Initiating Treatment with Low Fluorouracil Dose and Titrating According to Blood Levels in Patients Treated with a 46-Hour Continuous Infusion.

INTRODUCTION: Fluorouracil (5-FU) pharmacokinetics are variable, leading to a risk of toxicity in some patients and underdosing in others. Therapeutic drug monitoring of 5-FU was shown to reduce toxicity and increase efficacy. This study assessed the clinical utility of starting treatment with 70-80% of BSA calculated dose and titrating according to 5-FU blood levels and toxicity. METHODS: A retrospective analysis of a prospectively collected database of 126 patients treated with regimens containing 5-FU bolus and continuous infusion for 46 h for whom the 5-FU blood level was collected at least once. Response,and date of progression, and death were collected for patients with colon and pancreatic cancer. RESULTS: In multivariate analysis, 5-FU blood levels were correlated with 5-FU dose and with age, albeit a small effect size (coefficient = 0.007). Of patients with colon cancer treated with an initial lower 5-FU dose, 18% had a therapeutic 5-FU blood level. The median survival was similar in patients with metastatic colon cancer treated with lower doses and those treated with a full dose. Of patients with pancreatic cancer treated with lower doses, 40% had therapeutic blood levels. The median survival was 13 months in patients with metastatic pancreatic cancer treated with lower 5-FU doses. CONCLUSION: Starting treatment with low 5-FU dose was associated with patient survival comparable to other published data, and a sizeable percentage of patients had therapeutic blood levels. This approach can be considered, especially in elderly and frail patients.

Pro-BNP in the differential diagnosis of dyspnea in patients treated with immune-checkpoint inhibitors: Case Report.

INTRODUCTION: Immune checkpoint inhibitors (ICI) induced cardiac toxicity can present with non-specific symptoms and signs. Early recognition and treatment are important; however, diagnosis can be challenging. CASE REPORT: We describe a 67-year-old woman with a history of ICI induced pneumonitis who presented with dyspnea, hypoxemia and pulmonary infiltrates while treated with pembrolizumab for lung cancer, initially diagnoses with relapssed pneumonitis. When her condition did not improve with steroids, NT-pro-BNP level was tested and was markedly high, prompting additional tests for heart failure. MANAGEMENT AND OUTCOME: The patient was diagnosed with ICI induced left ventricular dysfunction and treated with steroids, beta blockers, diuretics, and ACE inhibitors. Her symptoms and imaging studies markedly improved. DISCUSSION: Here, we review the literature on ICI induced cardiac toxicity and the role of NT-pro -BNP in triage of patients presenting with dyspnea in the emergency setting. We suggest that measurement of NT-pro -BNP be utilized in patients receiving ICI's and presenting with respiratory abnormalities, to rapidly assess for possible cardiac toxicity.

[BREAST CANCER COMPLICATIONS DURING THE COVID-19 PANDEMIC - LESSONS LEARNT].

INTRODUCTION: In their article published in this issue of Harefuah, Greenhouse et al. describe a complicated case of a woman with delayed diagnosis of breast cancer, presenting with spinal cord compression due to spin metastases and a locally advanced breast lesion. The patient had concurrent symptomatic infection with COVID-19, and was successfully diagnosed and treated, resulting in neurologic recovery. This case raises several issues, relevant to the care of patients with breast cancer. Late diagnosis of breast cancer is not uncommon, but little is known regarding the reasons why some women forego breast cancer screening or delay diagnosis of symptomatic breast lesions. Available information points at fear of breast cancer and fear of surgery as common causes, and it seems that interventions aimed to increase screening rates should take these findings into account. The patient described by Greenhouse et al. complained of back ache and was treated by telemedicine for a month preceding hospitalization, during the initial stages of the COVID-19 outbreak. As the implementation of telemedicine increases, organizations should issue guidelines for its use. It seems prudent to avoid using telemedicine in patients with new symptoms or recurring symptoms without a definite diagnosis. There is currently sufficient data showing that breast cancer patients are not at higher risk for COVID-19 complications compared with the general population, even while treated for their cancer. Serologic studies performed in Israel following COVID-19 vaccination found that 85-90% of patients with solid tumors have positive serologic tests after the 2nd dose of the vaccine. Studies have estimated that delaying breast cancer screening during the pandemic would result in increased breast cancer mortality. Thus, efforts should be made to continue breast cancer screening, diagnostic workup of suspicious findings and treatment of confirmed breast cancer in the event of additional outbreaks of COVID-19.

