tbuckley/cabot-search huggingface dataset:
Randomized controlled phase II trial of simvastatin as prophylaxis against radiation-induced skin toxicity in breast cancer patients.
Authors: Shibu Joseph, Glenys Round, Michael B. Jameson, Jenny May Boyd, Rajan Ragupathy
Journal: Journal of Clinical Oncology (2013)

TPS1143 Background: Most women receiving adjuvant radiation (RT) for breast cancer (BC) have significant acute skin toxicities ranging from erythema to moist desquamation. Late skin toxicities include fibrosis and telangiectasia. The inflammatory response to RT is mediated by RT-induced endothelial cell expression of the cell adhesion molecule E-selectin, to which neutrophils and monocytes adhere and then infiltrate into tissues. Blockade of this mechanism could interrupt the inflammatory cascade at an early stage. Preclinical studies have shown that statins can inhibit RT-induced E-selectin expression and skin and intestinal inflammation in vivo without impairing DNA damage or tumour response to RT. Retrospective clinical studies have shown reduced relapse rates with statins in breast cancer patients. Thus statins have the potential to reduce the acute RT-induced inflammatory component without compromising the DNA-damaging effects essential to cancer cell death. This is the only registered trial evaluating the effects of statins on acute RT toxicity. Methods: Randomised open controlled phase II trial of simvastatin 40mg daily during and for 3 weeks after RT. Eligibility: women with invasive or in-situ BC receiving whole-breast +/- lymphatic RT; dose fractionation schedules include 50Gy/25 #, 45Gy/20#, 42.5Gy/16 # or 40Gy/15#, with or without a boost; may have had prior chemotherapy, and be on hormonal or Trastuzumab therapy during RT; no prior statins within 6 weeks of starting RT. Stratification by breast conserving surgery vs mastectomy, use of boost and fraction size (&lt;2 Gy vs &gt;2 Gy). Primary endpoint: incidence of &gt; grade 2 acute RT-related skin toxicity. Secondary endpoints: time to onset of skin toxicity, proportion requiring additional topical treatment, compliance with trial medication, statin-related toxicities and subjective RT-related toxicities (breast discomfort and fatigue). Statistical design: 130 randomised patients gives 90% power (one-sided a 0.20) to detect a reduction in &gt; grade 2 acute skin toxicity from 55% to 35%. Enrolment opened January 2013, planned to complete by April 2014. Clinical trial information: ACTRN12612000662864.
Antitumor activity of MP0250, a bispecific VEGF- and HGF-targeting darpin, in patient-derived xenograft models.
Authors: Ulrike Fiedler, Michael Tobias Stumpp, Andreas Cornelius, Savira Ekawardhani, Keith Martin Dawson, Pat Gilboy, Ignacio Dolado
Journal: Journal of Clinical Oncology (2014)

11039 Background: The interplay of tumor cells and their microenvironment is crucial in the growth of solid tumors. Key mediators of such interaction are the VEGF/VEGFR and the HGF/cMet pathways, which drive tumor survival, growth, angiogenesis, invasion and metastasis. It is anticipated that simultaneous inhibition of the VEGF/VEGFR and HGF/cMet pathways will interfere with crucial steps of tumor growth as well as with the onset of treatment resistance. MP0250 is a bispecific DARPin targeting both pathways simultaneously by specifically neutralizing VEGF and HGF. Its low toxicity offers the potential for combination with chemotherapy and other targeted therapies. Methods: Antitumor activity of MP0250 was tested in kidney, liver, lung and gastric patient-derived xenograft (PDX) models and compared to standard of care (SoC) therapies. Results: MP0250 showed consistent antitumor activity in 6 out of 7 investigated models. Its potency was superior to SoC in renal and gastric carcinoma models, and similar to SoC in liver and one lung cancer (NSCLC) model. Of note, neither MP0250 nor SoC (5-FU) showed potency in one SCLC lung cancer model. Tumor regression was induced by MP0250 in one liver and one renal model with optimal T/C values of 6.9% and 8.9%. Tumor growth inhibition was recorded in the other liver and one lung model (T/C values of 37% and 26%) whereas moderate efficacy was observed in the second renal cancer model (T/C value of 56%). Interestingly, MP0250 increased the potency of the SoC drug paclitaxel in the gastric cancer model (T/C values: MP0250 37%; paclitaxel 46%, MP0250/paclitaxel 21%). No toxicity of MP0250 was observed as monotherapy or in combination with SoC. Conclusions: MP0250, a bispecific DARPin blocking HGF and VEGF, is a potent inhibitor of tumor growth in PDX models, often surpassing the efficacy of SoC therapy. In a gastric cancer model, MP0250 increased potency of SoC. These results indicate that MP0250 has the potential to be used as monotherapy in a range of solid tumors and, as a result of its good safety profile, the possibility exists that it may be also combined with SoC and other tumor targeting molecules, i.e. TKIs. A phase I clinical trial is in preparation.
A family-based approach to primary prevention of breast cancer
Authors: Olufunmilayo Olopade
Journal: Journal of Clinical Oncology (2009)

