tbuckley/cabot-search huggingface dataset:
Topographical incidence and survival analysis of gastrointestinal tract cancer in adolescent and young adults compared with older adults in the United States.
Authors: Oren Hannun Levine, Kevin M. Zbuk, Archie Bleyer
Journal: Journal of Clinical Oncology (2017)

545 Background: Adolescent and young adults (AYAs) who develop gastrointestinal (GI) cancer are rare and have unique needs. There is limited literature defining the epidemiology of malignant disease across the entire GI tract in this age group. The objective of this study was to explore incidence and survival trends in the United States for all types of GI cancers in AYAs compared to older adults. Methods: We analyzed all incident cases of GI tract cancers in AYAs aged 15 to 39 and older adults aged 40 to 64 in the National Cancer Institute Surveillance, Epidemiology and End Results (SEER) program 2000-2013 database. For each age group and sex, we determined incidence rates, temporal changes in incidence, overall prognosis and stage-based prognosis for all primary tumor sites throughout the GI tract. Results: The incidence of colorectal cancer (CRC) distal to the splenic flexure has increased in AYAs whereas all CRC has decreased in older adults. We found that compared to older adults, AYAs have experienced better survival for most cancers arising at or proximal to the cecum regardless of stage. Conversely, more distal tumors were associated with worse prognosis in AYAs for regional or distant-stage disease. For distal CRC, the greatest age-based discrepancy in survival occurred for regional disease. Despite decreasing incidence of anal cancer in AYAs, young females have experienced worse survival with this disease compared to AYA males and older adults. Conclusions: We have identified age and gender-based disparities in survival relating to GI cancers. Rising rates of distal CRC in AYAs highlight the need for further exploration of molecular mechanisms and potential therapeutic targets for these malignancies which are also associated with worse survival in the younger population.
A phase I study of ombrabulin (O) combined with bevacizumab (B) in patients with advanced solid tumors.
Authors: Michael Ong, Gianluca Del Conte, Rastislav Bahleda, Joaquin Mateo, Silvia Damian, Antonella Perotti, Nathalie Lassau, Françoise Farace, Jimena Lovosgaldeano, Nina Tunariu, Marie Hospitel, Paola Mariani, Patrick Cohen, Giuseppe Capri, Jean-Charles Soria, Luca Gianni, L Rhoda Molife, Cristiana Sessa
Journal: Journal of Clinical Oncology (2013)

2535 Background: O, a vascular-disrupting agent derived from combretastatin A4-phosphate, induces rapid tumor vascular shutdown via endothelial cell damage. Resistance to O may occur by surges in circulating endothelial progenitors (CEP) that repopulate the tumor vasculature. Experimental models suggest prolonged and synergistic antitumor activity when O is combined with VEGF-blockade, with reduction in CEP surge. This phase I study was performed to determine the maximum tolerated dose, safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary antitumor activity of O combined with B. Methods: Patients (pts) with advanced treatment-refractory solid tumors, ECOG PS ≤1, and adequate organ function were eligible. O (mg/m²) was administered intravenously (IV) on day (d)1 with B (mg/kg) IV on d2 in 21d cycles (C). A Bayesian model informed dose escalation steps. PK sampling, dynamic contrast-enhanced ultrasound (DCE-US) for tumor perfusion, and CEP samples were collected. Results: 39 pts (M:F 10:29; median age 51 years [range 25-75]) were treated at 12 dose levels combining O [8 to 50mg/m 2 ] with B [5, 10, or 15mg/kg]. Ovary (16/39, 41%) and colon (4/39, 10%) were the most common primary sites. No C1 dose-limiting toxicities occurred in 37 evaluable pts. Drug-related grade 3-4 treatment emergent adverse events (AE) were hypertension (6/39, 15%), intestinal perforation (2/39, 5%), headache (1/39, 3%), myocardial infarction (1/39, 3%), and pulmonary embolism (1/39, 3%). 36 pts (14 ovarian) were evaluable for response by RECIST 1.1. Antitumor activity was observed at O 20mg/m 2 + B 10mg/kg and above, with confirmed partial responses in 2/14 pts with ovarian primary (14%), CA125 responses in 2 further ovary/endometrial cancers lasting ≥ 6 months, and stable disease in 15/36 pts (42%) lasting ≥ 6 months in 3 pts. PK indicated no interactions of O+B. Analyses of CEP levels post O and paired DCE-US data are ongoing. Conclusions: The maximum administered dose (MAD) was O 50mg/m 2 with B 15mg/kg, with no dose-limiting toxicities and vascular toxicity that was manageable. Promising antitumor activity was observed at doses below the MAD and warrants further evaluation. Clinical trial information: NCT01193595.
Association Between Elements of Electronic Health Record Systems and the Weekend Effect in Urgent General Surgery
Authors: Anai N. Kothari, Sarah A. Brownlee, Robert H. Blackwell, Matthew A. C. Zapf, Talar Markossian, Gopal N. Gupta, Paul C. Kuo
Journal: JAMA Surgery (2017)

