P.C. Mayor

History of hypertension, heart disease, and diabetes and ovarian cancer patient survival: evidence from the ovarian cancer association consortium

PurposeSurvival following ovarian cancer diagnosis is generally low; understanding factors related to prognosis could be important to optimize treatment. The role of previously diagnosed comorbidities and use of medications for those conditions in relation to prognosis for ovarian cancer patients has not been studied extensively, particularly according to histological subtype.MethodsUsing pooled data from fifteen studies participating in the Ovarian Cancer Association Consortium, we examined the associations between history of hypertension, heart disease, diabetes, and medications taken for these conditions and overall survival (OS) and progression-free survival (PFS) among patients diagnosed with invasive epithelial ovarian carcinoma. We used Cox proportional hazards regression models adjusted for age and stage to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) overall and within strata of histological subtypes.ResultsHistory of diabetes was associated with increased risk of mortality (n = 7,674; HR = 1.12; 95% CI = 1.01–1.25). No significant mortality associations were observed for hypertension (n = 6,482; HR = 0.95; 95% CI = 0.88–1.02) or heart disease (n = 4,252; HR = 1.05; 95% CI = 0.87–1.27). No association of these comorbidities was found with PFS in the overall study population. However, among patients with endometrioid tumors, hypertension was associated with lower risk of progression (n = 339, HR = 0.54; 95% CI = 0.35–0.84). Comorbidity was not associated with OS or PFS for any of the other histological subtypes. Ever use of beta blockers, oral antidiabetic medications, and insulin was associated with increased mortality, HR = 1.20; 95% CI = 1.03–1.40, HR = 1.28; 95% CI = 1.05–1.55, and HR = 1.63; 95% CI = 1.20–2.20, respectively. Ever use of diuretics was inversely associated with mortality, HR = 0.71; 95% CI = 0.53–0.94.ConclusionsHistories of hypertension, diabetes, and use of diuretics, beta blockers, insulin, and oral antidiabetic medications may influence the survival of ovarian cancer patients. Understanding mechanisms for these observations could provide insight regarding treatment.

Cancer in primary immunodeficiency diseases: Cancer incidence in the United States Immune Deficiency Network Registry

Background: We evaluated the overall and site‐specific incidence of cancer in subjects with primary immunodeficiency diseases (PIDD) enrolled in the United States Immune Deficiency Network (USIDNET) registry compared with age‐adjusted cancer incidence in the Surveillance, Epidemiology and End Results Program (SEER) database. Objective: We hypothesized that subjects with PIDD would have an increased incidence of cancer due to impaired immune function. Methods: Overall and site‐specific cancer incidence rates were evaluated in subjects with PIDD (n = 3658) enrolled in the USIDNET registry from 2003 to 2015 and compared with age‐adjusted incidence rates in the SEER database. Results: We observed a 1.42‐fold excess relative risk of cancer in subjects with PIDD compared with the age‐adjusted SEER population (P < .001). Men with PIDD had a 1.91‐fold excess relative risk of cancer compared with the age‐adjusted male population (P < .001), while women with PIDD had similar overall cancer rates compared with the age‐adjusted female population. Of the 4 most common malignancies in men and women in SEER (lung, colon, breast, and prostate cancers), we found no significant increase in these diagnoses in subjects with PIDD. Significant increases in lymphoma in both men (10‐fold increase, P < .001) and women (8.34‐fold increase, P < .001) with PIDD were observed. Conclusions: Excess incidence of cancer occurred in subjects with PIDD. An excess of lymphoma in specific PIDD populations principally drove this increased incidence, while no increased risk of the most common solid tumor malignancies was observed. These data point to a restricted role of the immune system in protecting from specific cancers.

Photodynamic Therapy in Gynecologic Malignancies: A Review of the Roswell Park Cancer Institute Experience.

Photodynamic therapy (PDT) is a treatment modality used in the management of solid tumor malignancies that employs the use of a photosensitizing agent, a light source and oxygen in order to illicit a direct cytotoxic effect. Its use in gynecologic malignancies is somewhat novel and has been used for palliative and curative intent. At the Roswell Park Cancer Institute, the use of PDT in the management of gynecologic cancers began in the mid 1980s and since that time 35 patients have received PDT as a treatment for recurrent or metastatic cutaneous and vulvar, vaginal, anal, and cervical recurrences. In our experience, 85% patients with metastatic cutaneous lesions had a complete response. Twenty-seven percent of patients with metastatic vaginal, cervical or anal recurrences had a complete response to therapy with a median response time of 28 months. Side effects from the treatment included moderate to severe burning sensation, pain and edema at the treatment site requiring narcotic pain medication for symptom management in patients who underwent treatment to cutaneous lesions as well as lower genital tract recurrences. PDT should be considered an option in patients who are too frail to undergo the standard of care or decline the standard of care in lieu of a less invasive treatment modality.