Feminism, gender medicine and beyond: a feminist analysis of "gender medicine".

The feminist women's health movement empowered women's knowledge regarding their health and battled against paternalistic and oppressive practices within healthcare systems. Gender Medicine (GM) is a new discipline that studies the effect of sex/gender on general health. The international society for gender medicine (IGM) was embraced by the FDA and granted funds by the European Union to formulate policies for medical practice and research.We conducted a review of IGM publications and policy statements in scientific journals and popular media. We found that while biological differences between men and women are emphasized, the impact of society on women is under- represented. The effect of gender-related violence, race, ethnic conflicts, poverty, immigration and discrimination on women's health is seldom recognized. Contrary to feminist practice, GM is practiced by physicians and scientists, neglecting voices of other disciplines and of women themselves.In this article we show that while GM may promote some aspects of women's health, at the same time it reaffirms conservative positions on sex and gender that can serve to justify discrimination and disregard the impact of society on women's lives and health. An alternative approach, that integrates feminist thinking and practices into medical science, practice and policies is likely to result in a deep and beneficiary change in women's health worldwide.

Oncology Treatments during the COVID-19 Pandemic in Israel: the ONCOR Study.

BACKGROUND: The increased susceptibility of cancer patients to coronavirus disease-2019 (COVID-19) infections and complications calls for special precautions while treating cancer patients during COVID-19 pandemics. Thus, oncology departments have had to implement a wide array of prevention measures. OBJECTIVES: To address issues associated with cancer care during the COVID-19 pandemic and to assess the implementation of measures aimed at containment of COVID-19 diffusion while allowing continuation of quality cancer care. METHODS: A national survey among oncology departments in Israel was conducted between 12 April 2020 and 14 April 2020. Eighteen heads of hospital-based oncology departments completed a self-report questionnaire regarding their institute's preparedness for treatment of cancer patients during the COVID-19 pandemic. RESULTS: In this national survey, prevention measures against COVID-19 spread were taken prior to patients' arrival and at arrival or while staying in the departments. Most participants (78-89%) reported using a quick triage of patients and caregivers prior to their entrance to the oncology units, limiting the entrance of caregivers, and reducing unnecessary visits to the clinic. Switching to oral therapies rather than intravenous ones when possible was considered by 82% and shortage in personal protective equipment was reported by five (28%) heads of oncology departments. Some differences between large and small/medium sized medical centers were observed regarding issues related to COVID-19 containment measures and changes in treatment. CONCLUSIONS: Oncology departments in Israel were able to prepare and adapt their services to guidelines and requirements related to the COVID-19 pandemic with little harm to their treatment capacity.

The intestinal microbiome, weight, and metabolic changes in women treated by adjuvant chemotherapy for breast and gynecological malignancies.

BACKGROUND: Adjuvant chemotherapy induces weight gain, glucose intolerance, and hypertension in about a third of women. The mechanisms underlying these events have not been defined. This study assessed the association between the microbiome and weight gain in patients treated with adjuvant chemotherapy for breast and gynecological cancers. METHODS: Patients were recruited before starting adjuvant therapy. Weight and height were measured before treatment and 4-6 weeks after treatment completion. Weight gain was defined as an increase of 3% or more in body weight. A stool sample was collected before treatment, and 16S rRNA gene sequencing was performed. Data regarding oncological therapy, menopausal status, and antibiotic use was prospectively collected. Patients were excluded if they were treated by antibiotics during the study. Fecal transplant experiments from patients were conducted using Swiss Webster germ-free mice. RESULTS: Thirty-three patients were recruited; of them, 9 gained 3.5-10.6% of baseline weight. The pretreatment microbiome of women who gained weight following treatment was significantly different in diversity and taxonomy from that of control women. Fecal microbiota transplantation from pretreatment samples of patients that gained weight induced metabolic changes in germ-free mice compared to mice transplanted with pretreatment fecal samples from the control women. CONCLUSION: The microbiome composition is predictive of weight gain following adjuvant chemotherapy and induces adverse metabolic changes in germ-free mice, suggesting it contributes to adverse metabolic changes seen in patients. Confirmation of these results in a larger patient cohort is warranted.

