tbuckley/cabot-search huggingface dataset:
Phase II trial of cabozantinib in patients with carcinoid and pancreatic neuroendocrine tumors (pNET).
Authors: Jennifer A. Chan, Jason Edward Faris, Janet E. Murphy, Lawrence Scott Blaszkowsky, Eunice Lee Kwak, Nadine Jackson McCleary, Charles S. Fuchs, Jeffrey A. Meyerhardt, Kimmie Ng, Andrew X. Zhu, Thomas Adam Abrams, Brian M. Wolpin, Sui Zhang, Amanda Reardon, Bridget Fitzpatrick, Matthew H. Kulke, David P. Ryan
Journal: Journal of Clinical Oncology (2017)

228 Background: Activation of VEGFR2 and c-MET has been implicated in driving growth of neuroendocrine tumors (NET); additionally, expression of c-MET has been associated with shorter survival. Cabozantinib inhibits VEGFR2 and c-MET. We performed a two-cohort phase II study to evaluate the efficacy of cabozantinib in patients (pts) with advanced carcinoid or pNET (NCT01466036). Methods: Pts with progressive, well differentiated, grade 1-2 carcinoid or pNET were enrolled in parallel cohorts and treated with cabozantinib 60 mg po qd . There was no limit to prior therapy. Pts were restaged every 2 mos for the first 6 mos, then every 3 mos. The primary endpoint was objective response rate as measured by RECIST 1.1. Enrollment of approximately 35 patients of each tumor type was planned. Results: 41 pts with carcinoid (median age 63 yrs, 44% male, % ECOG PS 0/1 = 51/49) were accrued. Accrual to the pNET cohort was halted due to investigator/sponsor decision after 20 pts (median age 55 yrs, 60% male, % ECOG PS 0/1 = 40/60). Carcinoid pts completed a median of 8 (range 0-44) 28-day treatment cycles; pNET pts completed a median of 10 (0-35) cycles. 14 pts remain on treatment. Reasons for discontinuation were progression or death (51%), withdrawal of consent or investigator decision (28%), adverse events (AE, 21%). 3/20 pts with pNET achieved PR (ORR 15%, 95% CI 5-36%); 15/20 had SD. 6/41 pts with carcinoid achieved PR (ORR 15%, 95% CI 7-28%); 26/41 had SD . Median PFS was 21.8 mo (95% CI, 8.5-32.0 mo) in pts with pNET and 31.4 mo (95% CI, 8.5 mo-NR) in pts with carcinoid. Gr 3/4 toxicity in ≥ 1 pt included hypertension (13%), hypophosphatemia (11%), diarrhea (10%), lymphopenia (7%), thrombocytopenia (5%), fatigue (5%), increased lipase or amylase (8%). Unexpected Gr 3/4 AEs included heart failure and autoimmune hemolytic anemia, each in 1 pt. 81% of 53 pts completing more than 1 cycle of treatment required dose reduction from the initial 60 mg dose. Conclusions: Treatment with cabozantinib was associated with objective tumor responses and encouraging PFS durations in patients with advanced carcinoid and advanced pNET. While dose reduction was common, treatment was tolerable. Further evaluation of cabozantinib is warranted in both NET subgroups. Clinical trial information: NCT01466036.
Cardiac safety of continuous trastuzumab therapy in breast cancer patients with asymptomatic left ventricular dysfunction.
