tbuckley/cabot-search huggingface dataset:
A semi-physiologic population pharmacokinetic/pharmacodynamic (PK/PD) model of thrombocytopenia (TCP) characterizing the effect of trastuzumab-DM1 (T-DM1) on platelet counts in patients with HER2-positive MBC.
Authors: B. C. Bender, F. Schaedeli Stark, A. Joshi, Y. Chu, H. S. Rugo, I. E. Krop, S. Girish, M. Gupta
Journal: Journal of Clinical Oncology (2011)

605 Background: T-DM1 is an antibody-drug conjugate in development for HER2-positive MBC. In clinical trials of single-agent T-DM1 for heavily pretreated patients (pts), TCP was the dose-limiting toxicity. TCP was generally transient, reversible and not associated with serious hemorrhage, with nadirs by day 8 post-treatment. In some pts, platelet (plt) time profiles drifted slowly down after multiple cycles of T-DM1, though development of grade ≥3 TCP was infrequent. Methods: A semi-physiologic population PK/PD model with transit compartments mimicking plt development and circulation was fit to the concentration-plt-time data from the phase I dose escalation study (TDM3569g; N=52) and a phase II study of single-agent T-DM1 (3.6 mg/kg q3w; TDM4258g; N=112). The rate and extent of plt drift was modeled as a time effect on the proliferation pool. NONMEM software was used for the modeling analyses, with a mixture model approach used to identify pt plt drifts. A separate phase II study (3.6 mg/kg; TDM4374g; N=110) was used for model validation. Results: The PK/PD model described the data well and predicted the 9% incidence of grade ≥3 TCP observed in the validation dataset (TDM4374g). The model also predicts that downward drifting plt profiles will eventually stabilize. In the model dataset, plt profiles from 25% of pts drifted downward much more rapidly than the rest of pts; these stabilized by 8 treatment cycles to typically 50% of the original baseline plt count. In 4374g, the overall plt response pattern was similar, with a subset of pts' plt profiles drifting then stabilizing by 8 treatment cycles. Pt baseline characteristics were not significantly correlated with plt kinetics. Conclusions: The model accurately reflects clinical observations of plt counts during T-DM1 treatment and supports T-DM1 3.6 mg/kg q3w as a well-tolerated dose, requiring minimal delays/reductions for TCP. In addition, the model supports partial depletion of the plt proliferation pool as a mechanism for the downward drift in plt count. Plt response to T-DM1 could not be predicted a priori from baseline characteristics.
Effect of PSK on FOLFOX4-induced peripheral neuropathy and bone marrow suppression in patients with metastatic colorectal cancer.
Authors: M. Shibata, T. Shimura, K. Gonda, I. Nakamura, S. Ohki, S. Takenoshita
Journal: Journal of Clinical Oncology (2011)

596 Background: FOLFOX4 has been confirmed as an effective treatment for metastatic colorectal cancer and is used as a postoperative adjuvant therapy. However adverse effects such as cold-sensitive paresthesia and bone marrow suppression are common and may necessitate changes in chemotherapy regimen despite FOLFOX effectiveness. PSK, a polysaccharide derived from a species of mushroom, has been developed in Japan as an immune-enhancing agent and is widely used in patients with gastric, colorectal and pulmonary cancer. PSK has also been reported to decrease some adverse effects of chemotherapy. Methods: FOLFOX4 combined with PSK was administered to patients with metastatic colorectal cancer and the results were evaluated. Eight cycles of FOLFOX4 and PSK (3.0 g/day, p.o.) were given to 25 patients with metastatic colorectal cancer (19 hepatic, 3 pulmonary and 3 peritoneal). Results: No patients showed CR (complete response, 0%) while PR (partial response), SD (stable disease) and PD (progressive disease) were seen in 48%, 36% and 16% of patients, respectively. Response rate was 48% and disease control rate was 84%. Frequency of adverse effects was significantly lower than described in the published data. Grades 1 and 3 neutropenia occurred in 48% and 24% of patients, respectively; grades 1 and 3 nausea in 48% and 4%, respectively; and grades 1, 2 and 3 sensory neurotoxicity in 52%, 4% and 0%, respectively. No patient dropped out due to adverse effects in this study. Conclusions: PSK plus FOLFOX4 seems as effective as FOLFOX4 monotherapy, and significantly less toxic. These results suggest that this combination therapy may be more effective when given for a longer period, with lower incidence of adverse effects. No significant financial relationships to disclose.
Factors influencing histopathology-assessed TME quality after low anterior rectal resection: Results of a prospective multicenter observational trial.
Authors: B. Garlipp, H. Ptok, U. Schmidt, P. Stuebs, F. Meyer, I. Gastinger, H. Lippert
Journal: Journal of Clinical Oncology (2011)