Association between palliative care and the rate of advanced care planning: A systematic review.

OBJECTIVE: Advanced care planning (ACP) is central to patients' dignity and autonomy; however, in many countries it is underutilized. Studies that tested the effects of palliative care (PC) often included the rate of documented ACP as a secondary end point. We aimed to assess the contribution of PC to the rate of ACP among terminally ill patients by systematically reviewing relevant clinical trials. METHOD: PUBMED and "Cochrane trials" databases were screened for clinical trials published until October 2017 that compared the addition of PC to standard treatment and that had ACP as a primary or a secondary end point. Studies were assessed for validity by three investigators using the Cochrane Collaboration tool and the ROBINS-I tool for randomized controlled trials (RCTs) and for cohort studies, respectively. RESULTS: Twenty-six trials with 37,924 patients were included. Four were RCTs, nine were cohort studies, and 12 were cross-sectional studies. Randomized trials had the lowest risk of bias. There was a positive correlation between the addition of PC and ACP in 25 studies, among them four randomized trials. SIGNIFICANCE OF RESULTS: In this systematic review, PC was associated with improvement in the rate of ACP. Understanding the significant effect of PC on the completion of ACP is an additional emphasis on the importance of this treatment among terminally ill patients.

Short-term complications of intra-operative radiotherapy for early breast cancer.

INTRODUCTION: IORT is becoming an accepted radiotherapy technique for treatment of early breast cancer. Data regarding the early complications of breast IORT are lacking. OBJECTIVES: Assess the nature and risk factors for early complications of breast conserving surgery (BCS) and intraoperative radiotherapy (IORT) with INTRABEAM®. METHODS: IORT with INTRABEAM® was administered to breast cancer patients in Carmel Medical Center as part of an institutional clinical registry project. Three hundred and ninety five patients treated during 2006-2013 were included. Clinical and treatment data and data regarding complications documented within 1 year of surgery were collected. The association between clinical and treatment variables and risk of complications was assessed. RESULTS: Complications were documented in 108 (27.3%) of patients. Grade III or IV complications were found in 5% of patients. Infections were diagnosed in 43 (10.8%) patients, seroma in 40 (10.1%), wound dehiscence in 32 (8.1%), and bleeding and hematomas in 11(2.8%). Two patients had a small size skin necrosis. Sixteen patients with a seroma had a secondary complication. All complications resolved. Diabetes mellitus and use of anticoagulants were associated with an increased risk of wound dehiscence and bleeding, respectively. CONCLUSIONS: IORT for breast cancer is safe in appropriately selected patients. Careful surgical technique and postoperative care is prudent. J. Surg. Oncol. 2016;113:370-373. © 2016 Wiley Periodicals, Inc.

Statins, aspirin and risk of thromboembolic events in ovarian cancer patients.