Effect of butyrate and Lactobacillus GG on a butyrate receptor and transporter during Campylobacter jejuni exposure

Abstract Campylobacter jejuni frequently infects humans causing many gastrointestinal symptoms, fever, fatigue and several long‐term debilitating diseases. Current treatment for campylobacteriosis includes rehydration and in some cases, antibiotic therapy. Probiotics are used to treat several gastrointestinal diseases. Butyrate is a short‐chain fatty acid known to promote intestinal health. Interaction of butyrate with its respective receptor (HCAR2) and transporter (SLC5A8), both expressed in the intestine, is associated with water and electrolyte absorption as well as providing defense against colon cancer and inflammation. Alterations in gut microbiota influence the presence of HCAR2 and SLC5A8 in the intestine. We hypothesized that adherence and/or invasion of C. jejuni and alterations in HCAR2 and SLC5A8 expression would be minimized with butyrate or Lactobacillus GG (LGG) pretreatment of Caco‐2 cells. We found that both C. jejuni adhesion but not invasion was reduced with butyrate pretreatment. While LGG pretreatment did not prevent C. jejuni adhesion, it did result in reduced invasion which was associated with altered cell supernate pH. Both butyrate and LGG protected HCAR2 and SLC5A8 protein expression following C. jejuni infection. These results suggest that the first stages of C. jejuni infection of Caco‐2 cells may be minimized by LGG and butyrate pretreatment.

History of thyroid disease and survival of ovarian cancer patients: results from the Ovarian Cancer Association Consortium, a brief report

Background:Findings from in vitro studies suggest that increased exposure to thyroid hormones can influence progression of ovarian tumours. However, epidemiologic evidence on this topic is limited.Methods:We pooled data from 11 studies from the Ovarian Cancer Association Consortium. Using multivariate Cox proportional hazards models, we estimated associations between hyper- and hypothyroidism and medications prescribed for these conditions with 5-year all-cause survival among women diagnosed with invasive ovarian cancer.Results:Overall, there was a nonsignificant association with history of hyperthyroidism (n=160 cases) and mortality (HR=1.22; 95% CI=0.97–1.53). Furthermore, diagnosis of hyperthyroidism within the 5 years before ovarian cancer diagnosis was associated with an increased risk of death (HR=1.94; 95% CI=1.19–3.18). A more modest association was observed with history of hypothyroidism (n=624 cases) and mortality (HR=1.16; 95% CI=1.03–1.31). Neither duration of hypothyroidism nor use of thyroid medications was associated with survival.Conclusions:In this large study of women with ovarian cancer, we found that recent history of hyperthyroidism and overall history of hypothyroidism were associated with worse 5-year survival.

Impact of Physical Inactivity on Risk of Developing Cancer of the Uterine Cervix: A Case-Control Study.

Objective In this study, we investigated whether physical inactivity was associated with risk of cervical cancer in women treated at an American cancer hospital. Methods This case-control study included 128 patients with cervical cancer and 512 controls matched on age. Controls were women suspected of having but not ultimately diagnosed with a neoplasm. Physical inactivity was defined in accordance with the 2008 Physical Activity Guidelines for Americans. Thus, participants reporting, on average, no moderate or vigorous recreational physical activity were classified as inactive. Unconditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Results Compared with noncancer controls, those with cervical cancer had significantly increased odds of reporting abstinence from recreational physical activity (OR, 2.43; 95% CI, 1.56–3.80). No association was noted between occupational-related physical inactivity and cervical cancer (OR, 0.88; 95% CI, 0.58–1.36). Conclusions Our findings suggest that abstinence from regular recreational physical activity is associated with increased odds of cervical cancer. To our knowledge, this is the first US-based study examining these associations. Given the 2008 Physical Activity Guidelines for Americans, this study has identified yet another potential public health benefit to regular physical activity. Further investigation is needed using a larger sample and prospectively collected data to characterize dose of activity to mitigate risk and the optimal window of susceptibility.