Authors: Anthony Francis Yu, Nandini U Yadav, Anne Eaton, Betty Y Lung, Howard T. Thaler, Jennifer Liu, Clifford A. Hudis, Chau T. Dang, Richard Steingart
Journal: Journal of Clinical Oncology (2015)

e11602 Background: Adjuvant trastuzumab is a highly effective targeted treatment that improves survival for patients with HER2-positive breast cancer. However trastuzumab interruption is recommended for patients that develop treatment-induced left ventricular dysfunction and can result in an incomplete course of breast cancer treatment. We studied the cardiac safety of continuous trastuzumab therapy among patients that developed asymptomatic declines in left ventricular ejection fraction (LVEF) during adjuvant trastuzumab therapy. Methods: We retrospectively evaluated patients with HER2-positive breast cancer treated with adjuvant trastuzumab at our institution between 2005 and 2010. Treatment-induced cardiotoxicity (TIC) was defined by an absolute decrease in LVEF > / = 10% to below 55% or an absolute decrease > / = 16%, as per manufacturer prescribing information. Logistic regression was used to determine the association between candidate risk factors and TIC. Results: Among 573 patients with median age of 50 years, 467 (82%) were treated with anthracycline chemotherapy. In total, 92 (16%) developed TIC. Seventy-four patients (12.5%) had an asymptomatic LVEF decline and 10 (1.7%) had New York Heart Association class III-IV heart failure. Risk factors associated with TIC included age (p = 0.011), anthracycline chemotherapy (p = 0.002), and lower pre-trastuzumab LVEF (p < 0.001). Trastuzumab was continued and completed without interruption in 31 of 92 patients with TIC—all were asymptomatic with LVEF > / = 50% at the time of TIC diagnosis with median LVEF of 53% (range, 50-63%), and none developed heart failure during follow-up. Conclusions: Among patients who develop TIC but are asymptomatic with LVEF > / = 50%, continuous trastuzumab therapy without interruption appears to be safe. Given the life-saving benefit of anti-HER2 therapy, efforts should be made to avoid unnecessary interruption or discontinuation of treatment.
Evaluation of family history in newly diagnosed children with cancer.
Authors: Kinley Garfield, Wendy Kohlmann, Clinton C Mason, Joshua David Schiffman
Journal: Journal of Clinical Oncology (2015)

1546 Background: The collection of cancer family history (FH) is a key component for risk assessment in adult cancer patients, but is not routine in pediatric oncology. We collected FH on all newly diagnosed pediatric cancer (PC) patients presenting at Primary Children’s Hospital to determine the feasibility of routine FH collection and risk prevalence for hereditary cancer syndromes. Methods: Parents of newly diagnosed children (age 0 to 20) were approached for enrollment and given a FH questionnaire to complete and return by mail assessing FH in first- and second-degree relatives. A genetic counselor contacted all participants by phone to review the reported history or to obtain a FH from those who did not return the form. Criteria for genetics referral were based on NCCN or peer-reviewed criteria. Results: Of the 91 families that completed a FH, 24 (26%) were considered eligible for further genetic risk evaluation. 16 (17%) warranted referral based on the child’s tumor type or personal/ FH criteria, 8 (9%) children did not meet criteria but had a first- or second-degree relative who met criteria for referral. 10 of 16 children meeting criteria were seen for genetic counseling. Conclusions: Collecting FH at the time of diagnosis is feasible and identifies at risk individuals for cancer predisposition. Approximately 30% of newly diagnosed PC patients meet criteria for further genetic risk evaluation. This is consistent with data from a survivorship clinic reported by Knapke et al. (2011), although our study enrollment occurred at diagnosis and is not biased by patient mortality. These findings support a high rate of genetic predisposition related to childhood cancer (at least 1 in 4), and highlight the importance of obtaining an accurate FH at the time of initial diagnosis. Cancer Type Patients (n) Child’s history + FH warranted evaluation Child’s history warranted evaluation FH warranted evaluation Total referrals warranted All types 91 6 10 8 24 Brain 7 0 1 0 1 Colon 1 0 1 0 1 Ewing sarcoma 3 0 0 0 0 Hepatoblastoma 5 2 3 0 5 Leukemia/lymphoma 44 0 0 3 3 Melanoma 1 1 0 0 1 Neuroblastoma 8 0 0 3 3 Optic tumor 2 1 1 0 2 Osteosarcoma 6 0 0 1 1 Pleuropulmonary blastoma 1 1 0 0 1 Retinoblastoma 1 0 1 0 1 Rhabdoid tumor 1 1 0 0 1 Rhabdomyosarcoma 4 0 3 0 3 Sarcoma 4 0 0 0 0 Wilms tumor 2 0 0 1 1
A multicenter phase II neoadjuvant trial of bevacizumab combined with docetaxel plus carboplatin in the treatment of triple-negative breast cancer: Korean Cancer Study Group (KCSG-BR 0905, NCT 01208480).