This cross-sectional review evaluates how specific components of electronic health record systems were associated with the weekend effect for patients undergoing acute cholecystectomy, acute appendectomy, and acute hernia repair.
Analysis of pretreatment nonpharmacologic, pharmacologic factors, and yoga intervention on CINV outcomes in breast cancer patients undergoing adjuvant chemotherapy.
Authors: Malur R. Usharani, Rao M. Raghavendra, Kodaganur Srinivasachar Gopinath, Ramesh Bilimagga S, Ravi B Diwakar, Nalini K Rao, Basavalinga S. Ajaikumar, P K Nandini
Journal: Journal of Clinical Oncology (2012)

1093 Background: Chemotherapy induced nausea and vomiting (CINV) is affected by both pretreatment patient factors, chemotherapy and antiemetic regimen and psychological interventions. In this study we evaluated the effects of mind body intervention such as yoga in modulating CINV outcomes controlled for the above factors. Methods: Chemotherapy naïve breast cancer patients with stage II and III disease participating in a randomized controlled trial comparing yoga (n=45) vs. supportive therapy (n=53) were assessed for CINV outcomes during adjuvant chemotherapy. Morrows Assessment of nausea and emesis was used to asses CINV symptoms including their frequency, severity and anticipatory nature. We developed a multiple regression analyses to test the role of intervention on CINV beyond that explained by the independent prognostic factors [age (&lt;50/≥50 years), stage of disease (II vs III), menopausal status (pre vs post), antiemetic regimen (5HT3 antagonists vs. antidopaminergics), administration of anxiolytics (yes/ no) and type of chemotherapy regimen (FAC vs. CMF)] that were included in model A. Model B includes these six variables plus intervention (yoga vs. supportive therapy) in predicting nausea and vomiting outcomes. Results: Intervention emerged as a primary predictor for nausea frequency (β= -0.38, p=0.002), intensity (β= -0.44, p=0.001 ), anticipatory nausea frequency (β=-0.26 , p= 0.04) and intensity (β=-0.38 , p=0.004 ). Age group emerged as a primary predictor for anticipatory vomiting frequency (β=-0.39 , p=0.01 ) and secondary predictor for nausea frequency (β=-0.41, p= 0.006). Administration of anxiolytics emerged as a primary predictor for vomiting intensity (β=-0.40, p= 0.001) and secondary predictor for anticipatory nausea frequency (β=-0.26 , p= 0.05). Conclusions: Yoga intervention influences CINV outcomes when controlled for pretreatment and pharmacological factors during chemotherapy in breast cancer patients poorly controlled for nausea and vomiting.
Phase l study assessing a two-consecutive-day (QD x 2) dosing schedule of the HSP90 inhibitor, AT13387, in patients with advanced solid tumors.
Authors: Khanh Tu Do, Giovanna Speranza, Alice P. Chen, Jane B. Trepel, Min-Jung Lee, Sunmin Lee, Larry Phillips, Jerry M. Collins, Marcie K. Weil, Robert J. Kinders, Sonny Khin, Deborah Allen, Ramya Parthasarathy, James H. Doroshow, Shivaani Kummar
Journal: Journal of Clinical Oncology (2012)

