tbuckley/cabot-search huggingface dataset:
Impact of body composition parameters on clinical outcomes in patients with metastatic castration-resistant prostate cancer treated with docetaxel
Authors: Derek Gerard Power, Samantha Cushen, Ray McDermott, Marvin Chang Jui Lim, Peter Mceneaney, Louise Daly, Brendan Griffin, Kevin P Murphy, Aoife M Ryan
Journal: Journal of Clinical Oncology (2015)

e16121 Background: Patients (pts) with loss of fat free mass (FFM) are prone to dose limiting toxicity (DLT) during chemotherapy. We investigated if body composition, by computed tomography (CT) predicted DLT from docetaxel chemotherapy in patients with metastatic castrate resistant prostate cancer (mCRPC). Methods: Pts with mCRPC, who were treated with ADT and docetaxel were included. Skeletal muscle cross-sectional area at L3 was measured by CT. Sarcopenia was defined using published cut offs. Toxicity profile was assessed after 3 cycles of the drug and graded according to the National Cancer Institute Common Toxicity Criteria (version 3). Results: 63 pts, mean age 69y (SD 8.3), were included. In total, 76.2% of pts were overweight or obese (BMI > 25kg/m2). Sarcopenia was present in 71.4% (n = 45) and of these 31 (68.8%) were both sarcopenic and overweight or obese. Common toxicities observed included fatigue (69.8%) pain (39.7%), neurosensory (28.6%). Neutropenia and neurosensory toxicities were significantly more frequent in sarcopenic patients than in non-sarcopenic pts (16.7% vs. 0% P = 0.012; 32.1% vs. 11.8% P = 0.011). Overall, patients with a SMI < 25th centile received less treatment compared to patients with a SMI > 75th centile (88 days vs. 154 days, P = 0.055). Analysing the drug dose according to FFM, 33.3% of patients receiving a dose > 75th centile (mg/FFM) experienced neutropenia in the first 3 cycles vs 0% receiving a dose < 25th centile (P = 0.017). On multivariate analysis, BMI was predictive of survival, with the heaviest patients showing the longest survival (BMI < 25 HR:2.02 [95% CI:1.03 -3.98] P = 0.042). Conclusions: Sarcopenia is highly prevalent in patients with CRPC receiving docetaxel (71%) but is masked by excessive adiposity. Very low skeletal muscle mass is associated with less treatment days and increased neurological and haematological toxicities. High BMI is associated with longer survival.
Phase II trial of the phosphatidyinositol-3 kinase (PI3K) inhibitor BKM120 in recurrent glioblastoma (GBM).
Authors: Patrick Y. Wen, W. K. Alfred Yung, Ingo K. Mellinghoff, Kathleen Lamborn, Shakti Ramkissoon, Timothy Francis Cloughesy, Mikael Rinne, Antonio Marcilio Padula Omuro, Lisa Marie DeAngelis, Mark R. Gilbert, Andrew S. Chi, Tracy Batchelor, Howard Colman, Susan Marina Chang, Cristian Massacesi, Emmanuelle DiTomaso, Michael Prados, David A. Reardon, Keith L. Ligon
Journal: Journal of Clinical Oncology (2013)

2015 Background: The PI3K pathway is activated in most GBMs and represents a potential therapeutic target. BKM120 is an oral, pan-Class I PI3K inhibitor that enters the brain at therapeutic concentrations demonstrated to inhibit PI3K pathway, and potently inhibits the growth of U87 GBM tumors and human glioma tumor spheres in vitro and in vivo. Methods: The Ivy Foundation Early Phase Clinical Trials Consortium is conducting a phase II study of BKM120 in recurrent GBM patients with activation of the PI3K pathway (mutation, homozygous deletion or loss of IHC of PTEN, PIK3CA or PIK3RI mutations, or detectable pAKT). Additional eligibility criteria included radiologic progression, 1 st or 2nd relapse, &gt; 18 yrs, KPS &gt; 60, adequate bone marrow and organ function, controlled blood glucose, and no enzyme-inducing antiepileptic drugs. Patients received BKM120 100mg daily. The study consisted of 2 parts conducted concurrently. Part 