s2 We are currently focusing on the interplay of genes and environment in the development of estrogen receptor (ER)-negative breast cancer, which is aggressive, less responsive to treatment, and more likely to strike young women and those of African ancestry. Unfortunately, there are no strategies to prevent ER-negative breast cancer and research is urgently needed. Nevertheless, we have made progress in understanding genetic risk factors for some familial forms of breast cancer, which is reason enough to adopt family-based interventions for breast cancer prevention, especially among families with identifiable highly penetrant mutations in breast cancer susceptibility genes. In 1997, I chaired the ASCO Task Force on Cancer Genetics Education, charged to educate oncologists about the importance of genetics in clinical oncology practice. Since then, a growing body of evidence documents the benefits of preventive measures with minimal risk to women with identifiable highly penetrant mutations in BRCA1 and BRCA2 genes. Whereas other genes, such as TP53 in Li-Fraumeni Syndrome and PTEN in Cowden syndrome, contribute to a small fraction of hereditary breast cancer, mutations in these genes are rare. Germ-line mutations in BRCA1 or BRCA2 are strong predictors of breast and/or ovarian cancer development, and the contribution of these mutations to breast cancer risk within any specific population is a function of both their prevalence and penetrance. Mutation prevalence varies among ethnic groups and may be influenced by founder mutations as observed in Ashkenazi Jews and Icelanders. Although estimates of mutation prevalence and penetrance rates are inconsistent and occasionally controversial, understanding them is critical for providing individualized risk assessment. Although the contribution of other genes to early onset and familial breast cancer needs clarification, genetic testing for BRCA1 and BRCA2 has become standard of care and an important component of personalized breast cancer risk assessment and prevention.
Pulmonary complications and survival after autologous stem cell transplantation: predictive role of pulmonary function and pneumotoxic medications
Authors: Simone Scarlata, Ombretta Annibali, Simona Santangelo, Valeria Tomarchio, Silvia Ferraro, Daniele Armiento, Alessandra Scardocci, William Arcese, Raffaele Antonelli Incalzi, Giuseppe Avvisati
Journal: European Respiratory Journal (2017)

Autologous stem cell transplantation (ASCT) is the standard of care for multiple myeloma patients eligible for high-dose therapy, lymphoma patients undergoing second-line treatments and for acute myelogenous leukaemia (AML) [1]. Immune system impairment and chemotherapies significantly increase the risk of infections, particularly pneumonia [2]. Overall, pulmonary complications, both infectious and non-infectious, occur in 40–60% of patients after stem cell transplantation [3], and are usually classified as early or late onset, depending on whether they occur within 100 days of the transplant [4]. The underlying disease and baseline pulmonary function, along with conditioning regimens consisting of carmustine, etoposide, aracytin and melphalan for lymphoma, melphalan alone for multiple myeloma or busulpan and cyclophosphamide for acute myeloid leukaemia, all concur to cause pulmonary complications [3, 4]. Pneumotoxic agents prior to ASCT associate with worse event/infection free survival and overall mortality <http://ow.ly/1xkL308x3D2>
Predictors of hand-foot syndrome (HFS) in randomised double-blind, placebo-controlled trial of pyridoxine for prevention of capecitabine induced HFS.
Authors: Yoon Sim Yap, Li-Lian Kwok, Raymond C.H. Ng, Nan Soon Wong, Soo Kien Lo, Wen Yee Chay, John Whay Kuang Chia, Chee Kian Tham, Si Li Tan, Vanessa Zuan Yu Mok, Jeffrey King Xin Koh, Marie Loh, Han Chong Toh, Wen Hsin Koo, Richie Chuan Teck Soong, SuPin Choo
Journal: Journal of Clinical Oncology (2015)

