tbuckley/cabot-search huggingface dataset:
Effect of a combination of pertuzumab, trastuzumab, and weekly paclitaxel on pCR rates and side-effect profile as a neoadjuvant treatment regimen for HER2-positive breast cancer.
Authors: Niraj K. Gupta, Erica Giblin, Christopher A. Leagre, Kristen Govert, Stanley Givens, Tiffany Chichester, Matthew Locker, Parin Bhayani, Riesa Burnett, Tara Spivey, Stephanie Cohen, Robert Paul
Journal: Journal of Clinical Oncology (2018)

e12652 Background: A combination of Pertuzumab (P),trastuzumab (H) and chemotherapy is the standard of care for the neo-adjuvant treatment of locally advanced/inflammatory Her-2 +ve breast cancer. Neutropenia and diarrhea are the two common significant side-effects observed with the currently used chemotherapy regimens. We evaluated the efficacy and safety of a combination of P and H with weekly paclitaxel (T) given in a neo-adjuvant fashion to Her-2 +ve patients. Methods: Women with a tumor size > 2 cm or LN positive or inflammatory breast Ca with Her-2 positivity by IHC or FISH were treated. The treatment regimen evaluated was; P on D-1 at a loading dose of 840 mg, followed by 420 mg every 3 weeks , T on D-1 at a dose of 8 mg/kg loading dose, followed by 6 mg/kg every 3 weeks, and Paclitaxel on D-1/8 at a dose of 80 mg/m2. Six cycles were given at 3 week intervals. Herceptin was continued for a total of one year. Adjuvant radiation and hormonal treatments were given per the NCCN guidelines. Data on the pCR rate and safety profile was collected. LVEF was measured at baseline and every 6 weeks during neoadjuvant treatments. Results: A total of 48 women were treated from Mar 2014 – Jul 2017. Median age was 52 years (31-80). Eleven pts had T-1 disease, 31 had T-2, 5 had T-3 and, 1 pt. had inflammatory breast ca. 22 pts had LN involvement. Receptor profile was: ER/PR +ve: 33 pts., ER+/PR-ve: 4 pts., ER/PR - ve: 11 pts.. All patients were able to complete the planned six cycles. Twenty pts. achieved a pCR (41.6%). Seven out of 11 ER/PR-ve patients (63.6%) had a pCR. Grade-3/4 neutropenia was seen in 5 patients (10.4%), febrile neutropenia was not observed in any pt. (0%). Grade-3/4 diarrhea was seen in 1 pt. (3.2%).Grade-3/4 neuropathy was seen in 3 pts. (6.2%). LVEF drop of more than 10% from baseline to less than 50% was seen in 1 patient (3.2%). Conclusions: A combination of Pertuzumab, Trastuzumab and weekly Paclitaxel (PHT) yields impressive pCR rates with very acceptable side-effects compared to the other commonly used chemotherapy regimens. This combination could be explored further in larger trials.
Gene expression subtypes in early stage oral cavity squamous cell carcinoma and subclinical nodal metastasis.
Authors: Angela Mazul, Jose Zevallos, Lin Wang, Vonn Walter, David N. Hayes
Journal: Journal of Clinical Oncology (2017)

e17525 Background: Patients with early stage oral cavity squamous cell carcinoma (OCSCC) without clinical or radiographic evidence of cervical lymphadenopathy present as a therapeutic dilemma. Although studies show a survival advantage with elective neck dissection, about 70% of patients have pathologically negative nodes. In this study, we examine four previously described head and neck squamous cell carcinoma gene expression subtypes [basal (BA), mesenchymal (MS), atypical (AT), and classical (CL)] and subclinical nodal metastasis in early stage, clinically node negative OCSCC. Since the MS subtype is characterized by expression of epithelial to mesenchymal transition (EMT) genes, which is important in the initiation of nodal metastasis, we hypothesize the MS subtype is associated with higher rates of nodal metastasis and worse overall survival. Methods: Using a previously validated integrative genomic analysis, we determined gene expression subtype for T1-T2, clinically node negative OCSCC cases undergoing elective neck dissection from the Cancer Genome Atlas (TCGA) database. We compared rates of pathologically positive lymph nodes and survival in stage by gene expression subtype. Results: We identified 67 T1-T2, clinically N0 cases with pathologic node data. Most of OCSCC cases were BA (N = 24) or MS (N = 26) subtype. Few were either AT (N = 9) or CL (N = 8) subtype. Three of the BA subtype and 11 of the MS subtype tumors were pathologically node positive. MS tumors were 3.38 times (95% Confidence Interval (CI): 1.08-10.69) as likely to have pathologically positive lymph nodes compared to the BA subtype. The MS subtype was associated with worse overall survival (hazard ratio: 2.33, 95% CI 0.79-6.87) compared with the BA subtype. Conclusions: Our findings suggest gene expression subtypes can potentially identify early stage OCSCC patients at higher risk for subclinical nodal metastasis and may reflect high EMT gene expression associated with this phenotype. Gene expression subtype, along with tumor mutation and clinical profiles, could be used to determine the need for neck dissection in early stage OCSCC, and could translate into a reduction in treatment morbidity and length of hospitalization.
Advice Regarding Alcohol Use by Individuals With Nonalcoholic Fatty Liver Disease: Primum non nocere
Authors: Winston Dunn, Naga Chalasani
Journal: Hepatology (2018)