3087 Background: AT13387, a synthetic, non-ansamycin, small molecule inhibitor of HSP90 (Kd 0.71 nM), binds to the N-terminal ATP-binding site resulting in down-regulation of key oncoproteins (HER2 and ERK). In xenograft models AT13387 produced tumor growth inhibition on a QD x 2 dosing schedule. Objectives: To determine toxicity, MTD, PK, and pharmacodynamic (PD) effect of AT13387 given IV QD x 2, 3 weeks out of 4. Methods: Adult patients (pts) with advanced cancers progressing following standard therapy; ECOG ≤ 2; adequate organ function. One pt cohorts for first three dose levels (DLs, 20, 40, 80 mg/m 2 ), planned 3+3 design at DL 4 (120 mg/m 2 ). PK evaluations on C1D1 and C1D15. Mandatory tumor biopsies in expansion cohort at MTD for HER2+ tumors (baseline, C1D17) to evaluate HSP70 and HSP27 mRNA by RT-PCR; and client protein by IHC and immunoassay. HSP70 in PBMCs as a PD marker (pre-dose, D2, D15, D16) assessed by Western blot; serum markers of cell death, M30 and M65 (baseline and pre-dose C1D16), assessed by ELISA. Results: 12 pts treated up to DL 5 (160 mg/m2). Median age, 59; median # prior therapies, 3; diagnosis (# pts): colorectal (7); esophageal (2), liposarcoma (1); head and neck (1); synovial sarcoma (1). Drug-related toxicities (gr ≤ 2; # pts) in 9 evaluable pts: fatigue (5), rash (2), nausea (5), diarrhea (7), QTc prolongation (2), thrombocytopenia (5), AST (3) and ALT (2). Vision disorder (2 pts): gr 1, reversible, no objective findings on eye exams. DLT (1 pt, with liver metastases): DL 5, gr 3 AST/ALT. PK was dose proportional; T 1/2 8 hrs. In one paired tumor biopsy (DL 3) an increase in HSP70 (&gt; 1.5 fold) and HSP27 (2 fold) mRNA and a decrease in pERK was observed. M30 and M65 increased in 5/6 pts (p-value n.s.). Induction of HSP70 (1.48 - 5.01 fold) in PBMCs was noted at all time points following first dose (≥ DL 2). 3/9 pts had SD after 2 cycles. Conclusions: Preliminary data indicate that AT13387 QD x 2 is well tolerated and produces a sustained induction of HSP70 in PBMCs. Accrual is ongoing to establish the MTD and obtain further tumor biopsies for assessment of drug effect. Optional Indium-labeled trastuzumab scan will be used to evaluate drug effect on HER2 levels in pts with HER2 expressing tumors.
Induction chemotherapy with weekly cetuximab, carboplatin, and paclitaxel in the treatment of locally advanced head and neck cancer: The University of Pennsylvania experience.
Authors: Jessica R Bauman, Corey J. Langer, Harry Quon, Kenneth M. Algazy, Arati Suvas Desai, Faith Mutale, Alexander Lin, Jared Weiss
Journal: Journal of Clinical Oncology (2012)