3547 Background: Total mesorectal excision (TME) has become standard of care in rectal cancer surgery, leading to a massive reduction in local recurrence rate. However, incomplete TME is associated with an increase in local recurrences. To date, there are no reliable data on clinical factors predicting incomplete TME in patients undergoing rectal cancer surgery. We used the data set of the German Quality Assurance in Rectal Cancer Surgery prospective multicenter observational trial to investigate this issue under routine clinical care conditions. Methods: This is a retrospective analysis of a prospectively gathered data set involving >300 German hospitals of all levels of care. Patients undergoing low anterior rectal resection for rectal cancer between 01/01/05 and 12/31/09 were included. Multivariate analysis using a stepwise logistic regression model was performed in order to identify factors predicting suboptimal TME as determined at postoperative histopathology. Risk factors analyzed included age, BMI, tumor distance from the anal verge, neoadjuvant therapy, duration of surgery, surgeon experience, laparoscopic vs. open approach, dissection technique, intraoperative complications, and pT stage. Results: A total of 6,179 patients were included. Due to missing data for one or more parameters 1,573 patients had to be removed from the data set, leaving 4,606 patients for analysis. pT stage >2 (OR 1.22), tumor distance from the anal verge <8 cm (OR 1.27), advanced age (>65 years, OR 1.24; >80 years, OR 1.59), presence of intraoperative complications (OR 2.06), monopolar dissection technique (OR 1.44), and low experience of the operating surgeon (OR 1.20) were identified as being independently associated with moderate or poor TME quality. Conclusions: This is the largest analysis of factors predicting incomplete TME to date. Since good TME quality is a prerequisite for a low recurrence rate, rectal cancer surgery should be performed or supervised by experienced colorectal surgeons. Monopolar pelvic dissection technique should be avoided. On the other hand, laparoscopic approach and use of neoadjuvant therapy do not seem to increase the risk for incomplete TME.
Impact of geriatric vulnerability parameters on pegylated liposomal doxorubicin (PLD) tolerance and outcome in elderly patients with metastatic breast cancer: Results of the DOGMES multicenter phase II GINECO trial.
Authors: C. Falandry, E. Brain, M. Bonnefoy, F. Mefti, A. Savoye, O. Rigal, S. Oddou-Lagranière, C. El Kouri, L. Uwer, S. Abadie-Lacourtoisie, J. Cretin, J. Jacquin, G. Freyer
Journal: Journal of Clinical Oncology (2011)

9122 Background: Few trials have prospectively evaluated MBC chemotherapy tolerance and outcomes in the elderly. Due to its decreased cardiotoxicity, PLD appears to be an interesting option. Methods: This trial was designed to evaluate tumour response (primary endpoint), feasibility and outcomes after 6 courses of an adapted dose of PLD (40mg/m²/4 wks) in first line hormone-resistant MBC. Results: Out of 60 patients (median age 77, range 70-88), 15% had performance status≥2, 13% initially HR-negative tumours and 70% visceral metastases. Geriatric risk factors included: medical: ≥2 co morbidities: 42%; functional: ≥1 ADL deficit: 10%, ≥1 IADL deficit: 82%, nursing home care: 12%; nutritional: albumin ≤35G/L: 26,7%, BMI<21: 20%; psychological: depression 17%; biological: lymphocytes ≤ 1G/L: 23%. Thus, 23% and 58% reached Fried criteria for frailty and prefrailty. Response rates were respectively 5%, 15% and 60% for complete, partial and stable disease (clinical benefit 80%) but only 48% completed 6 cycles. Causes of premature discontinuation included progression: 18%, severe toxicities: 22%, death: 10% and fracture: 2%. Despite a manageable hamatological (H) profile, many patients presented severe (gr 3-4) non-hematological (NH) toxicities: hand foot syndromes 14%, fatigue 22%, anorexia 9%, infection 19%, pain 17% and non-pathological fractures 7%. Thus, 15% of the patients needed dose reductions and 17% treatment delays≥7 d. Six patients died during treatment (3 possibly related to PLD) and 15 had unplanned hospital admissions. H and NH severe toxicities were differently correlated with geriatric covariates: H was significantly correlated to lymphocytes≤1G/L and NH to age≥80 and nursing home care. Considering outcomes, progression free survival (median: 6.1 months) was negatively correlated with initially HR-negative tumours and increasing age and overall survival (median: 15.7 months) with nursing home care. Conclusions: Despite manageable hematological toxicities and expected response rates, PLD tolerability was poor in light of non-hematological toxicities and geriatric outcomes.
Improving risk stratification in superficial (T1) gastroesophageal adenocarcinoma: Association of the intestinal phenotype (MUC2 positive) with prognosis.
Authors: Jon M. Davison, Shane Ellis, Tyler Foxwell, Ali H Zaidi, Blair A Jobe, Michael K. Gibson, Shih-Fan Kuan, Katie Sue Nason
Journal: Journal of Clinical Oncology (2012)