1 involved up to 15 patients who received BKM120 daily for 8-12 days prior to surgery for recurrent disease. Patients underwent FDG PET, pharmacokinetic (PK) studies, and tumor was obtained for drug concentrations and pharmacodynamic effects. Part 2 consisted of up to 50 patients with unresectable GBM treated with BKM120. The primary endpoint for Part 2 was 6-month progression-free survival (p0 =15%; p1= 32%). Results: To date 7 patients have been enrolled into Part 1, 33 into part 2. There were 5 women and 35 men. Median age was 54 yrs (29-68). Treatment was fairly well-tolerated. Major grades 3/4 toxicities were asymptomatic lipase elevation (5), fatigue (3), hyperglycemia (3), rash (3) elevated AST (1), and depression (1). Analysis of tumor from Part 1 showed reduction of pAkt by IHC. Genotyping of tumor specimens is ongoing. To date 33 patients had positive pAkt, 21 had PTEN loss by IHC. Of the first 19 patients who underwent whole exome sequencing, 3 had PIK3Ca mutations and 6 had PTEN mutations. Conclusions: BKM120 is generally well tolerated in patients with recurrent GBM and achieves adequate tumor concentration to inhibit pAkt. Updated PK and efficacy data and correlation of the latter with tumor genotype will be presented. Clinical trial information: NCT01339052.
Survival of de novo and secondary acute promyelocytic leukemia: A propensity matched analysis of the Surveillance, Epidemiology and End Results database.
Authors: Ranjan Pathak, Smith Giri, Michael Gary Martin, Vijaya Raj Bhatt
Journal: Journal of Clinical Oncology (2015)

7046 Background: Secondary acute promyelocytic leukemia (sAPL) is an uncommon entity with no prior large population-based studies. It is unclear whether there is any difference in the overall survival (OS) of sAPL and de novo APL. Methods: We used the Surveillance, Epidemiology, and End Results (SEER) 13 database and appropriate International Classification of Disease (ICD-O-3) histology codes to identify adult patients with sAPL and de novo APL diagnosed between 1992 and 2011. Propensity matching was performed using the MatchIt package of R v2.15.2 to create a matched dataset of sAPL and de novoAPL. Kaplan Meier survival and multivariate analysis (Cox proportional hazard regression model) was performed using SPSS v22.0. Results: sAPL (n = 109) accounted for 5.5% of all APL cases (n = 1964). Crude incidence of sAPL was 0.85 per 10,000 primary malignancies. Patients with sAPL, compared to de novo APL, were more likely to be older (65 vs. 44 years, p < 0.001), White (85% vs. 79%, p = 0.003) and diagnosed after year 2005 (53% vs. 40%, p = 0.008). The two subgroups did not differ by gender (p = 0.665) and marital status (p = 0.745). Mortality rate within 1 month of diagnosis was similar between sAPL and de novo APL (28.9% vs. 23.0%, p = 0.20). One-year (55% vs. 57%, p = 0.70), two-year (51% vs. 54%, p = 0.79) and five-year (42% vs. 50%, p = 0.24) OS rates were similar. In a multivariate analysis, sAPL was not associated with a significantly worsened OS as compared to de novoAPL (HR 1.11; 95% CI 0.78-1.58; p = 0.546). OS was worse with older age at diagnosis but better in more recent years. Compared to patients < 55 years, patients 55-70 years (HR 1.86, 95% CI 1.02-3.41, p = 0.043) and > 70 years (HR 4.64, 95% CI 2.54-8.46, p < 0.001) were more likely to have worse OS. Compared to patients diagnosed before 1995, OS was better among patients diagnosed in the recent years (HR after 2005, 0.37, 95% CI 0.17-0.80, p = 0.012). Conclusions: This is the largest population-based study utilizing propensity matched analysis that demonstrates similar OS in sAPL and de novo APL. This indicates that the patients with sAPL can be managed very similarly to de novo APL and do not need to be excluded from clinical trials of APL.