Authors: Hye Ryun Kim, Kyung Hae Jung, Seock-Ah Im, Young-Hyuck Im, Seok Yun Kang, Kyong Hwa Park, Keun Seok Lee, Soohyeon Lee, Jin-Hee Ahn, Sung-Bae Kim, Kyung-Hun Lee, Yeon Hee Park, Jin Seok Ahn, Ku Sang Kim, Hye Yoon Lee, Jungsil Ro, Byeong-Woo Park, Seung Il Kim, Joo Hyuk Sohn
Journal: Journal of Clinical Oncology (2012)

2542 Background: Triple negative breast cancer (TNBC) is dismal disease that is ineligible for endocrine or anti-HER2 therapy. We have conducted a phase II neoadjuvant trial to evaluate efficacy and tolerability of bevacizumab combined with docetaxel plus carboplatin in TNBC. Methods: Women with a histologically confirmed stage II or III TNBC were eligible. Hormone receptors and HER2 negativity were confirmed by immunohistochemistry and/or fluorescence in situ hybridization. Patients received 6 cycles of docetaxel 75 mg/m 2 , carboplatin AUC 5, and bevacizumab 15 mg/kg on day1 every 21 days. Bevacizumab was omitted in the last cycle to avoid wound complication. The primary endpoint was pathologic complete response (pCR) rate in both breast and axillary lymph node and secondary endpoints were clinical response rate, toxicity profiles, and breast conserving surgery (BCS) rate. Results: Forty-five TNBC patients were recruited from 7 institutes in the Korean Cancer Study Group (KCSG) between October 2010 and August 2011. The median age of the patients was 45 years (30-72 years). The T1, T2, and T3 were 4.4 %, 68.9 %, and 26.7 %, respectively and axillary lymph node was positive in 80% by breast MRI. Among 45 patients, 44 patients completed 6 cycles of therapy followed by surgery and one patient was withdrawn due to patient’s refusal of further therapy after 3 rd cycle. The pCR rate was 42.2 % (19/45) and clinical response rate was 95.5 % (43/45) (CR, n= 6; PR, n=37; SD, n=1; not evaluable, n=1) based on RECIST criteria 1.1. BCS was undertaken in 77.7 % (35/45). The grade 3 or 4 adverse events were neutropenia (38), febrile neutropenia (4), vomiting (3), nausea (2), anemia (1), thrombocytopenia (1), stomatitis (1), gastrointestinal bleeding (1), and increased ALT (1). Only one patient experienced delayed wound healing after breast surgery. Conclusions: Bevacizumab in combination with docetaxel and carboplatin as neoadjuvant treatment provided an encouraging pCR rate (42.2 %) and a negligible wound healing problem after surgery. The adverse events were manageable.
Accelerated hypofractionated hemithoracic intensity modulated radiation therapy (IMRT) followed by extrapleural pneumonectomy (EPP) for malignant pleural mesothelioma (MPM): Results of a phase I/II study.
Authors: Marc de Perrot, Ronald Feld, Natasha B. Leighl, Isabelle Opitz, Masaki Anraku, BC John Cho
Journal: Journal of Clinical Oncology (2013)

7526 Background: We developed a protocol with accelerated hypofractionated hemithoracic IMRT followed by EPP for MPM. Advantages include optimal delivery of radiation to the whole tumor bed in a short period limiting the risk of viable tumor cell spread during surgery. Methods: Patients with resectable clinical T1-3N0M0 histology proven MPM were eligible for the study. 25 Gy in 5 daily fractions over 1 week was delivered to the entire ipsilateral hemithorax by IMRT with concomitant boost of 5 Gy to volumes at high risk based on CT and PET scan findings. EPP was performed one week after the end of radiation. Adjuvant chemotherapy was offered to patients with ypN2 on final pathology. The primary end-point was treatment related mortality. Secondary endpoint included overall survival and disease-free survival (DFS). Initial sites of recurrence were also recorded. Results: Twenty five patients were accrued between 11/2008 and 10/2012. Patients had a median age of 64 years (range, 45-75), 76% were males, 64% had epithelioid histology. All patients completed IMRT and EPP. IMRT was well tolerated with no grade 3-5 toxicity. EPP was performed 6±2 days after completion of IMRT. Surgical complications occurred in 18 patients. One patient died from empyema at 88 days. All but one patient (stage IB) had stage III (n=11) or IV (n=13) disease on final pathology. Five out of 13 patients with ypN2 disease underwent adjuvant chemotherapy. After a median follow-up of 19 months (range, 3-51), the estimated 3-year survival reached 62%. Survival was significantly better in epithelioid compared to biphasic pathologic subtypes (83% survival at 3 years vs 19%, respectively; p=0.004). 14 patients remain disease free after a median follow-up of 17 months (range, 3-37). 2-year DFS was 85% in stage III and 37% in stage IV disease (p=0.03). Recurrences occurred in the ipsilateral chest only (n=2), ipsilateral chest and distant sites (n=2), and distant sites only (n=6). Conclusions: Accelerated hypofractionated hemithoracic IMRT followed by EPP is feasible. This treatment could improve survival in selected patients with epithelial subtype. Clinical trial information: NCT00797719.