OBJECTIVES: Studies suggest that statins and low dose aspirin reduce risk of VTEs in the general population. We aimed to study the effect of these drugs on the incidence of VTEs in patients with ovarian cancer. METHODS: Patients diagnosed with ovarian cancer between 2000 and 2011 were identified through the Clalit Health Services (CHS) chronic disease registry. Data were extracted from CHS database and from computerized pharmacy records. Use of medications was analyzed as a time dependent covariate in a Cox regression model. RESULTS: Of 1746 patients 175 (10%) had a VTE during a median follow up of 3.13 years. 83 patients (5.6%) had a VTE within 2 years of diagnosis of ovarian cancer. Use of chemotherapy and stage 3 and 4 at presentation were associated with an increased risk for VTEs. Statins were used by 43.5% of the patients, and 32.3% used aspirin. Aspirin use was associated with a marginally significant reduction in incidence of VTEs within 2 years of diagnosis, HR 0.423 (95% CI 0.182-1.012, p-value 0.053). Statin use was not associated with risk of VTEs. CONCLUSION: This is the first study looking at the effect of statins and aspirin on the incidence of VTEs in ovarian cancer patients. In our cohort, statins did not decrease the risk for a VTE and aspirin use was associated with a reduced risk which was marginally significant. Our results might be explained by use of low potency statins and by alternate mechanisms for VTE formation in cancer patients.

Statins, aspirin and risk of venous thromboembolic events in breast cancer patients.

Venous thromboembolic events (VTE's) are associated with decreased survival in breast cancer patients. Studies suggested that statins reduce the risk of VTE's in the general population. Low dose Aspirin reduces risk of VTE's in high risk populations. The Breast Cancer in Northern Israel Study is a case-control study of consecutive breast cancer cases diagnosed in northern Israel and matched controls. The present analysis was limited to cases with breast cancer enrolled in the study. Data was extracted from Clalit Health Services (CHS) database and from computerized pharmacy records. Out of 3,585 patients enrolled, 261 (7.3%) had a VTE during median follow up of 4.2 years. The 1 and 2 year cumulative incidence was 2.64 and 3.65%. 55.7% of patients used statins, predominantly simvastatin (75.8%). 44.5% used aspirin. In multivariate analysis neither statins nor aspirin use was associated with a reduced risk for a VTE. Unadjusted HR for statin and aspirin was 1.461 (1.018-2.096) and 1.293 (0.846-1.976), respectively, and the adjusted HR were 0.86 (0.648-1.14) and 1.013 (0.737-1.392). Results were similar when only simvastatin use was assessed. Metastatic disease, chemotherapy, age, BMI and presence of comorbidities were significantly associated with risk of VTE's. Our study is the first to look at the effect of statins and aspirin on the incidence of VTE's in patients with breast cancer. In our cohort, statin and aspirin use did not decrease the risk for a VTE. Our results might be explained by use of low potency statins (simvastatin and pravastatin) and by alternate mechanisms for VTE formation in patients with cancer.

Durvalumab Plus Carboplatin/Paclitaxel Followed by Maintenance Durvalumab With or Without Olaparib as First-Line Treatment for Advanced Endometrial Cancer: The Phase III DUO-E Trial.

PURPOSE: Immunotherapy and chemotherapy combinations have shown activity in endometrial cancer, with greater benefit in mismatch repair (MMR)-deficient (dMMR) than MMR-proficient (pMMR) disease. Adding a poly(ADP-ribose) polymerase inhibitor may improve outcomes, especially in pMMR disease. METHODS: This phase III, global, double-blind, placebo-controlled trial randomly assigned eligible patients with newly diagnosed advanced or recurrent endometrial cancer 1:1:1 to: carboplatin/paclitaxel plus durvalumab placebo followed by placebo maintenance (control arm); carboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab plus olaparib placebo (durvalumab arm); or carboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab plus olaparib (durvalumab + olaparib arm). The primary end points were progression-free survival (PFS) in the durvalumab arm versus control and the durvalumab + olaparib arm versus control. RESULTS: Seven hundred eighteen patients were randomly assigned. In the intention-to-treat population, statistically significant PFS benefit was observed in the durvalumab (hazard ratio [HR], 0.71 [95% CI, 0.57 to 0.89]; P = .003) and durvalumab + olaparib arms (HR, 0.55 [95% CI, 0.43 to 0.69]; P < .0001) versus control. Prespecified, exploratory subgroup analyses showed PFS benefit in dMMR (HR [durvalumab v control], 0.42 [95% CI, 0.22 to 0.80]; HR [durvalumab + olaparib v control], 0.41 [95% CI, 0.21 to 0.75]) and pMMR subgroups (HR [durvalumab v control], 0.77 [95% CI, 0.60 to 0.97]; HR [durvalumab + olaparib v control] 0.57; [95% CI, 0.44 to 0.73]); and in PD-L1-positive subgroups (HR [durvalumab v control], 0.63 [95% CI, 0.48 to 0.83]; HR [durvalumab + olaparib v control], 0.42 [95% CI, 0.31 to 0.57]). Interim overall survival results (maturity approximately 28%) were supportive of the primary outcomes (durvalumab v control: HR, 0.77 [95% CI, 0.56 to 1.07]; P = .120; durvalumab + olaparib v control: HR, 0.59 [95% CI, 0.42 to 0.83]; P = .003). The safety profiles of the experimental arms were generally consistent with individual agents. CONCLUSION: Carboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab with or without olaparib demonstrated a statistically significant and clinically meaningful PFS benefit in patients with advanced or recurrent endometrial cancer.