Thioguanine Combined with Decitabine Can Overcome Resistance to Hypomethylating Agents: Final Results of a Phase I Trial of a Pharmacodynamically-Conceived Thioguanine/Decitabine Combination in Patients with Advanced Myeloid Malignancies
Authors: Daniel J. Lee, Todd L. Rosenblat, Mark Lawrence Heaney, Joseph G. Jurcic, Azra Raza, Kristina Gazivoda, Katherine Harwood, Ryan Shelton, Hakim Djaballah, Joseph M. Scandura, Anthony Letai, Mark G. Frattini
Journal: Blood (2016)
A phase I trial of the farnesyl transferase inhibitor tipifarnib plus doxorubicin-cyclophosphamide in patients with metastatic breast cancer
Authors: J. A. Sparano, U. Hopkins, S. Moulder, L. Vahdat
Journal: Journal of Clinical Oncology (2004)

676 Background: Tipifarnib is an orally administered farnesyltransferase inhibitor (FTI) that is active in metastatic breast cancer (J Clin Oncol 21; 2492–2499, 2003). The purpose of this phase I trial was to determine the feasability of combining tipifarnib with doxorubicin and cyclophosphamide in patients with metastatic breast cancer (MBC); the intent was to identify a suitable regimen for subsequent study in locally advanced breast cancer (LABC). Methods: Eligible patients with MBC received tipifarnib plus standard AC chemotherapy (doxorubicin [60 mg/m2] and cyclophosphamide [600 mg/m2]) given every 3 weeks, or every 2 weeks in conjunction with granulocyte-colony stimulating factor (G-CSF), in cohorts of 3–6 patients per dose level. Dose-limiting toxicty (DLT) was defined as cycle 1 grade 3–4 febrile neutropenia, thrombocytopenia, or non-hematologic toxicity. Patients received a maximum of 4 cycles of therapy. Results: After accrual of 2 patients to the every 3 week schedule without G-CSF, the protocol was modified to a 2 week schedule with G-CSF because of evidence for a superior outcome for dose-dense therapy in operable breast cancer (J Clin Oncol 21: 1431–1439, 2003). The recommended phase II dose (RPTD) of tipifarnib was 200 mg BID on days 1–7 when combined with AC plus G-CSF given every 2 weeks. Febrile neutropenia was dose-limiting at 300 mg BID for 7 days. Objective response occurred in 8 of 9 evaluable patients. Conclusions: The RPTD of tipifarnib is 200 mg PO BID for 7 days on days 1–7 when given with standard dose-dense AC plus G-CSF. This regimen is now being evaluated in patients with LABC. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Johnson & Johnson
Outcomes of male breast cancer in the United States: A SEER database analysis from 1973 to 2008.
Authors: Akm Mosharraf Hossain, Ravi Kiran Bobba, Carl G. Kardinal, Carl Freter
Journal: Journal of Clinical Oncology (2012)

1586 Background: Male breast cancer (MBC) is rare compared to female breast cancer (FBC). There has been no systemic study to examine the epidemiology of MBC in USA in the past decade. Methods: We examined 6,157 cases of MBC reported in SEER database from 1973-2008 (released 2011). We performed rate, frequency and survival sessions to examine age, sex, stage, grade, treatment modalities and survival using the SEER*Stat Software 7.0.5. These variables were compared with that of 877,885 FBC cases reported in SEER 1973-2008. Results: The incidence rate was 1.3 (MBC) and 124 (FBC) per 100,000, respectively. Median age of diagnosis was higher in MBC compared to FBC (72 vs. 61 yrs. P&lt;0.001). 18% of MBC were seen at age less than 60 years compared to 32% in FBC (p&lt;0.001). FBC tend to be more hormone receptor positive (74% vs. 61%; p&lt;0.001). There were 5,145 Caucasians (WH), 701 African Americans (AA), 258 Hispanics and 42 Asian patients. Stage III and IV, Grade III and IV histologies were more common in MBC. Staging and Grading did not differ among the different ethnicities except for Grade IV histology in AA 19%, Asians 20% when compared to WH 13% (p&lt;0.001). Treatment modalities included, surgery (MBC 78% vs. FBC 93%; p&lt;0.001), chemotherapy (MBC 82% vs. FBC 43%; p&lt;0.001) and radiation therapy (MBC 19% vs. 36% FBC; p&lt;0.001). Treatment modalities were similar among WH and AA. Survival was higher in FBC compared to MBC (table) but improved over time in MBC. AA and Asians had lower 1-5 year survival compared to WH. Conclusions: MBC presents at a later age, higher stage and grade, predominantly requiring chemotherapy with an overall poor survival compared to FBC. But 1-5 year survival improved over time in MBC. This can be explained by early diagnosis, better treatment and other factors. Further studies should be performed in this regard. [Table: see text]
Potential use of Pain Vision as an objective method to evaluate chemotherapy-induced peripheral neuropathy.