Individuals with nonalcoholic fatty liver disease (NAFLD) often ask their health care providers about routinely consuming non-heavy amounts of alcohol for pleasure and potential health benefits.According to the American Association for the Study of Liver Diseases (AASLD) Practice Guidance published in 2018, there are insufficient data to make a recommendation with regard to nonheavy alcohol consumption by individuals with NAFLD. (1)Although several cross-sectional studies
Studying chemotherapy toxicity levels in district cancer care delivery model.
Authors: Dinesh Pendharkar, Chandramavli M. Tripathi, Suhas Aagre
Journal: Journal of Clinical Oncology (2017)

e18003 Background: To increase the access to cancer care an innovative delivery model has been initiated in 77 district general hospitals of India , empowering general duty medical officers and offering 24x7 technology based backup. All the districts along with other care also offer chemotherapy services. Major concerns raised by medical community were of toxicity associated with administration of chemotherapy. Methods: Data from chemotherapy patients undergoing chemotherapy over short period of three months in one of the district hospital was collected using proforma and common terminology criteria for adverse events(CTCAE v. 4).Data was recorded in all patients by personal interview and clinical examination when patient reported for next c0urse of chemotherapy and during the administration. Results: Total number of 196 patients (136 female and 60 male) taking chemotherapy in district were evaluated. Majority of them had breast( 92), lung (24) head and neck cancer(18).A total number of 285 cycle in all lines –first, second, etc were administered. In breast cancer majority cycles were of adjuvant chemotherapy. Chemotherapy regimens in use included all standard combinations of Doxorubicin cyclophosphamide, docetaxel ,carboplatin , 5FU, paclitaxel . Commonest toxicity included nausea , vomiting, fatigue, diarrhea and anemia. Nausea was commonest (181 events)followed by vomiting (179) diarrhea (122) fatigue, anemia and neutropenia. Most toxicity was grade 1 and 2 only. Only 3 cases of febrile neutropenia were reported and there were 3 emergency admissions for vomiting ,diarrhea. No patient had to be shifted out for medical emergency to higher center. Conclusions: The level of toxicity in peripheral center matches that of standard toxicity levels reported in literature .It is feasible to safely manage chemotherapy at peripheral centers with training generalist and offering distant supervised care. For achieving universal health core goals, with extreme shortage of oncology personnel and services specially in in LMIC only such models appear to be feasible and practicable.
Lenvatinib + pembrolizumab in patients with renal cell carcinoma: Updated results.
Authors: Chung-Han Lee, Vicky Makker, Drew W. Rasco, Matthew H. Taylor, Daniel E. Stepan, Robert Charles Shumaker, Emmett V. Schmidt, Matthew Guo, Corina E. Dutcus, Robert J. Motzer
Journal: Journal of Clinical Oncology (2018)