HER2-Low Breast Cancer: Current Landscape and Future Prospects.

More than 50% of breast cancers are currently defined as "Human epidermal growth factor receptor 2 (HER2) low breast cancer (BC)", with HER2 immunohistochemistry (IHC) scores of +1 or +2 with a negative fluorescence in situ hybridization (FISH) test. In most studies that compared the clinical and biological characteristics of HER2-low BC with HER2-negative BC, HER2-low was not associated with unique clinical and molecular characteristics, and it seems that the importance of HER2 in these tumors is being a docking site for the antibody portion of antibody drug conjugates (ADCs). Current pathological methods may underestimate the proportion of BCs that express low levels of HER2 due to analytical limitations and tumor heterogeneity. In this review we summarize and contextualize the most recent literature on HER2-low breast cancers, including clinical and translational studies We also review the challenges of assessing low HER2 expression in BC and discuss the current and future therapeutic landscape for these tumors.

Treating Alpelisib-Induced Hyperinsulinemia in Patients with Advanced Breast Cancer - A Real-Life Experience.

PIK3CA activating mutations are found in 40% of advanced breast cancer and are associated with worse prognosis. PI3K blockage is associated with insulin resistance, leading to hyperglycemia and hyperinsulinemia. Alpelisib is the first PI3K inhibitor used in cancer treatment. Laboratory evidence indicated that alpelisib-induced hyperinsulinemia offsets the drug's efficacy, but insulin levels were not tested in the clinical trials that evaluated alpelisib for breast cancer. Hyperglycemia could also interfere with anti-tumor effects of PI3K inhibitors by inducing Immune tolerance and altered mitochondrial metabolism. We have monitored insulin levels in 4 breast cancer patients with concomitant metabolic syndrome treated with alpelisib, and pre-treated patients with baseline increased insulin levels with pioglitazone, a potent insulin sensitizer, to target both hyperinsulinemia and hyperglycemia, and we report the treatment course of these patients. All patients achieved glycemic control and were able to maintain alpelisib dose intensity. Duration of response to alpelisib was longer than anticipated in this treatment setting. Insulin dynamics confirmed the efficacy of pioglitazone as a specific on-target hypoglycemic and hypo-insulinemic agent in the unique setting of PI3K blockade. Our experience suggests that targeting hyperinsulinemia in patients with is safe and feasible and results in good metabolic and oncologic outcomes.

Inhibiting mutant KRAS G12D gene expression using novel peptide nucleic acid-based antisense: A potential new drug candidate for pancreatic cancer.