9596 Background: Hand-foot syndrome (HFS)is a common side effect of capecitabine, although East Asian patients appear to have better tolerability. Methods: This study aimed to evaluate the incidence of grade ≥ 2 HFS in patients receiving pyridoxine versus placebo (primary objective), compare the time to onset of grade ≥ 2 HFS, and identify biomarkers predictive of HFS, including baseline folate and vitamin B12 levels, plus genetic polymorphisms (secondary objectives). Patients starting capecitabine single-agent chemotherapy for breast, colorectal and other cancers in National Cancer Centre Singapore were randomized to receive concurrent pyridoxine (200mg) or placebo daily for a maximum of 8 cycles of capecitabine, with stratification by gender and use in adjuvant/neoadjuvant versus palliative setting. Patients were withdrawn from the study upon development of grade ≥ 2 HFS or cessation of capecitabine. Results: The trial was terminated before reaching the original target of 296 patients due to slow accrual. Grade ≥ 2 HFS occurred in 33 of 105 patients (31.4%, 95% CI: 22.6% - 40.3%) receiving pyridoxine compared to 39 of 103 patients (37.9%, 95% CI: 28.5% - 47.2%) receiving placebo (p = 0.329). The median starting dose of capecitabine was 1000mg/m2 (range 793-1250 mg/m2) bid in the pyridoxine arm, and 1011mg/m2 (range 845-1250 mg/m2) bid in the placebo arm (p = 0.667). The median time to onset of grade ≥ 2 HFS was not reached in patients on pyridoxine, compared to 174 days in patients on placebo (p = 0.677). On multivariate analysis, baseline serum folate (odds ratio 1.27 for every increase of 5nmol/l; 95% CI: 1.10-1.47; p = .001) was associated with increased risk of grade ≥ 2 HFS. Pyridoxine did not significantly decrease the risk compared to placebo (odds ratio 0.50; 95% CI: 0.24-1.03; p = 0.061). Initial dose intensity and baseline red cell folate were associated with increased risk of grade ≥ 2 HFS on univariate, not multivariate analysis. Genotyping with Zhonghua SNP arrays is in progress. Conclusions: Pyridoxine did not significantly prevent or delay the onset of grade ≥ 2 HFS. Serum folate was a significant predictor of HFS. Clinical trial information: NCT00486213.
Impact of up-to-seven criteria and neutrophil-to-lymphocyte ratio in liver transplantation for patients who received pretreatment for hepatocellular carcinoma.
Authors: Tomoharu Yoshizumi, Toru Ikegami, Shohei Yoshiya, Takashi Motomura, Yohei Mano, Jun Muto, Rumi Matono, Takeo Toshima, Tetsuo Ikeda, Yuji Soejima, Ken Shirabe, Yoshihiko Maehara
Journal: Journal of Clinical Oncology (2012)

e14536 Background: There is currently no consensus on how to manage patients with hepatocellular carcinoma (HCC) while awaiting liver transplantation (LT). The guideline published in UK states that locoregional therapy should be considered for all listed patients with HCC. Living donor LT (LDLT) is a choice for treating HCC patients in organ shortage era. The aim of the present study is to clarify the risk factors of tumor recurrence after LDLT in patients who had received pre-transplant treatments (pre-Tx) for HCC. Methods: One hundred two adult patients (39 females and 63 males) who had undergone LDLT due to end-stage liver disease with recurrent HCC after pre-Tx were enrolled. The primary end-point of this study was HCC recurrence after LDLT. Recurrence-free survival rates after LDLT were calculated. Risk factors of tumor recurrence were identified using univariate and multivariate analysis. Results: The 1-, 3-, and 5-year recurrence-free survival rates were 89.4%, 80.7%, and 78.8%, respectively. Seventy-four of 102 patients underwent pre-Tx more than twice. Moreover, the times of pre-Tx, the interval between the first treatment and LDLT, and the interval between the last treatment and LDLT did not affect the outcome of LDLT. On univariate analysis, the factors affecting recurrence-free survival were exceeding the up-to-seven criteria (p&lt;0.0001), exceeding the Kyushu University criteria (p&lt;0.0001), neutrophil-to-lymphocyte ratio (NLR) &gt; 4 (p=0.0001), Alpha-fetoprotein &gt; 400 ng/ml (p&lt;0.0001), and bilobar tumor distribution (p=0.047). A multivariate analysis identified independent risk factors for post-LDLT tumor recurrence were exceeding the up-to-seven criteria (p=0.001) and NLR &gt; 4 (p=0.002). The 1- and 3-year recurrence-free survival rates in the recipients with exceeding the up-to-seven criteria and NLR &gt; 4 were 30.0% and 15.0%, respectively. Conclusions: The kind or duration of pre-Tx did not affect the outcome of LDLT, but LDLT should not be performed for the patients with exceeding the up-to-seven criteria and NLR more than 4 after pre-Tx for HCC to prevent tumor recurrence.
Mannose receptor modulates macrophage polarization and allergic inflammation through miR-511-3p
Authors: Yufeng Zhou, Danh C. Do, Faoud T. Ishmael, Mario Leonardo Squadrito, Ho Man Tang, Ho Lam Tang, Man-Hsun Hsu, Lipeng Qiu, Changjun Li, Yongqing Zhang, Kevin G. Becker, Mei Wan, Shau-Ku Huang, Peisong Gao
Journal: Journal of Allergy and Clinical Immunology (2017)
<i>Notes from the Field:</i> Obstetric Tetanus in an Unvaccinated Woman After a Home Birth Delivery — Kentucky, 2016
Authors: Anna Q. Yaffee, David L. Day, Glenda Bastin, Mary Powell, Sandra Melendez, Nancy Allen, Julie Miracle, Margaret Jones, Robert Brawley
Journal: MMWR Morbidity and Mortality Weekly Report (2017)
One-dimensional and two-dimensional tumor size measurement for prediction of lymph node metastasis in differentiated early gastric cancer with minute submucosal invasion.
Authors: Tae Jun Kim, Hyuk Lee, Jeunghui Pyo, Yang Won Min, Byung-Hoon Min, Jun Haeng Lee, Jae J. Kim
Journal: Journal of Clinical Oncology (2017)