4560 Background: Lenvatinib, a multikinase inhibitor of vascular endothelial growth factor (VEGF) receptors and other targets, has been approved in combination with everolimus to treat advanced renal cell carcinoma (RCC) after 1 prior VEGF-targeted therapy. We report results for the RCC cohort of a phase 1b/2 trial of lenvatinib + pembrolizumab in patients (pts) with selected solid tumors (NCT02501096). Methods: In this multicenter, open-label study, pts with metastatic clear cell RCC and measurable disease per immune-related RECIST (irRECIST) received oral lenvatinib 20 mg daily + pembrolizumab 200 mg IV every 3 weeks. Tumor assessments were performed by study investigators using irRECIST, and retrospectively by independent radiographic review (IRR) per irRECIST and RECIST 1.1. The phase 2 primary endpoint was objective response rate at 24 weeks (ORRWK24). Results: 30 Pts were enrolled: 12 (40%) pts had 0 and 18 (60%) pts had ≥1 prior anticancer therapy; 16 (53%) pts received ≥1 prior VEGF-targeted therapy. At data cutoff of August 1, 2017, median follow-up for progression-free survival (PFS) was 13.8 mos (95% CI, 11.9–15.7). ORRWK24 was 63.3% (95% CI, 43.9–80.1) by investigator review, per irRECIST. ORR by IRR using RECIST 1.1 was 66.7% (95% CI, 47.2–82.7), and median PFS was 17.7 mos (95% CI, 9.6–NE). Efficacy outcomes are summarized in the table. Grade 3 or 4 adverse events (AEs) occurred in 21 (70%) pts; however, 4 (13%) discontinued treatment due to AE. The most common AEs were diarrhea (83%), fatigue (70%), hypothyroidism (67%), stomatitis (63%), and nausea (60%). Conclusions: The combination regimen of lenvatinib + pembrolizumab showed promising antitumor activity with manageable AEs, and no new safety signals were identified. A phase 3 trial of lenvatinib + pembrolizumab and lenvatinib + everolimus versus sunitinib for the first-line treatment of advanced RCC is underway (NCT02811861). Clinical trial information: NCT02501096.Outcome N = 30 Independent radiographic review Investigator review RECIST 1.1 irRECIST irRECIST ORR*, n (%) 20 (66.7) 20 (66.7) 21 (70.0) 95% CI 47.2–82.7 47.2–82.7 50.6–85.3 Median duration of response, mos 16.3 NE 18.4 95% CI 8.9–NE 14.9–NE 10.3–NE Median PFS, mos 17.7 17.7 19.8 Median PFS, mos 95% CI 9.6–NE 10.2–NE 11.6–NE *Overall ORR. NE, not estimable.
Anti-LeY monoclonal antibody (mAb) hu3S193 as consolidation therapy for patients (pts) with relapsing platinum sensitive ovarian cancer (OC) after achieving a second complete response (2CR).
Authors: Oren Smaletz, Gustavo Ismael, Maria Del Pilar Estevez-Diz, Ivana Lucia Oliveira Nascimento, Ana Luiza Gomes de Morais Wiermann, Geraldo Felicio Cunha, Sergio J Azevedo, Venâncio A Alves, Ana M Moro, Fernanda Perez Yeda, Mariana Lopes dos Santos, Indrani Majumder, Eric W. Hoffman
Journal: Journal of Clinical Oncology (2017)

e17039 Background: Lewis-Y (LeY) antigen is a blood group related antigen expressed in 75% of OC. hu3S193 is a humanized anti-LeY IgG1 mAb with strong complement and antibody dependent cytotoxicity with clinical benefit shown in a phase II study in pts with platinum-resistant OC and small tumor burden. Improving progression free survival (PFS) in pts who achieve a 2CR is an unmet need. Methods: This phase II study accrued pts with relapsed OC, LeY expression by IHC, and a KPS ≥ 70% who had achieved a 2CR after 5-8 cycles of platinum doublet chemotherapy (chemoRx). Patients received intravenous infusions of hu3S193, 30mg/m 2 every 2 weeks starting ≤ 8 weeks after the last dose of chemoRx and continuing for 12 doses (24 weeks) or until disease progression or unacceptable toxicity. Primary endpoint was PFS with a sample size calculated to detect a 50% increase in PFS, compared to a historical value of 10.8 months. Secondary objectives were safety and pharmacokinetics (PK). Results: 29 pts were enrolled. Median age: 55 yrs (range 29-67); Median KPS: 90% (range 80-100); LeY expression by IHC (N): strong (20), weak (9); stage at initial diagnosis: I/II (2), III/IV (27); median CA-125 prior to 2CR chemoRx: 104 (range 9-514); chemoRx agents to achieve 2CR: paclitaxel/platin (21), liposomal doxo/carboplatin (8); median cycles of prior chemoRx to achieve a 2CR:6; median doses of hu3S193 delivered: 10 (range 10-12). Evaluable pts: 28 (1 pt did not have 2CR); median PFS: 11.8 months (95% CI: 10.6-13.9) while 3 pts achieved PFS of 25+ months. Grade 4 toxicities observed: none. Most frequent toxicities (any grade/grade 3): Nausea (16/2), Vomiting (15/3), Hypersensitivity (9/0). PK data will be presented. Conclusions: Despite the good tolerance and the longer PFS compared to historical control, this trial did not show a significant improvement with hu3S193 as a consolidative strategy in patients with 2CR in platinum-sensitive OC. Tumor molecular analysis of patients with long PFS may provide insight for future studies. Clinical trial information: NCT01137071.
Association of Levels of Physical Activity With Risk of Parkinson Disease
Authors: Xuexian Fang, Dan Han, Qi Cheng, Pan Zhang, Chunhui Zhao, Junxia Min, Fudi Wang
Journal: JAMA Network Open (2018)