e16062 Background: Although Tax 324 demonstrated superior survival for induction docetaxel, cisplatin, and 5-fluorouracil (TPF) compared to PF in the management of locally advanced head and neck cancer, TPF is associated with serious toxicities and logistical challenges leading many institutions to seek alternative regimens. One promising regimen, piloted by Kies and Wanebo, combines weekly cetuximab with carboplatin and paclitaxel, which the University of Pennsylvania adopted in 2008. Methods: We retrospectively evaluated all LA-SCCHN patients treated with this regimen from May 2008 to December 2011, during which time it was the only one used. Most commonly, cetuximab was dosed at 400mg/m 2 IV alone week one, followed by 250mg/m 2 weekly in combination with weekly carboplatin AUC 2 and paclitaxel 90 mg/m 2 over eight weeks. Our primary endpoint was feasibility. Results: Thirty patients were included. Median follow-up was 13.7 months (range, 5.0-38.7). Median age was 58.3 (range, 37.4-83.6). All but one had Stage IV SCCHN. 77% had oropharyngeal carcinoma. 70% were smokers. p16 staining as a surrogate for HPV positivity was available on 13 patients, of whom 10 were positive. For induction, high tolerability was observed based on 90% of patients receiving all planned cycles or missing only one cycle. Grade 3-4 toxicities included rash (7%), neutropenia (7%), and infusion reaction (3%). Only 10% were hospitalized at some point during induction therapy. All patients subsequently received definitive chemoradiotherapy (29) or surgery (1). All completed their full treatment course. At the time of post-treatment imaging, 19 (63%) had a complete response and 11 (37%) had a partial response. Of p16 positive patients, 8/10 (80%) had a CR. Of p16 negative patients, 1/3 (33%) had a CR. At the time of last follow-up, 30% of patients had recurrent disease. Median overall survival and progression free survival have not yet been reached; Kaplan-Meir curves will be shown. Conclusions: Induction chemotherapy with weekly, outpatient, cetuximab, carboplatin, and paclitaxel is feasible and well tolerated in LA-SCCHN. Preliminary efficacy results are promising.
HSP90 expression and early recurrence in gastroenteropancreatic neuroendocrine tumors: Potential for novel therapeutic targets.
Authors: Cecilia Grace Ethun, Lauren McLendon Postlewait, Alexandra Grace Lopez-Aguiar, Kristen Zhelnin, Alyssa Krasinskas, Bassel F. El-Rayes, Maria C. Russell, David A. Kooby, Charles A. Staley, Kenneth Cardona, Shishir Kumar Maithel
Journal: Journal of Clinical Oncology (2017)

235 Background: Heat shock protein (HSP) 90 promotes tumor growth and is overexpressed in many malignancies. HSP90 expression profile and its potential as a therapeutic target in primary and metastatic neuroendocrine tumors (NETs) are not known. Methods: HSP90 cytoplasmic expression and Ki-67 index were re-reviewed and scored by a pathologist blinded to all other clinicopathologic variables using tissue microarray (TMA) blocks created in triplicate for patients who underwent resection of primary and metastatic gastroenteropancreatic (GEP) neuroendocrine tumors at a single institution from 2000-2013. Primary outcome was recurrence-free survival (RFS). Results: Of 278 tumors reviewed, 194 (68%) were primary GEP NETs, and 31 (11%) were NET liver metastases. Of the primary GEP NETs, mean age was 56yrs, 42% were male; 103 (53%) were pancreas and 44 (23%) were small bowel. HSP90 expression was high in 66 (34%) and low in 128 (66%). Compared to low expression, high HSP90 was associated with lymphovascular invasion (70vs42%; p = 0.049) and advanced T-stage (T3/T4: 48vs27%; p = 0.01). Among patients who underwent curative-intent resections for primary, non-metastatic NETs (n = 147), high HSP90 was associated with decreased 1-, 3-, and 5-yr RFS (80%, 72%, 62%) compared to low (89%, 86%, 83%; p = 0.03), which persisted on multivariable analysis (HR 5.2, 95%CI 1.7-16.0; p = 0.004), after accounting for positive margin, LN involvement, increased tumor size, site of primary tumor, and Ki-67 index. When assessing NET liver metastases, high HSP90 expression was seen in 4 (13%) patients and low in 27 (87%). Similar to primary GEP NETs, patients with liver metastases that exhibited high HSP90 expression had decreased 1-, 3-, and 5-yr progression-free survival (25%, 25%, 0%) compared to those with low HSP90 (69%, 49%, 33%; p = 0.052). Conclusions: Heat shock protein 90 exhibits differential expression in resected GEP NETs and liver metastases. High cytoplasmic expression is associated with early recurrence of disease, even after accounting for other adverse pathologic factors, including Ki-67 index. HSP90 inhibition is a potential target for novel therapeutic strategies for neuroendocrine tumors.
A Rationale for Relaxing the Requirement to Undergo a Noncurative Chemotherapy for Advanced Cancer in a Phase I Immunotherapy Trial
Authors: Adelaide Doussau, Clark B. Hanmer
Journal: The American Journal of Bioethics (2017)