KRAS mutations, which are the main cause of the pathogenesis of lethal pancreatic adenocarcinomas, impair the functioning of the GTPase subunit, thus rendering it constitutively active and signaling intracellular pathways that end with cell transformation. In the present study, the AsPC-1 cell line, which has a G12D-mutated KRAS gene sequence, was utilized as a cellular model to test peptide nucleic acid-based antisense technology. The use of peptide nucleic acids (PNAs) that are built to exhibit improved hybridization specificity and have an affinity for complementary RNA and DNA sequences, as well as a simple chemical structure and high biological stability that affords resistance to nucleases and proteases, enabled targeting of the KRAS-mutated gene to inhibit its expression at the translation level. Because PNA-based antisense molecules should be capable of binding to KRAS mRNA sequences, PNAs were utilized to target the mRNA of the mutated KRAS gene, a strategy that could lead to the development of a novel drug for pancreatic cancer. Moreover, it was demonstrated that introducing new PNA to cells inhibited the growth of cancer cells and induced apoptotic death and, notably, that it can inhibit G12D-mutated KRAS gene expression, as demonstrated by RT-PCR and western blotting. Altogether, these data strongly suggest that the use of PNA-based antisense agents is an attractive therapeutic approach to treating KRAS-driven cancers and may lead to the development of novel drugs that target the expression of other mutated genes.

The Effectiveness and Safety of Medical Cannabis for Treating Cancer Related Symptoms in Oncology Patients.

The use of medical cannabis (MC) to treat cancer-related symptoms is rising. However, there is a lack of long-term trials to assess the benefits and safety of MC treatment in this population. In this work, we followed up prospectively and longitudinally on the effectiveness and safety of MC treatment. Oncology patients reported on multiple symptoms before and after MC treatment initiation at one-, three-, and 6-month follow-ups. Oncologists reported on the patients' disease characteristics. Intention-to-treat models were used to assess changes in outcomes from baseline. MC treatment was initiated by 324 patients and 212, 158 and 126 reported at follow-ups. Most outcome measures improved significantly during MC treatment for most patients (p < 0.005). Specifically, at 6 months, total cancer symptoms burden declined from baseline by a median of 18%, from 122 (82-157) at baseline to 89 (45-138) at endpoint (-18.98; 95%CI= -26.95 to -11.00; p < 0.001). Reported adverse effects were common but mostly non-serious and remained stable during MC treatment. The results of this study suggest that MC treatment is generally safe for oncology patients and can potentially reduce the burden of associated symptoms with no serious MC-related adverse effects.

Cytomegalovirus pneumonia complicating immune checkpoint inhibitors-induced pneumonitis: A case report.

A 63-year-old man was hospitalized for immune check-point inhibitors (ICIs) medicated pneumonitis, secondary to treatment with pembrolizumab for non-small cell lung cancer. He was treated with high dose steroids, mycophenolate mofetil, empiric broad spectrum antibiotics and empiric trimethoprim-sulfamethoxazole and intravenous immunoglobulin. Despite the aforementioned treatment, his condition continued to deteriorate. The patient was admitted to the intensive care unit. While intubated, he underwent bronchoscopy and lavage, which was analyzed for potential infectious agents. Cytomegalovirus (CMV) pneumonia was diagnosed and treated. He passed away despite antiviral treatment and maximal supportive care. CMV infection should be suspected in patients failing to recover from toxicities of ICIs with appropriate immunosuppression.

Risk-Reducing Mastectomy and Reconstruction Following Prophylactic Breast Irradiation: Hope Sustained.

Risk-reducing mastectomy (RRM) is often advocated for BRCA1/2 mutation carriers who face a heightened lifetime risk of breast cancer. However, many carrier patients seek alternative risk-reducing measures. In a phase II nonrandomized trial, we previously reported that prophylactic irradiation to the contralateral breast among BRCA carriers undergoing breast-conserving treatment significantly reduced subsequent contralateral breast cancer. Herein, we report the outcome of salvage mastectomy and reconstruction in 11 patients that suffered reoccurrences of breast cancer in either the ipsilateral or contralateral breast or elected to have the procedure for risk reduction during the eight-year follow-up period. Patients' satisfaction with the procedure and physicians' assessment of the cosmetic outcome were not inferior for previously irradiated compared to non-irradiated breasts. Although the numbers are small, the results are encouraging and sustain hope in a challenging population. Our findings support continuing research as well as a discussion of risk-reduction alternatives besides mastectomy, including prophylactic breast irradiation, in BRCA1/2 mutation carriers.