Authors: Yuko Tanabe, Chikako Shimizu, Akihiro Hirakawa, Eriko Nara, Emi Noguchi, Makoto Kodaira, Harukaze Yamamoto, Mayu Yunokawa, Kan Yonemori, Kenji Tamura, Yasuhiro Fujiwara
Journal: Journal of Clinical Oncology (2013)

e20557 Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting adverse event, but no objective method exists to evaluate CIPN in an easy-to-use and reproducible manner. Pain Vision (PS-2100; Nipro Co., Osaka, Japan) (PV) was developed to quantitatively evaluate peripheral neuropathy using minimum threshold electric current (mTEC) by painless stimulus. PV has been reported useful in evaluating diabetic neuropathy and neuropathic pain induced by other causes. We investigated the usefulness of PV as an objective method to evaluate CIPN. Methods: Breast and ovarian cancer patients, who were intended to receive adjuvant chemotherapy including paclitaxel (PTX), were enrolled in a clinical study to explore SNPs related to CIPN (UMIN000005294). CIPN was prospectively evaluated at baseline, mid-treatment after receiving a total PTX dosage of 480mg/m 2 and three weeks following treatment completion using NCI-CTC (v4), FACT-Neurotaxane (FACT-Ntx) and mTEC as measured by PV. Correlations between changes of mTEC readings and NCI-CTC or FACT-Ntx were analyzed using generalized estimating equations. Results: Ninety-four women were enrolled in this study between April 2011 and December 2012, 15 patients had not reached the post-treatment evaluation point at time of this analysis. Median age was 50 years (range, 27-78) and the incidence of CIPN was 99%. No patient had CIPN at baseline. Mid-treatment and post-treatment CIPN grades were 0/1/2/3=9/70/15/0 and 3/41/30/5 using NCI-CTC while median mTEC readings at baseline, mid-treatment and post-treatment points were 7.8 (4.9-19.9), 8.6 (5.1-17.8) and 9.7 (5.3-22.4)μA, respectively. In baseline and post-treatment comparisons, median mTEC reading changes were significantly correlated with every NCI-CTC grade (median mTEC changes for grades 1/2/3=0.39/0.36/0.64; p=0.003/0.019/0.004) and FACT-Ntx questionnaire item nine, “I have trouble feeling the shape of small objects when they are in my hand” (median mTEC change of 0.14; p=0.049). Conclusions: PV may be potentially useful as an objective method to evaluate CIPN, in particular sensory dominant CIPN, but further study is necessary. Clinical trial information: 000005294.
A randomized phase II/III study of naptumomab estafenatox plus IFN-α versus IFN-α in advanced renal cell carcinoma.
