for everything cells do oncology researchers became focused on finding and fixing the defective genes that give rise to cancer.

In that postwar era, Warburgs focus on cell metabolism was seen as outmoded, like studying the fuel line in hopes of understanding a high-tech engine.

Beginning in the 1990s, however, some leading researchers realized that certain cancer-causing genes known for their role in cell division also regulated cells glucose consumption. One of those scientists, Chi Van Dang, former director of the University of Pennsylvanias Abramson Cancer Center and now scientific director at the Ludwig Institute for Cancer Research, showed that MYC, a family of genes regulating cell proliferation, also targets an enzyme that can turn on the Warburg effect.

Metabolism-centered cancer therapies that effectively starve tumors are no longer just a concept. Two drugs, ivosidenib and vorasidenib, have already been approved by the Food and Drug Administration for a form of leukemia and are now being tested in brain cancer patients. Rafael Pharmaceuticals experimental therapy, devimistat, has had impressive early results in bile duct cancer trials.

But as Apple points out, cancer is an incredibly persistent foe. It can mutate to evade chemotherapy, molecularly targeted therapies, and even newer immune-boosting therapies. The same thing may happen with metabolic therapies. Whats more, virtually all cancer treatments come with significant side effects.

Thats why the implications for preventing cancer in the first place are so important.

Population-wide studies have directly linked 13 cancers including breast, bladder, lung, colon, liver, and gynecological cancers to the same metabolic abnormalities that are driving the twin worldwide epidemics of obesity and diabetes. The most striking thing that the cancers, obesity and diabetes have in common is resistance to insulin, the vital hormone that enables cells to absorb blood glucose and turn it into energy. To compensate for this resistance, the pancreas pumps out more and more glucose.

The hypothesis is that patients high blood sugar impacts tumor growth by providing cancer cells with an abundance of the fuel they thrive on.

Apple spends almost half his book taking deep, incisive dives into research on the insulin connection. Refined sugar, which is a combination of glucose and fructose called sucrose, contributes to insulin resistance, So does fructose, or fruit sugar especially when it is concentrated in high-fructose corn syrup, the ubiquitous processed-food additive. Consuming fructose, a carbohydrate, also appears to make people add fat tissue more readily than actual fats, such as such as butter.

Precisely how much sugar is too much may be different for each person, depending on genes and age and exercise habits and capacity to store fat safely, he writes. But the path from refined sugar added to our diets to insulin resistance ... to cancer is now well understood and based on widely accepted science.

He touches only glancingly on a fundamental problem: Even if sugars role as a cancer-promoter becomes an article of faith, cutting back on it is tough. And controversy, not to mention quackery, abounds in the field of nutrition. The ketogenic diet, for example, restricts carbohydrates, which are converted to glucose in the body. The diet has shown promise in weight loss studies, as well as in relieving neurological disorders such as epilepsy. But the esteemed Mayo Clinic says the diets high level of saturated fats, combined with limits on nutrient-rich fruits, veggies and grains, is a concern for long-term heart health.

In the final chapter, Apple weaves in a chilling anecdote:

Sugar, of course, cannot be blamed for Nazism or for turning Hitler into a madman. But as his madness grew, so, too, did his taste for sweets. It wasnt only his cherished Viennese pastries. On any given day, Hitler might consume two full pounds of chocolates. He even added sugar to his wine.

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An old idea from a German Jewish scientist spared by the Nazis is getting new life: Prevent and treat cancer by cutting out sugar - The Philadelphia...