Expression of immunohistochemical markers in locally advanced breast carcinoma and their use as predictors of pathological response: A prospective analysis of a retrospective cohort. (EXIPAR study).
Authors: Animesh Saha, Sonali Nayak, Sanjit Agarwal, Indu Arun, Rosina Ahmed, Sanjoy Chatterjee, Mayur Parihar, Subir Sinha
Journal: Journal of Clinical Oncology (2015)

e11509 Background: Neoadjuvant chemotherapy (NACT) leads to tumour volume changes but there is increasing interest in transcriptional changes post NACT. Expression of estrogen (ER), progesterone (PR), Ki-67 index and Her-2 neu (IHC-4) is key to clinical management of breast cancer. Methods: 156 unselected patients (January 2012- December 2013) receiving NACT using anthracycline-taxane regimes were recruited. Factors were analyzed to identify clinico-pathological predictors of pathological complete response (pCR). Post NACT IHC-4 changes were analysed. Patients were classified as: 1) LA (ER/ PR+ve, HER-2 -ve, and Ki-67 <14%); 2) LB (ER /PR +ve and either Her-2- +ve or Ki-67 ≥14%); 3) HE (ER/ PR -ve and Her-2-+ve); and 4) TN (ER/ PR- ve and Her-2-ve). Associations between pCR and other categorical and continuous variables were assessed using the chi-square and independent Student t-tests respectively. Changes in IHC-4 status post NACT were done using the McNemar test for ER, PR, HER2 and paired Student’s t-test for the Ki-67. Results: 62% completed treatment >85% dose density. At a median follow up of 13 months 1.28% patients developed locoregional recurrence, 6.41% distant metastases. Overall 25.3.% had pCR, 27.4% of which had Grade 3 tumours compared to 16.9% with grade 1/ 2. pCR rates based on LA,LB,HE, TN subtypes were 13.6%,24.4, 26.3 and 33.3% respectively. Those with Ki-67( <14%) had pCR rate of 17.14% compared to 23.07% in Ki- 67(≥14%) group. Table 1 tabulates the changes in IHC-4 post NACT. Significant changes in ER and Ki-67 expression occurred post NACT. Conclusions: pCR rates and clinical outcomes were comparable to western literature. Her2+ve tumours not receiving trastuzumab (77%) had higher pCR rates than LA subtypes. Post NACT there are transcriptional changes resulting in alteration of ER status and KI-67 indices, clinical significance of which though uncertain should be explored. IHC markers ER +ve ER -ve PR +ve PR -ve Her2neu +ve Her2neu -ve Low KI High KI Pre NACT 77.23% 22.77% 55.44% 44.56% 37.62% 62.38% 28.92% 71.08% Post NACT 66.34% 33.66% 57.42% 42.58% 31.68% 68.32% 50.6% 49.4% P value 0.03 0.82 0.26 0.003
FDG-PET/CT versus contrast enhanced CT for prediction of progression-free and disease-specific survival in stage IV breast cancer patients.