Adoptive cell transfer using autologous tumor infiltrating lymphocytes in gynecologic malignancies

During the last decade, the field of cancer immunotherapy has been entirely transformed by the development of new and more effective treatment modalities with impressive response rates and the prospect of long survival. One of the major breakthroughs is adoptive cell transfer (ACT) based on autologous T cells derived from tumor-infiltrating lymphocytes (TILs). TIL-based ACT is a highly personalized cancer treatment. T cells are harvested from autologous fresh tumor tissues, and after ex vivo activation and extensive expansion, are reinfused to patients. TIL-based therapies have only been offered in small phase I/II studies in a few centers given the highly specialized care required, the complexity of TIL production and the very intensive nature of the three-step treatment protocol. The treatment includes high-dose lymphodepleting chemotherapy, the infusion of the expanded and activated T cells and interleukin-2 (IL-2) injections to increase survival of the T cells. Despite the limited data on ACT, the small published studies consistently confirm an impressive clinical response rate of up to 50% in metastatic melanoma patients, including a significant proportion of patients with durable complete response. These remarkable results justify the need for larger clinical trials in other solid tumors, including gynecologic malignancies. In this review we provide an overview of the current clinical results, future applications of TIL-based ACT in gynecologic malignancies, and on risks and challenges associated with modern T cell therapy.

BRCA1 reversion mutation acquired after treatment identified by liquid biopsy

Highlights • Secondary, reversion mutations in BRCA genes can restore protein function.• Reversion mutations can underlie resistance to therapies such as PARP inhibitors.• Reversion mutations arise during the course of treatment.

Impact of ascites volume on clinical outcomes in ovarian cancer: A cohort study

OBJECTIVES To investigate the impact of ascites volume on ovarian cancer outcomes. METHODS Clinicopathologic features of a cohort of patients with ovarian cancer were obtained from a curated database at a single institution. Progression free survival (PFS) and overall survival (OS) were recorded. Ascites volume at primary surgery was dichotomized at 2000mL and comparisons for high and low volume ascites were made. Additionally, to elucidate interactions between ascites and ovarian tumor progression, we evaluated the effect of intraperitoneal administrations of murine cell-free ascites versus saline in a syngeneic mouse model of epithelial ovarian cancer. RESULTS Out of 685 patients identified, 58% had ascites present at the time of initial surgery. Considering the volume of ascites continuously, each liter of ascites was associated with shorter PFS (HR=1.12, 95% CI: 1.07-1.17) and OS (HR=1.12, 95%CI: 1.07-1.17). Patients with ascites greater than the median of 2000mL had significantly shorter PFS (14.5months vs. 22.7months; p<0.001) and OS (27.7months vs. 42.9months; p<0.001). After adjusting for stage, presence of ascites was inversely associated with ability to achieve optimal cytoreductive surgery. Consistent with these correlative results in patients, intraperitoneal administrations of murine cell-free ascites accelerated ovarian cancer progression in mice. CONCLUSIONS The volume of ascites at initial diagnosis of ovarian cancer correlated with worse PFS and OS. The effect of large volume on prognosis is likely to be in part related to reduced likelihood for complete resection of tumor (R0). If these findings are confirmed in independent studies, consideration should be made to add the presence of large volume ascites at diagnosis to the staging criteria for ovarian cancer.

No evidence that genetic variation in the myeloid-derived suppressor cell pathway influences ovarian cancer survival

Background: The precise mechanism by which the immune system is adversely affected in cancer patients remains poorly understood, but the accumulation of immunosuppressive/protumorigenic myeloid-derived suppressor cells (MDSCs) is thought to be a prominent mechanism contributing to immunologic tolerance of malignant cells in epithelial ovarian cancer (EOC). To this end, we hypothesized genetic variation in MDSC pathway genes would be associated with survival after EOC diagnoses. Methods: We measured the hazard of death due to EOC within 10 years of diagnosis, overall and by invasive subtype, attributable to SNPs in 24 genes relevant in the MDSC pathway in 10,751 women diagnosed with invasive EOC. Versatile Gene-based Association Study and the admixture likelihood method were used to test gene and pathway associations with survival. Results: We did not identify individual SNPs that were significantly associated with survival after correction for multiple testing (P < 3.5 × 10−5), nor did we identify significant associations between the MDSC pathway overall, or the 24 individual genes and EOC survival. Conclusions: In this well-powered analysis, we observed no evidence that inherited variations in MDSC-associated SNPs, individual genes, or the collective genetic pathway contributed to EOC survival outcomes. Impact: Common inherited variation in genes relevant to MDSCs was not associated with survival in women diagnosed with invasive EOC. Cancer Epidemiol Biomarkers Prev; 26(3); 420–4. ©2016 AACR.