33 Background: An increasing proportion of esophageal and gastroesophageal junction adenocarcinomas (EAC) are limited to the superficial mucosal layer (stage classification T1) at the time of diagnosis. Intramucosal lesions (stage classification T1a) are increasingly managed with endoscopic resection due to their relatively low risk of nodal metastasis and favorable prognosis compared to those with submucosal invasion (stage classification T1b). At esophagectomy, however, the majority of T1b EAC are node-negative; conversely, a small proportion of T1a EAC will have nodal metastasis at esophagectomy and/or develop recurrent disease. Additional prognostication tools, such as tumor biomarker panels, are needed to optimize treatment algorithms. Known to carry prognostic significance in other tumors, we evaluated mucin protein expression to determine whether the mucin phenotype in early EAC was associated with survival outcomes. Methods: We classified 141 induction naive, resected, T1 EAC as intestinal-, gastric- or ductal-type depending on the expression pattern of gastrointestinal mucins (MUC2, MUC5AC, MUC6 and MUC1) determined by immunohistochemistry (IHC) on tissue microarrays. CDX2 expression was assessed by IHC and EGFR amplification was assessed by in situ hybridization. The association between survival and mucin subtypes was determined in univariate and multivariate analyses. Results: The intestinal phenotype (MUC2+) is associated with poor prognosis in T1b (HR 2.1, 95%CI 1.1-4.0) and node negative T1 EAC (HR 2.5, 95%CI 1.1-5.7) after adjusting for other significant prognostic factors. Intestinal type EAC also showed accelerated time to first recurrence in these subgroups. The colloid histologic subtype and CDX2 expression were positively associated with MUC2 expression, but EGFR amplification was not. Conclusions: The mucin phenotype may serve as a useful adjunct to conventional risk assessment for optimizing therapy for potentially resectable, superficial EAC.
Possible Two Different Mechanisms of Engraftment Failure in Cord Blood Transplantation: Graft Rejection and Poor Graft Function
Authors: Hikari Ota, Kazuhiro Masuoka, Naoyuki Uchida, Izumi Kaihori, Yuki Taya, Aya Nishida, Taichi Ikebe, Kazuya Ishiwata, Masanori Tsuji, Yuki Asano-Mori, Koji Izutsu, Naofumi Matsuno, Atsushi Wake, Akiko Yoneyama, Shigeyoshi Makino, Shuichi Taniguchi
Journal: Blood (2011)
Quality of life in a multicenter phase II trial of neoadjuvant full-dose gemcitabine, oxaliplatin, and radiation in patients with resectable or borderline resectable pancreatic adenocarcinoma.
Authors: Pablo Emilio Serrano Aybar, Joseph M. Herman, Mark Zalupski, Edward Jae-hoon Kim, Edgar Ben-Josef, Tanios S. Bekaii-Saab, Christopher Lee Wolfgang, Daniel A. Laheru, Malcolm J. Moore, Laura A. Dawson, Jolie Ringash, Alice Chia-chi Wei
Journal: Journal of Clinical Oncology (2013)