<h3>Importance</h3> The association between physical activity and the risk of Parkinson disease (PD) has been increasingly recognized. However, to our knowledge, a comprehensive assessment of the quantitative dose-response association between physical activity and PD risk has not been performed previously. <h3>Objective</h3> To quantify the dose-response association between physical activity and the risk of developing PD. <h3>Data Sources</h3> PubMed, Embase, and Web of Science were systematically searched for peer-reviewed articles published through February 2018 reporting the association between physical activity and PD risk. <h3>Study Selection</h3> Prospective studies that examined the association between physical activity and PD risk were included. <h3>Data Extraction and Synthesis</h3> Data were extracted independently by 2 investigators. Adjusted risk estimates were extracted and pooled using a random-effects model. The study adhered to Meta-analysis of Observational Studies in Epidemiology (MOOSE) reporting guidelines. <h3>Main Outcomes and Measures</h3> The main outcome was the incidence of PD diagnoses confirmed by the treating neurologists or the authoritative medical records. <h3>Results</h3> Eight prospective studies totaling 544 336 participants included 2192 patients with PD with a median (range) follow-up period of 12 (6.1-22.0) years were identified. A significantly reduced risk of PD was associated with the highest levels of either total physical activity (relative risk, 0.79; 95% CI, 0.68-0.91) or moderate to vigorous physical activity (relative risk, 0.71; 95% CI, 0.58-0.87), with stronger associations among men than among women. In contrast, light physical activity was not associated with PD risk (relative risk, 0.86; 95% CI, 0.60-1.23). The dose-response analysis revealed that for each 10 metabolic equivalent of task–hours/week increase in total or moderate to vigorous physical activity, the risk of PD among men decreased by 10% and 17%, respectively. No linear dose-response association was found between physical activity and PD risk among women. <h3>Conclusions and Relevance</h3> This analysis revealed an inverse dose-response association between physical activity and PD risk among men; importantly, even moderate exercise was associated with a significant reduction in the risk of PD. Future studies with quantified measurements of physical activity will help identify the precise relative risk estimates for various levels of activity with respect to PD risk.
A pivotal randomized phase II study of anetumab ravtansine or vinorelbine in patients with advanced or metastatic pleural mesothelioma after progression on platinum/pemetrexed-based chemotherapy (NCT02610140).
Authors: Raffit Hassan, Ross Jennens, Jan P. Van Meerbeeck, John J. Nemunaitis, George R. Blumenschein, Dean Anthony Fennell, Hedy L. Kindler, Silvia Novello, Cem Elbi, Annette Walter, Danila Serpico, Jonathan Monty Siegel, Barrett H. Childs
Journal: Journal of Clinical Oncology (2016)