"A Rationale for Relaxing the Requirement to Undergo a Noncurative Chemotherapy for Advanced Cancer in a Phase I Immunotherapy Trial." The American Journal of Bioethics, 17(4), pp. 68–69
Implications of rapidity of response to initial therapy in multiple myeloma.
Authors: Krishna Bilas Ghimire, Vincent Rajkumar, Angela Dispenzieri, Martha Lacy, Morie Gertz, Francis Buadi, David Dingli, Suzanne R. Hayman, Nelson Leung, Stephen Russell, John Anthony Lust, Steven R. Zeldenrust, Yi Lin, Prashant Kapoor, Arleigh Robertson McCurdy, Robert A. Kyle, Shaji Kumar
Journal: Journal of Clinical Oncology (2013)

8606 Background: The rapidity of response to initial therapy in multiple myeloma (MM) depends on a variety of factors. There is limited data on its implications on long term outcomes in patients (pts) with newly diagnosed MM. Methods: We retrospectively examined the outcomes in a cohort of 454 pts with newly diagnosed MM between Jan 2000- Dec 2011 undergoing induction therapy. Results: The median age at diagnosis was 66 yrs (29-92). Pts had measurable serum M-spike (&gt;= 1 g/dL), dFLC (&gt;=10 mg/dl) or 24 hour urinary M protein excretion (UrM; &gt;=200 mg) in 70, 63 and 39% respectively. We first examined the relationship between the response to first cycle of therapy and overall survival (OS). We divided pts into quartiles based on their % reduction in the serum M spike, dFLC or UrM. The median OS (Table) was poorest for pts with the least reduction of serum M protein (P&lt;0.001) and of dFLC. The cutoffs for Q1 was 25, 40and 40% decrease for serum M spike, dFLC and 24 hr UrM respectively. Among various baseline characteristics only higher age was predictive of a poor (Q1) response. Given the trend toward worse OS among the Q 4 group (maximum decrease in serum M spike), we examined the relationship to cytogenetic risk. Among 232 pts with FISH data available, proportion of pts with high-risk disease was 27, 12, 22 and 31% respectively in quartiles 1 - 4). In a multivariate analysis, quartile 1 and 4 of serum M-protein response and the high-risk FISH were independent risk factors associated inferior OS. Conclusions: Both shallow and very deep response to therapy in cycle 1 is a strong indicator of eventual disease outcome and should be considered as marker of high-risk disease, likely through different mechanisms. For the shallow responders, prospective trials should assess if a change in therapeutic management will alter the outcome of these pts. The rapid deep responders also appear represent a different high-risk biology, emphasizing the fact that pts with high-risk disease often have excellent initial responses, but poor long term outcomes. [Table: see text]
Secular trends of bloodstream infections during neutropenia in 15 181 haematopoietic stem cell transplants: 13-year results from a European multicentre surveillance study (ONKO-KISS)
Authors: M. Weisser, C. Theilacker, S. Tschudin Sutter, R. Babikir, H. Bertz, T. Götting, M. Dettenkofer, W.V. Kern, A.F. Widmer
Journal: Clinical Microbiology and Infection (2017)
Epoetin-alfa initiation at Hb 10–11 or Hb &lt;10 g/dL: Analysis of safety and efficacy
Authors: T. K. Szczudlo, C. Croot, R. McKenzie, D. Henry
Journal: Journal of Clinical Oncology (2007)