226 Background: Pancreatic cancer remains incurable for the great majority of patients afflicted with the disease. The purpose of this study was to evaluate health related quality of life (HRQoL) following neoadjuvant full dose gemcitabine, oxaliplatin and radiation therapy (30 Gy) for pancreatic adenocarcinoma in a multi-institutional Phase-II trial. Methods: Fifty-seven patients were evaluable for the HRQoL component of this trial that consisted of two cycles of neoadjuvant chemoradiation with gemcitabine and oxaliplatin followed by pancreatectomy and two additional cycles of adjuvant chemotherapy. The effects of therapy on HRQoL were evaluated using: EORTC-C30, EORTC-PAN26 and FACT-HEP. Results: There were 20 patients (35%) with untreated resectable and 37 (65%) with borderline resectable pancreatic cancer. Thirty-nine patients (69%) completed two cycles of preoperative chemotherapy and surgery, 26 (40%) underwent a pancreaticoduodenectomy and 9 (14%) a distal pancreatectomy. Twenty-six patients completed postoperative adjuvant therapy. The median age was 64 (range 42-82); patients younger than 65 had a higher global HRQoL score at 6 months (p=0.046) following the initiation of treatment. There was no difference in the HRQoL according to type of operation performed. EORTC-C30 Global HRQoL remained statistically and clinically unchanged compared to baseline levels at all time-points. FACT-Hep Trial Outcome Index and Total score showed a statistically significant but not clinically meaningful decline following cycle 2 of neoadjuvant treatment (p=0.002 and p=0.004), returning back to baseline levels after 6 months. This may in part be explained by a decrease in the functional (p=0.004) and physical (p=0.001) wellbeing, an increase in diarrhea (p=0.044), digestive symptoms (p=0.037) and an increased fatigue (p&lt;0.001). Conclusions: We report that this neoadjuvant chemoradiation protocol did not have a clinical impact on global HRQoL. Overall this regimen was well tolerated with no negative effect on quality of life following the conclusion of treatment. Clinical trial information: NCT00456599.
Deciphering the genomic fingerprint of small cell prostate cancer with potential clinical utility.
Authors: Mohammed Alshalalfa, Harrison Tsai, Zaid Haddad, Ashley Ross, R. Jeffrey Karnes, Elai Davicioni, Edward M. Schaeffer, Tamara L. Lotan
Journal: Journal of Clinical Oncology (2016)

303 Background: Small cell (SC) neuroendocrine carcinoma of the prostate has very poor prognosis and does not respond well to androgen receptor (AR)-targeted therapies. Neuroendocrine prostate carcinomas are increasingly recognized to show a spectrum of morphologic changes, and may not always be distinguishable from adenocarcinoma (adeno) based on morphology alone. Here we hypothesize that SC carcinoma harbor a unique gene expression signature that, when measured in primary prostatic adenocarcinoma, may help guide subsequent management. Methods: In total, 617 whole genome expression profiles were retrieved from the Decipher GRID providing gene expression data for 1.4 million markers. 17 morphologically-diagnosed SC carcinoma samples were compared to 32 Gleason 8-10 and 77 Gleason 6 RP adeno samples with no prior treatment and no evidence of metastasis, and this comparison was used to define SC Genomic Fingerprint (SCGFt) through adjusted median fold difference and Wilcoxon test. An additional 493 RP adeno from Mayo Clinic and John Hopkins Hospital were used to evaluate the utility of the SCGFt for predicting outcome. Results: Based on genomic prognostic tests calculated using the Decipher assay including Decipher, Penney and microarray-derived Cell Cycle Progression, SC carcinomas have very poor prognosis compared to high grade adeno. A total of 356 genes defined the SCGFt with 258 gene upregulated in SC and 98 down-regulated. PEG10, HELLS and RB1-loss program are the most overexpressed genes in SC and AR-related genes the most down-regulated. As expected, SC lacked ERG and alternative ETS expression and showed relatively low SPINK1 expression. A median summarization of the 356 genes in SCGFt was used to build a small cell genomic score (SCGS). Evaluating SCGS in RP adeno cohorts showed that patients with high SCGS are at higher risk of developing metastasis after RP in a natural history cohort or after adjuvant hormonal therapy based on Kaplan Meier analysis (both p&lt; 0.001). When restricted to patients with high Decipher scores, SCGS provided independent prognostic information. Conclusions: SC carcinoma has a distinct genomic profile that may be useful for treatment management of patients with adenocarcinoma.
Meta-analysis on the impact of post-mastectomy radiotherapy on breast reconstruction outcome.
Authors: M. J. Barry, M. R. Kell
Journal: Journal of Clinical Oncology (2010)