172 Background: Differentiated minute submucosal cancers ≤ 3 cm that exhibit no lymphovascular invasion are considered eligible for endoscopic resection; however, the ≤ 3 cm criterion remains debatable. The aim of this study was to verify the optimal tumor size cutoff for endoscopic resection eligibility, and to determine whether two-dimensional tumor size measurement would be more accurate for this purpose. Methods: The clinicopathological data of 574 patients undergoing curative surgery for differentiated minute submucosal cancer were reviewed retrospectively. A receiver operating curve analysis and bootstrapped samples were used to identify the optimal cutoff values for predicting lymph node (LN) metastasis. Results: Four hundred fourteen patients were eligible for the study.LN metastasis accompanied 2.5% of differentiated minute submucosal cancers that were ≤ 3 cm in size and lacked lymphovascular invasion. There was no lymph node metastasis in the tumors with 1D sizes ≤ 1.0 cm and 2D sizes ≤ 1.0 cm 2 . Using 10,000 bootstrapped data, optimal cutoff values were 2.9 cm (LN metastasis: 2.1%) and 8.3 cm 2 (LN metastasis: 2.5% incidence) for one- and two-dimensional tumor size, respectively. Although the area under the curve was 0.611 ( P = 0.046) for two-dimensional size, specificity and accuracy were greater for the dichotomized two-dimensional measure than for the dichotomized one-dimensional measure ( P&lt; 0.001, McNemar’s test). In addition, two-dimensional tumor size was the only significant risk factor for LN metastasis (odds ratio 1.09, 95% confidence interval 1.01–1.20). Conclusions: One-and two-dimensional cutoff values of 2.9 cm and 8.3 cm 2 might be suitable for patients at high risk of post-operative morbidity and mortality. Two-dimensional tumor size is an acceptable measurement method for estimating the risk of LN metastasis.
Phase I/Ib study of enzalutamide and gemcitabine and cisplatin in bladder cancer.
Authors: Shilpa Gupta, Mayer N. Fishman, Jasreman Dhillon, Anthony Martin Magliocco, John Puskas, Gisela Caceres, Taymeyah E Al-Toubah, Badrinath R. Konety, Matthew Lindemam, Gautam Gopalji Jha, Jingsong Zhang
Journal: Journal of Clinical Oncology (2017)