19628 Background: Current guidelines recommend consideration of epoetin alfa (EPO) therapy for chemotherapy-induced anemia (CIA) either when Hb &lt;11 g/dL (National Comprehensive Cancer Network) or when Hb &lt; 10g/dL (ASCO/ASH 2002). The objective was to evaluate the safety and efficacy of EPO in patients (pts) with CIA when EPO was initiated at Hb 10–11 or at &lt;10 g/dL. Methods: A post hoc analysis was performed on data from randomized, well-controlled trials conducted from 2002–2006. Trials in which EPO therapy was initiated at the approved dose of 40,000 Units weekly in male and female pts with Hb &lt;11g/dL and =1 post-baseline Hb value were included. Two trials were identified, T1 and T2. Safety was assessed by the proportion of pts experiencing clinically relevant thrombovascular events (CR- TVEs) who received =1 dose of EPO. Efficacy was assessed by RBC transfusion requirements (Day 1 - end of treatment [EOT] and Day 29 - EOT) and achievement of durable Hb response (Hb =11 g/dL for =2 consecutive weeks). Results: Baseline (BL) characteristics (age, gender, platinum-based therapy, ECOG PS, and tumor type) were similar between the Hb 10–11 and &lt;10 g/dL groups. BL Hb was 10.53 and 9.29 g/dL in T1 and 10.28 and 9.53 g/dL in T2 for the Hb 10–11 and Hb&lt;10 g/dL subsets, respectively. Results are summarized below ( table ). Conclusions: These results show that patients treated with EPO at an Hb of 10–11 g/dL appear to have a lower incidence of CR-TVEs compared to patients treated at Hb &lt;10 g/dL. In addition, patients who started EPO treatment at an Hb of 10–11 g/dL had fewer RBC transfusions and higher durable Hb response. Trial 1 - Waltzman et al. The Oncologist. 2005;10:642–650. Trial 2 - Henry et al. Curr Med Res Opin. 2006;22:1403–1413. No significant financial relationships to disclose. [Table: see text]
Adult B-Cell Acute Lymphoblastic Leukemia Dominated by Osteolytic Bone Involvement on CT But Less Impressive PET on FDG PET/CT Images
Authors: Sijuan Zou, Yanxia Shen, Dongling Zhu, Donghua Zhang, Xiaohua Zhu
Journal: Clinical Nuclear Medicine (2017)

A 47-year-old man presented with abdominal pain, vomiting, and bone pain. Laboratory findings revealed severe hypercalcemia, anemia, and renal insufficiency with decreased serum parathyroid hormone. FDG PET/CT was performed for characteristics suggestive of multiple myeloma and other occult malignancy. The images revealed widespread osteolytic lesions with only 1 focus of definite abnormal FDG uptake. B-cell acute lymphoblastic leukemia was confirmed by pathological examination following bone marrow biopsy.
Characteristics of 1q amplification in adenocarcinoma of the lung (LUAD).
Authors: Siddhartha H. K. Devarakonda, Saiama Naheed Waqar, Kalin Guebert, Leonard B. Maggi, Danielle Carpenter, Bradley Ozenberger, Ramaswamy Govindan, Daniel Morgensztern
Journal: Journal of Clinical Oncology (2014)

e22195 Background: Somatic copy number alterations (SCNA) affect a large portion of the cancer genome. Several peaks of large scale and focal amplifications have been reported in LUAD, including amplification of 1q. We examined The Cancer Genome Atlas (TCGA) data to examine the frequency of 1q amplification in patients with LUAD, and potentially targetable genes in this region. Methods: The cBioPortal for Cancer Genomics (CBP) was queried to obtain putative GISTIC SCNA and clinical data for 230 LUAD samples sequenced by TCGA. A list of all protein coding and microRNA genes on 1q was obtained through Ensembl. Samples were defined as “Oncogene Positive” (OP) if they harbored either mutations in KRAS, EGFR, BRAF, MAP2K1, AKT1, NRAS, HRAS, NF1, or RIT1, fusions involving ALK, ROS1 or RET, or mutations/amplifications in ERRB2 or MET, and “Oncogene Negative” (ON) if they lacked these alterations. The Drug Gene Interaction database (DGIdb) was queried to explore the targetability of all amplified genes. Results: SCNA data were available for 968 queried genes. Of these, 360 were amplified in >10% of the samples, with the majority in the 1q21-q23 region, including genes such as TARS2, ARNT, SF3B4, SETDB1, RIT1, and ADAR. Genes residing on 1q21.3 were the most frequently amplified (14-16%). 1q21 amplification (queried on CBP using ARNT) was observed in 23% of ON and 14% of OP samples. Among the OP samples, 1q21 amplifications frequently co-occurred with KRAS(46%) mutations. 1q21 amplification was not related to gender or smoking status. DGIdb identified at least one potentially targeted drug for 126 amplified genes. Conclusions: Several genes on 1q are frequently amplified in LUAD. It is possible that the amplification of one or more of these genes is capable of driving oncogenesis. Further studies are needed to functionally validate the role and therapeutic potential of genes in the 1q amplified region in LUAD.