622 Background: Immediate breast reconstruction (BR) following cancer surgery results in improved quality of life and survivorship. Post-mastectomy radiotherapy (PMRT) improves local control and long-term survival in high-risk patients. PMRT may compromise the long-term outcome of the reconstructed breast. Therefore, patients whom receive PMRT and undergo breast reconstruction should be offered the most appropriate surgery to optimize their reconstructive outcome. Methods: A comprehensive search for published trials that examined postoperative qualitative outcome after PMRT and immediate or delayed BR was performed using MEDLINE and cross referencing available data. Reviews of each study were conducted and data were extracted. The primary outcome was postoperative complications. Results: 1,190 patients were identified from eligible studies. Patients undergoing PMRT and BR are more likely to suffer morbidity when compared to patients not receiving PMRT ([OR] = 4.2; 95% CI, 2.4-7.2 [no PMRT vs. PMRT]). We examined the effect of delaying BR until after PMRT delivery, this had no significant effect on outcome (OR = 1.22; 95% CI, 0.7-2.1 [delayed vs. immediate]). Finally we examined reconstruction technique with outcome, if PMRT was delivered after BR, and demonstrated that autologous reconstruction is superior in this setting (OR = 0.21; [95% CI, 0.1-0.4 {autologous vs. implant based}]). Conclusions: In the United States, less than 20% of patients requiring a mastectomy undergo immediate breast reconstruction; this may be due to concerns over complications associated with PMRT use. Data from this metaanalysis confirms that PMRT has a detrimental effect on outcome irrespective of timing or technique. Our results suggest that if PMRT is indicated, the optimum method of BR is an immediate autologous reconstruction. No significant financial relationships to disclose.
Value of <sup>18</sup>F-FDG PET-CT scan in the evaluation of recurrent asymptomatic epithelial ovarian cancer patients with rising serum CA-125
Authors: J. Ghosh, L. Kumar, S. Thulkar, R. Kumar, A. Malhotra, A. Kumar
Journal: Journal of Clinical Oncology (2008)

16535 Background: We conducted a pilot study to evaluate role of 18F-FDG PET- CT scan in the diagnosis of recurrent asymptomatic Epithelial Ovarian (EOC) cancer patients with rising serum CA-125. Methods: BetweenJuly 2006 and December 2007, 12 patients of recurrent EOC who were asymptomatic and had rising serum CA-125 on follow up were included in the study. All 12 patients (median age 53.5 years, range 40 to 75 years) had advanced disease at baseline (stage III, IV). They all had undergone cytoreductive surgery and platinum based chemotherapy and achieved complete response (clinical, normal CT scan and CA-125). At the detection of raised CA-125, patients underwent detailed clinical examination followed by contrast enhanced CT of whole abdomen. Patients with no evidence of disease clinically or on CT scan were further evaluated with 18F-FDG PET-CT. Those found to have increased uptake on FDG PET-CT underwent ultrasound guided fine needle aspiration cytology (FNAC) from that area. If the FNAC was positive they were considered as true positive, if negative, they were considered false positive. Patients, in whom FNAC was inconclusive or not possible, were followed closely for six months. If there was evidence of recurrence on clinical examination or on CT scan within this period, they were considered true positive else false positive. Patients with negative FDG PET-CT scan were also followed for six months, those who did not show any evidence of disease on clinical examination or CT scan were considered true negative. If they however showed evidence of recurrence during this period they were considered false negative. Results: All the twelve patients showed increased uptake on FDG PET-CT scan. Of these ten were true positive (seven positive on FNAC and three on follow up, two at 3 months and one at 4 months). There were two false positive (one on FNAC and the other on a follow up of 1year continues to be in remission). There was no true or false negative among the 12 patients analyzed. Conclusions: FDGPET-CT is a sensitive method to detect asymptomatic patients of recurrent epithelial ovarian cancer with only rising serum CA-125. However, a larger study is needed to confirm the results. No significant financial relationships to disclose.
Glucagon-Like Peptide-1 Receptor Agonists (GLP-1RAs) in the Brain–Adipocyte Axis
Authors: Bruno Geloneze, José Carlos de Lima-Júnior, Lício A. Velloso
Journal: Drugs (2017)

The complexity of neural circuits that control food intake and energy balance in the hypothalamic nuclei explains some of the constraints involved in the prevention and treatment of obesity. Two major neuronal populations present in the arcuate nucleus control caloric intake and energy expenditure: one population co-expresses orexigenic agouti-related peptide (AgRP) and neuropeptide Y and the other expresses the anorexigenic anorectic neuropeptides proopiomelanocortin and cocaine- and amphetamine-regulated transcript (POMC/CART). In addition to integrating signals from neurotransmitters and hormones, the hypothalamic systems that regulate energy homeostasis are affected by nutrients. Fat-rich diets, for instance, elicit hypothalamic inflammation (reactive activation and proliferation of microglia, a condition named gliosis). This process generates resistance to the anorexigenic hormones leptin and insulin, contributing to the genesis of obesity. Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) have increasingly been used to treat type 2 diabetes mellitus. One compound (liraglutide) was recently approved for the treatment of obesity. Although most studies suggest that GLP-1RAs promote weight loss mainly due to their inhibitory effect on food intake, other central effects that have been described for native GLP-1 and some GLP-1RAs in rodents and humans encourage future clinical trials to explore additional mechanisms that potentially underlie the beneficial effects observed with this drug class. In this article we review the most relevant data exploring the mechanisms involved in the effects of GLP-1RAs in the brain-adipocyte axis.