Authors: Robert E. Hawkins, Martin Eric Gore, Yaroslav Shparyk, Vladimir Bondar, Oleg Gladkov, Tosho Ganev, Mihai Harza, Serhii Polenkov, Igor Bondarenko, Petr A Karlov, Oleg Karyakin, Rustem Khasanov, Gunnar Eric Hedlund, Goran Forsberg, Orjan Nordle, Tim Eisen
Journal: Journal of Clinical Oncology (2013)

3073 Background: Naptumomab estafenatox/ANYARA (Nap) is a fusion protein of an antibody (5T4) and a superantigen (SEA/E-120). After phase I studies (Borghaei. J Clin Oncol. 2009, 27:4116) a prospective, randomized phase II/III trial of Nap + IFN-α (A) vs IFN-α (I) was conducted. Methods: Patients (pts) with RCC were randomized in an open label study to receive A or I. The primary endpoint was OS. Secondary endpoints were PFS, response rate and safety. Baseline (bl) plasma IL-6 was predictive of pazopanib (Tran. Lancet Oncol. 2012, 13:827) and MVA-5T4 vaccine (Harrop. Cancer Immunol Immunother. 2012, 61:2283) benefit in RCC pts. IL-6 and anti-SEA/E-120 antibodies (a-S) were analyzed. A subgroup SG1 had bl levels below median for IL-6 (&lt;7 pg/ml) and a-S. Another subgroup SG2 had IL-6 below 13 pg/ml (Tran. Lancet Oncol. 2012, 13:827) and excluding upper quartile of a-S according to phase 1 levels (Borghaei. J Clin Oncol. 2009, 27:4116). Results: From 5/2007 to 10/2010 513 pts were treated (ITT) with a median follow-up time for censored pts of 43 months. Unexpectedly, pts in certain territories had increased bl a-S (median of 61 pmol/ml in Russia vs 34 in UK). The table summarizes efficacy results. The primary endpoint was not met. Multivariate analysis adjusted for risk scores and subsequent TKI usage verified Nap benefit in pts with low IL-6 and normal a-S. Nap was well tolerated. Pyrexia (A:46%/I:18%), nausea (21%/11%), back pain (18%/6%), vomiting (16%/7%) and chills (12%/4%) were more common after Nap. Conclusions: The study did not meet primary endpoint. In pts with low IL-6 and normal levels of a-S, addition of Nap to IFN-α improves OS and PFS. The results warrant further studies with Nap in sequence or combo with e.g. TKIs in this subgroup. More generally, as bl IL-6 appears to be prognostic and predictive of outcome on treatment with TKIs and immunotherapies this may be a stratification factor for RCC studies. Clinical trial information: NCT00420888. [Table: see text]
Perioperative epirubicin, oxaliplatin, and capectabine (EOX) in locally advanced resectable gastroesophageal junction and gastric adenocarcinoma.
Authors: Roshni Deepa Kalachand, Anne-Marie Mongan, Mark Doherty, Sinead King, Niamh O'Farrell, John Vincent Reynolds, Kenneth John O'Byrne
Journal: Journal of Clinical Oncology (2013)

e15142 Background: Perioperative chemotherapy with epirubicin, cisplatin and fluorouracil (ECF) confers a 13% absolute 5-year survival benefit over surgery alone in resectable gastroesophageal cancer. In the metastatic setting, the EOX regimen is at least as effective as ECF, with a favourable toxicity profile. This retrospective analysis presents the experience of a high-volume tertiary referral center with perioperative EOX in patients with resectable GEJ and gastric adenocarcinoma. Methods: Patients with cTxN+/cT3N0 gastroesophageal adenocarcinoma treated between 2006-2012 with perioperative EOX (epirubicin 50mg/m2 d1 q22d, oxaliplatin 130mg/m2 d1 q22d and capecitabine 625 mg/m2 bd d1-21 q22d), given as three neoadjuvant and three adjuvant cycles, were retrospectively identified from a prospectively recorded upper gastrointestinal cancer database. Efficacy and toxicity data were assessed. Results: 52 patients, including 41 (82%) males, with a median age of 62 (range 35-79) received perioperative EOX with curative intent. GEJ tumours represented 39 (75%) of cases, and the others were gastric cancers. 47 patients (90%) completed 3 cycles of neoadjuvant EOX. One patient died of non-neutropenic sepsis after cycle 2. 44 (85%) of patients progressed to surgery, 5 of whom were deemed unresectable. 28 (71%) surgeries were D2 resections, and the R0 resection rate was 67%. There was one postoperative death, due to pancreatitis. 28 (54%) of patients commenced adjuvant EOX, and 25 (48%) completed the planned treatment. Grade 3-4 toxicities were observed in 17% of patients, with the commonest being fatigue (8%) and nausea (4%). Pathological response rate, as defined by Mandard Tumour Regression Grade 1-3, was seen in 26%, with 3 (6%) pathological complete response. The median progression-free survival was 7 months, with a median overall survival of 22 months, and a 2-year survival rate of 45%. Conclusions: In our institution, perioperative EOX in gastroesophageal cancer is associated with a reasonable safety profile, and efficacy consistent with that reported in the MAGIC trial.