TPS8576 Background: Mesothelioma is a rare but aggressive cancer with a poor prognosis. Anetumab ravtansine (BAY 94-9343) is a novel fully human anti-mesothelin IgG1 antibody conjugated to the mytansinoid tubulin inhibitor DM4. In a phase I study, anetumab ravtansine at 6.5 mg/kg on a q3w IV schedule was well tolerated and showed encouraging efficacy in patients with previously treated mesothelioma. We therefore initiated a randomized, open-label, active-controlled, 2-arm, multicenter, phase II trial to evaluate the efficacy and safety of anetumab ravtansine in patients with advanced or metastatic malignant pleural mesothelioma (MPM) overexpressing mesothelin and who have progressed on first-line platinum/pemetrexed-based chemotherapy. Methods: The primary objective is to test the superiority of anetumab ravtansine monotherapy over vinorelbine in progression-free survival (PFS). The secondary objectives of this study include overall survival, patient-reported outcomes (PRO), tumor response, and safety. Exploratory objectives include immunogenicity of anetumab ravtansine, pharmacokinetics, and biomarkers of response. Biomarker-positive patients with moderate (2+) and/or strong (3+) level in at least 30% of tumor cells will be eligible. Approximately 183 patients will berandomized in a 2:1 ratio to receive anetumab ravtansine 6.5 mg/kg Q3W or vinorelbine 30 mg/m2 QW. Randomization will be stratified by geographic region (Asia vs other) and time to progression on 1st line treatment ( ≥ vs < 6 months). The primary endpoint, PFS per modified RECIST criteria for MPM per central review, will be tested using a stratified log-rank test, with 1-sided significance level 0.0125. The primary analysis will occur after approximately 117 PFS events. Assuming true median PFS of 3.6 months under vinorelbine treatment, the primary hypothesis test is designed to detect a 100% prolongation of true PFS (median 7.2 months) with 90% power. Novel study methods include a grading system for AEs of special interest and the PRO instruments. This trial is open and currently accruing patients. Clinical trial information: NCT02610140.
Association of tumor infiltrating lymphocytes (TILs) with molecular subtype and prognosis in stage III colon cancers (CC) from a FOLFOX-based adjuvant chemotherapy trial.
Authors: Frank A. Sinicrope, Thomas C. Smyrk, Nathan R. Foster, Jeffrey P. Meyers, Stephen N. Thibodeau, Richard M. Goldberg, Qian Shi, Daniel J. Sargent, Steven R. Alberts
Journal: Journal of Clinical Oncology (2016)

3518 Background: High levels of TILs are associated with favorable prognosis in some solid tumors. We examined TIL levels in CC subtyped using mutations in KRAS or BRAF oncogenes as well as DNA mismatch repair (MMR) status, and examined association with patient (pt) prognosis. Methods: Stage III CC (N=2293) from a randomized trial of adjuvant FOLFOX + cetuximab (NCCTG N0147) were analyzed for TILs; dichotomized as high (> 4 TILs per HPF) vs low at light microscopy. We determined the association of TILs with clinicopathological features, mutations in KRAS exon 2 or BRAF(V600E), MMR status, and DFS by multivariate Cox regression analyses. Results: Higher TIL densities were found in tumors with wild-type (wt) vs mutated (mut) KRAS (p=.038) or BRAF (p<.0001). Among tumors with mut BRAFV600E or mut KRAS, high vs low TILs were found in 19.2% and 9.5%, respectively. In tumors with mut BRAF, high TILs were detected in 31.2% of dMMR vs 9.5% of pMMR cancers (p<.0001). TILs were increased 3.6-fold in dMMR vs proficient (p) MMR tumors (p<.0001). Also associated with high vs low TILs were female vs male (p=.011), white vs non-white (p=.008), proximal vs distal (p<.0001), lower T stage (p=.004), fewer positive/examined nodes (p=.015), and high vs low grade (p=.0001). High vs low TILs were associated with better DFS overall [HR=0.76 (0.57-1.01), p=0.047], and among tumors with wt KRAS [HR= 0.61 (0.41-.89), p=.006] or wt KRAS and BRAF [HR= 0.56 (0.34-.92), p=.013]. TILs were not prognostic in tumors with mut KRAS (p=.71; TIL*KRAS interaction p= 0.097) or mut BRAF (p=.18). High vs low TILs were associated with favorable DFS in pt tumors with dMMR [HR= 0.55 (.30-1.01), p=.045], but not pMMR (p=.301; interaction p=0.17]. No significant differences were found by treatment arm. Conclusions: Significantly lower TILs are found in tumors with mut vs wt KRAS or BRAF suggesting reduced immunogenicity. Among tumors with wt, but not mut, KRAS and BRAF, high vs low TILs were associated with better survival. TILs were increased 3.6-fold in dMMR vs pMMR, and favorably prognostic within dMMR pts. These results for wt tumors and those with dMMR suggest that immune activation improves survival outcomes.
US hospitals launch non-profit generic drug producer to counter rising prices
Authors: Bob Roehr
Journal: BMJ (2018)

Several American healthcare systems have joined forces to form a new non-profit pharmaceutical company to counter price gouging and scarcity of generic drugs by increasing their supply.

Civica Rx was launched on 6 September with the healthcare systems and three foundations providing initial capital of $100m (£77m; €86m).

The company will focus on about 20 drugs primarily used in hospitals—which it declined to name “for competitive reasons”—and hopes to ship its first pills in early 2019.

The byelaws require unanimous consent to change certain provisions of the company charter, such as the requirement that it remain a not-for-profit organisation, and that …