338 Background: Metastatic bladder cancer (mBC) is a fatal disease and novel therapies are urgently needed. Preclinical evidence suggests role of AR in BC progression. Enzalutamide (ENZ) is a novel AR antagonist that inhibits nuclear translocation of AR, DNA binding, and co activator recruitment. Our ongoing phase 1 trial is is assessing safety and tolerability of ENZ in combination with gemcitabine and cisplatin (GC) in mBC and explore novel correlatives in tumor tissues and CTCs. Methods: The study has 2 phases, dose escalation phase and dose expansion phase. The dose escalation phase had 2 cohorts testing ENZ at doses of 80 mg and 160 mg respectively with GC (gemcitabine 10000 mg/m2 on days 1 and 8 and cisplatin 70 mg/m2 on day 1 every 21 days). The dose escalation phase allowed both AR + and AR - mBC pts. Patients will be monitored for safety and tolerance with laboratory studies, clinical exam, and CT scans to assess response. Primary objective is safety and tolerability of ENZ and GC. Secondary objectives are objective tumor response, time to progression, and overall survival. Exploratory objectives include qualitative and quantitative evaluation of AR and pAKT expression with AQUA in tumor tissues and correlation with outcomes. CTCs are being evaluated at baseline and cycle 3, including AR expression in CTCs and correlation will be done with tumor AR expression and clinical outcomes. Key eligibility criteria are ECOG PS of 0-1, and no contraindications to study drugs. Results: In the dose expamnsion phase, 3 patients were enrolled in each cohort of 80 mg and 160 mg of ENZ respectively with GC and there were no DLTs or significant AEs related to the combination; the MTD of ENZ is 160 mg. Enrollment on dose expansion phase is ongoing. detectable CTCs were seen in 4/6 BC patients with 2 patients showing AR + CTCs at baseline. Further CTC analysis, including AR expression and tissue analysis for AR and pAKT analysis in tissues is ongoing. (Trial identifier: NCT02300610). Conclusions: This is a first of its kind clinical trial exploring the role of AR signaling in BC and targeting it with ENZ along with GC. The data gathered form this study will help us understand the clinical relevance of targeting AR in BC. Clinical trial information: NCT02300610.
Anti-estrogenic effect of TAS-108 in breast cancer cell lines.
Authors: Hadong Kim, Young Choi, Tae-Hoon Kim
Journal: Journal of Clinical Oncology (2012)

e11029 Background: TAS-108 (TAS) is an antiestrogen that binds to both ERα and ERβ and inhibits both estrogen-dependent and independent tumors and TAM resistant tumors. Breast cancer cell lines (BCC) with different pheno- and genotypes are reasonably acceptable models of in vivo breast cancer cell behavior. Thus, we have investigated anti-estrogenic activity of TAS on BCC in the presence of diarylpropionitrile (DPN), a pure ERβ agonist to find ERβ role in TAS activity. Methods: Cultured cells of (1) MCF-7 and ZR-75 (luminal epithelial cells), (2) BT-474 and SK-BR-3 (weakly luminal epithelial cells), and (3) MDA-MB-231 and Hs578T (invasive, mesenchymal-like cells) were treated with: (1) increasing concentrations of DPN or E2, (2) 100nM of 4-hydroxytamoxifen (4-HT) or TAS, and (3) 100nM of DPN or E2 with increasing concentrations of either 4-HT or TAS. After 6 days, cell proliferation was analyzed. The mRNA levels of ERβ and ERα isoform were determined by RT-qPCR. ERα, PR, and Her-2 status was determined by IHC. Percent proliferation compared to the control was calculated and P &lt;0.05 based on T-test was considered significant. Results: The most significant proliferation and growth inhibition was seen in MCF-7 BCC. In the presence of DPN, IC 50 (50% inhibitory concentration) was 12.5nmol of TAS vs 33.1nmol of 4-HT. In the presence of E2, IC 50 was 2.15 nmol of TAS vs 49.7nmol of 4-HT. Other BCC showed insignificant or variable proliferative and inhibitory response. Overall, DPN displayed high proliferation in most BCC. TAS exhibited higher growth inhibition than 4-HT. Conclusions: Variable responses of different BCC lines to ERα and ERβ agonists and antagonists may be instructive in modeling in vivo breast cancer response to these compounds. Overall, exposure to ERβ agonists showed a significant proliferation in ERα+, ERα- and ERβ+ cells. TAS activity was more pronounced and its anti-estrogen activity may involve ERβ in addition to ERα. [Table: see text]
GPs challenge claim that they fail to take women’s health seriously
Authors: Anne Gulland
Journal: BMJ (2017)

Many women with fibroids and endometriosis are unhappy with their care, a survey of more than 2600 women has found, and many resort to finding out about their condition online.1

A survey by the All Party Parliamentary Group on Women’s Health found that 62% of women were not satisfied with the information they received about treatment options for fibroids and endometriosis, 50% were not told about the short or long term side effects of their treatment, and 42% thought that they were not treated with dignity or respect.

The report also found that 40% of respondents had had to have 10 GP appointments or more before being referred to a specialist, 39% had sought a second opinion, and 67% …