Authors: Christopher Riedl, Katja Pinker, Leonard Ong, Maxine S. Jochelson, Gary Ulaner, Heather L. McArthur, Maura N. Dickler, Wolfgang Weber
Journal: Journal of Clinical Oncology (2015)

1051 Background: To compare FDG PET/CT to contrast-enhanced CT (CECT) for the prediction of progression-free and disease-specific survival in stage IV breast cancer patients undergoing systemic therapy. Methods: The hospital database was searched for patients with stage IV breast cancer, who received first or second line systemic therapy in clinical trials from 2007-2012 and had received a (CECT)and a FDG PET/CT at baseline and within 3 months after therapy initiation. In the 71 evaluable patients identfied, response to treatment was evaluated by RECIST 1.1 for CT. For FDG PET/CT SUVmax of up to 5 FDG avid target lesions (SUVmax ≧4) was summed and response categorized by PERCIST criteria. If there was no FDG avid lesion (5 patients) response was assessed by RECIST 1.1. Response to treatment was correlated with progression-free (PFS) and disease-specific (DSS) survival. Results: All responders by RECIST (n = 24) were responders by PERCIST, but 43% (20/47) of the non-responders by RECIST were responders by PERCIST (Tab. 1). 2-year-PFS of responders and non-responders by RECIST was 39% and 19%, whereas 2-year PFS by PERCIST was 41% and 0%. 4-year-DSS of responders and non-responders by RECIST was 58% and 40%, whereas 4 year-DSS by PERCIST was 64% and 6% (Fig. 1). 4-year DSS of patients classified as non-responders by RECIST but as responders by PERCIST, was 72%. Conclusions: FDG PET/CT seems to improve prediction of PFS and DSS in stage IV breast cancer patients. Additional information gained with PET/CT, can change treatment in up 22% of patients. Prospective evaluation of FDG PET/CT for response assessment in randomized clinical trials is warranted. PET/CT CR PR SD PD Total CT CR 2 0 0 0 2 PR 8 14 0 0 22 SD 5 12 8 6 31 PD 3 0 1 12 16 Total 18 26 9 18 71
Primary chemotherapy with doxorubicin followed by docetaxel-cisplatin in locally advanced breast cance
Authors: A. Ezzat, M. Rahal, T. Twegieri, S. Akhtar, A. Al Sayed, D. Ajarim, A. Tulbah, O. Al Malik, M. Al Shabanah
Journal: Journal of Clinical Oncology (2004)

703 Background: Primary chemotherapy is increasingly used as preoperative therapy for patients (pt) with locally advanced breast cancer. Methods: A prospective study was designed using sequential delivery of Doxorubicin: 75 mg/m2 q 3 weeks x 3 cycles followed by a combination of Docetaxel: 75 mg /m2 and Cisplatin: 75 mg/m2 q 3 weeks x 3cycles followed by surgery. Radiation therapy +/- Tamoxifen were given when indicated. Primary end points were pathologic response, rate of conservative surgery and relapse free survival. Eligible pts included biopsy proven invasive breast cancer, T2-T4 (primary ≥ 4 cm) N0-N1, M0. Results: 33 pts (23 premenopausal), median age 41(range 24–60), median tumor size 6 cm (4.5–10), N0: 6, Stage IIIA/IIIB: 24/9, ER/PR positive 18. All 33 pts completed 3 cycles of Doxorubicin, for a total of 99 cycles. The most commonly observed grade III toxicity on Doxorubicin included a 10 % incidence of mucositis. Relative delivered dose intensity (RDI) for Doxorubicin 96%. Only 92 cycles of the second sequence with Docetaxel and Cisplatin were delivered, 7 were omitted in 4 pts for grade III hypersensitivity, grade IV vomiting, septic shock and pt refusal. Other grade III toxicity included 9% myalgia and bone pain. RDI for Docetaxel - Cisplatin 91%. 32 pts were evaluable for response: clinical complete response 40%, partial response 60%. All pts were operated: lumpectomy 56%, mastectomy 44%. Pathologic response in the breast: no residual invasive tumor 34 %, < 1 cm 15%. Pathologic response in the nodes: node negative 40%, 1–3 node 25%. Overall complete pathologic response (NSABP criteria): 9/ 32 (28%). Data on DFS is not yet available. Conclusion: Sequential combination of Doxorubicin followed by Docetaxel - Cisplatin is a safe and feasible combination that offers the possibility of conservative surgery in over than 50% of pts with a high pathologic response rate. No significant financial relationships to disclose.