Association Between Spousal Suicide and Mental, Physical, and Social Health Outcomes
Authors: Annette Erlangsen, Bo Runeson, James M. Bolton, Holly C. Wilcox, Julie L Forman, Jesper Krogh, M. Katherine Shear, Merete Nordentoft, Yeates Conwell
Journal: JAMA Psychiatry (2017)

<h3>Importance</h3> Bereavement after spousal suicide has been linked to mental disorders; however, a comprehensive assessment of the effect of spousal suicide is needed. <h3>Objective</h3> To determine whether bereavement after spousal suicide was linked to an excessive risk of mental, physical, and social health outcomes when compared with the general population and spouses bereaved by other manners. <h3>Design, Setting, and Participants</h3> This nationwide, register-based cohort study conducted in Denmark of 6.7 million individuals aged 18 years and older from 1980 to 2014 covered more than 136 million person-years and compared people bereaved by spousal suicide with the general population and people bereaved by other manners of death. Incidence rate ratios were calculated using Poisson regressions while adjusting for sociodemographic characteristics and the presence of mental and physical disorders. <h3>Main Outcomes and Measures</h3> Mental disorders (any disorder, mood, posttraumatic stress disorder, anxiety, alcohol use disorders, drug use disorders, and self-harm); physical disorders (cancers, diabetes, sleep disorder, cardiovascular diseases, chronic lower respiratory tract diseases, liver cirrhosis, and spinal disc herniation); causes of mortality (all-cause, natural, unintentional, suicide, and homicide); social health outcomes; and health care use. <h3>Results</h3> The total study population included 3 491 939 men, 4814 of whom were bereaved by spousal suicide, and 3 514 959 women, 10 793 of whom were bereaved by spousal suicide. Spouses bereaved by a partner's suicide had higher risks of developing mental disorders within 5 years of the loss (men: incidence rate ratio, 1.8; 95% CI, 1.6-2.0; women: incidence rate ratio, 1.7; 95% CI, 1.6-1.8) than the general population. Elevated risks for developing physical disorders, such as cirrhosis and sleep disorders, were also noted as well as the use of more municipal support, sick leave benefits, and disability pension funds than the general population. Compared with spouses bereaved by other manners of death, those bereaved by suicide had higher risks for developing mental disorders (men: incidence rate ratio, 1.7; 95% CI, 1.5-1.9; women: incidence rate ratio, 2.0; 95% CI, 1.9-2.2), suicidal behaviors, mortality, and municipal support. Additionally, a higher level of mental health care use was noted. <h3>Conclusions and Relevance</h3> Exposure to suicide is stressful and affects the bereaved spouse on a broad range of outcomes. The excess risks of mental, physical, and social health outcomes highlight a need for more support directed toward spouses bereaved by suicide.
Autosomal Recessive Cardiomyopathy Presenting as Acute Myocarditis
Authors: Serkan Belkaya, Amy R. Kontorovich, Minji Byun, Sonia Mulero-Navarro, Fanny Bajolle, Aurelie Cobat, Rebecca Josowitz, Yuval Itan, Raphaelle Quint, Lazaro Lorenzo, Soraya Boucherit, Cecile Stoven, Sylvie Di Filippo, Laurent Abel, Shen-Ying Zhang, Damien Bonnet, Bruce D. Gelb, Jean-Laurent Casanova
Journal: Journal of the American College of Cardiology (2017)