Targeting hyperactivation of the AKT survival pathway to overcome therapy resistance of melanoma brain metastases.
Authors: Friedegund Elke Meier, Andrea Forschner, Bernhard Klumpp, Keith T. Flaherty, Juergen Bernd Honegger, Maria Witte, Antje Bornemann, Reinhard Dummer, Juergen Bauer, Ghazaleh Tabatabai, Benjamin Weide, Thomas K. Eigentler, Dirk Schadendorf, Leticia Quintanilla-Fend, Heike Niessner, Claus Garbe
Journal: Journal of Clinical Oncology (2012)

8526 Background: Brain metastases are a major contributor to mortality in stage IV melanoma patients. In melanoma, the RAF-MEK-ERK (MAPK) and PI3K-AKT-mTOR (AKT) signaling pathways play a major role in tumor progression and therapy resistance. On the basis of significant improvement in overall survival, the BRAF inhibitor vemurafenib recently gained FDA approval for the treatment of patients with metastatic BRAFV600E mutated melanoma. However, ongoing clinical studies suggest short-lived responses to BRAF inhibitors in melanoma brain metastases. Methods: We observed in several melanoma patients that chemotherapeutics or BRAF inhibitors yielded a significant regression of extracerebral metastases while brain metastases progressed or newly occurred. We therefore aimed at identifying factors that may contribute to treatment resistance of brain metastases. Results: Immunohistochemistry of matched brain and extracerebral melanoma metastases demonstrated an identical pattern of ERK, p-ERK and AKT staining but a different pattern of p-AKT and PTEN staining with hyperactivation of AKT and loss of PTEN expression in brain metastases. Mutation analysis revealed no difference in BRAF, NRAS or KIT mutation status in matched brain and extracerebral metastases. By contrast, in monolayer culture expression of ERK, p-ERK, AKT, p-AKT and PTEN was identical in cell lines derived from brain and extracerebral metastases. Furthermore, melanoma cells stimulated by astrocyte-conditioned medium showed hyperactivation of AKT compared to melanoma cells stimulated by fibroblast-conditioned medium. When inhibiting the MAPK and AKT signaling pathways at different levels in cells freshly isolated from melanoma brain metastases, growth inhibition and apoptosis induction was most pronounced with novel PI3K inhibitors such as BKM120 and BEZ235. Conclusions: These data suggest that 1) hyperactivation of the AKT survival pathway is brain environment-induced and relevant for the survival of melanoma cells in the brain parenchyma and that 2) inhibition of AKT signaling may be a suitable strategy to enhance and/or prolong the antitumor effect of chemotherapeutics or BRAF inhibitors in melanoma brain metastases.
World Health Organization treatment guidelines for drug-resistant tuberculosis, 2016 update
Authors: Dennis Falzon, Holger J. Schünemann, Elizabeth Harausz, Licé González-Angulo, Christian Lienhardt, Ernesto Jaramillo, Karin Weyer
Journal: European Respiratory Journal (2017)

Antimicrobial resistance is a major global concern. Tuberculosis (TB) strains resistant to rifampicin and other TB medicines challenge patient survival and public health. The World Health Organization (WHO) has published treatment guidelines for drug-resistant TB since 1997 and last updated them in 2016 based on reviews of aggregated and individual patient data from published and unpublished studies. An international expert panel formulated recommendations following the GRADE approach. The new WHO guidelines recommend a standardised 9–12 months shorter treatment regimen as first choice in patients with multidrug- or rifampicin-resistant TB (MDR/RR-TB) strains not resistant to fluoroquinolones or second-line injectable agents; resistance to these two classes of core second-line medicines is rapidly detectable with molecular diagnostics also approved by WHO in 2016. The composition of longer regimens for patients ineligible for the shorter regimen was modified. A first-ever meta-analysis of individual paediatric patient data allowed treatment recommendations for childhood MDR/RR-TB to be made. Delamanid is now also recommended in patients aged 6–17 years. Partial lung resection is a recommended option in MDR/RR-TB care. The 2016 revision highlighted the continued shortage of high-quality evidence and implementation research, and reiterated the need for clinical trials and best-practice studies to improve MDR/RR-TB patient treatment outcomes and strengthen policy.