tbuckley/cabot-search huggingface dataset:
Intraperitoneal chemohyperthermia (IPCH) with oxaliplatin for patients with colorectal peritoneal carcinomatosis
Authors: S. Yongqian, L. Lingxiang
Journal: Journal of Clinical Oncology (2005)

3668 Background: To determine the activity and side-effect of intraperitoneal chemohyperthermia (IPCH) with oxaliplatin (LOHP), comparing with biweekly oxaliplatin, fluorouracil (FU) and leucovorin (LV) chemotherapy, as the therapy for patients with colorectal peritoneal carcinomatosis. Methods: 60 patients with measurable colorectal peritoneal carcinomatosis,proved pathologically, were divided into A and B groups at random. Group A: Patients were treated by IPCH with oxaliplatin 85 mg/m2, soluted in 500ml 5% GS, at an i.p. temperature of 42–44 degrees. Whereupon local radiofrequency hyperthermic chemotherapy was applied for 1 hours. Group B: Patients were treated with intravenous oxaliplatin 85 mg/m2 in 2 hours. During the hour preceding IPCH, all of them received an intravenous administration of 5-fluorouracil and leucovorin. The treatments were repeated every 2 weeks. One cycle lasts 30 days. Results: In group A, 27 patients can be evaluated. 2 patients achieved complete response, and 14 patients achieved partial response, for a response rate of 59.3%(95% CI, 29% to 68%). Median time to progression was 9.2 months (95% CI, 7.1 to 10.8 months) with median survival time of 11.1 months (95% CI, 8.4 to 19.7 months). In group B, 28 patients can be evaluated. 1 patients achieved complete response, and 9 patients achieved partial response, for a response rate of 35.7%(95% CI, 19% to 56%). Median time to progression was 7.0 months(95% CI, 4.1 to 12.5 months) with median survival time of 9.7 months(95% CI, 6.5 to 18.2 months).The response rate of ascites treatment was 86.7% with significant differences between two groups (P<0.05). Major toxicities included cumulative neuropathy grade 2 (9.4%) and grade 3 (1.2%); requiring discontinuation of oxaliplatin), diarrhea grade 3 to 4 (15.3%) and grade 3 to 4 hematologic toxicity (2.4%). Abdominal discomfort was significant(85.9%,p<0.05). Conclusions: The regimen of intraperitoneal chemohyperthermia (IPCH) with oxaliplatin (LOHP) seems to have activity comparable to intravenous programs of LOHP, combined with 5-fluorouracil and leucovorin. All side effects were tolerable. Prospective trials are warranted to determine the result. No significant financial relationships to disclose.
Small bowel neuroendocrine tumors: A critical analysis of diagnostic work-up and operative approach.
Authors: Cecilia Grace Ethun, Lauren McLendon Postlewait, Gillian G. Baptiste, Nina Le, Mia R. McInnis, Kenneth Cardona, Maria C. Russell, David A. Kooby, Charles A. Staley, Shishir Kumar Maithel
Journal: Journal of Clinical Oncology (2016)

203 Background: Small bowel neuroendocrine tumors (SB-NET) are rare, and often small and multifocal. They are difficult to localize preoperatively and can be overlooked during operative exploration. The optimal work-up and operative approach is not known. Methods: Patients who underwent resection of SB-NET at a single institution from 2000-2014 were included. Primary aim was to describe the diagnostic work-up, pathologic characteristics, and compare minimally-invasive (MIS) to open resection. Results: 93pts underwent resection for SB-NET. Median age was 61yrs; 52% were male. On presentation, 71% of pts were symptomatic and underwent an average of 3 diagnostic tests prior to resection: 45% had octreoscans, which identified the region of primary disease in 85%; 11% had small bowel enteroscopy, with a 10% diagnostic yield; 19% had capsule endoscopy, which saw a lesion in 83%, but in only 21% was the correct number of tumors seen. The diagnostic yield of capsule was 28% overall, but 82% in pts presenting with GI bleeding. 79pts (85%) underwent curative-intent resections. Median tumor size was 1.8cm and multiple primary tumors were seen in 34pts(42%), of whom 50% had &gt; 3 tumors. 37% had metastatic and 70% had LN positive disease. 27pts underwent MIS resections vs 66 open. MIS pts were younger (56vs61yrs;p0.035) and less likely to have obstructive symptoms (4vs24%;p = 0.19) and metastatic disease at resection (19vs44%;p = 0.038). Compared to open, the MIS group had smaller (1.7vs2.4cm;p = 0.03) and fewer tumors resected (2vs5;p = 0.049), but similar LN yield (13vs12;p = 0.7). In pts without metastases undergoing curative-intent resection, MIS approach was still associated with fewer tumors removed compared to open (1.5vs4;p = 0.034). Conclusions: Capsule endoscopy appears to be better than small bowel enteroscopy at identifying occult small bowel neuroendocrine tumors, particularly when pts present with bleeding, but still may underestimate tumor burden. While MIS may be appropriate in select patients, recognizing the limitations of preoperative evaluation is critical when selecting the operative approach for these tumors, as heightened operative vigilance is often required.
Strenghening and protecting families: How to handle the familial colorectal cancer risk—A prospective observational study in Upper Bavaria.
Authors: Ulrich Robert Mansmann, Gabriele Woelke, Jutta Engel, Juergen Stausberg
Journal: Journal of Clinical Oncology (2014)

427 Background: Lynch defines patients with familial colorectal cancer (CRC) risk as those with two or more first- or second-degree relatives (or both) with CRC. They make up about 20 percent of all CRC patients. Also, first degree relatives of CRC patients have an increased CRC risk. It is our goal to create population based data on familial CRC risk in a German population. Methods: Incident CRC cases in Upper Bavaria are collected and their family trees constructed. The patient’s relatives are documented by name, address and date of birth, but without health related information. Cancer history is added to a family by a record linkage procedure combining members of the family trees with cancer histories in the Munich CancerRegistry (MCR). A specific data protection concept guarantees anonymity for families and their cancer histories. Prevalence of familial CRC risk in upper Bavaria and the posterior probability of a family to carry CRC risk can be inferred from the anonymous data. Strength of simple familial CRC risk detection tools can also be assessed. Results: Per year, 141 clinical departments and 24 oncological practices report about 1300 incident CRC cases (below 70 years) to the MTR. Recruitment of patients started in September 2012. During the first year, we recruited 456 patients in 27 clinical departments and 6 oncological practices and contacted 1,600 relatives. Participation of relatives is reluctant in spite different information sources (leaflet, call center, internet) on the study purpose are provided. Record linkage creates an anonymous collection of CRC family histories. 37 families with a CRC patient below the age of 50 are recorded. They are recruited into a psycho-oncological substudy. First risk estimates will be available end of 2013. Conclusions: For the first time, the study offers population based data on familial CRC risk in a German population of 4.6 mio. people. The results strengthen the concept of familial CRC risk for the development of appropriate preventive screening strategies.
Palliative care consultation and advance care planning for adults with poor-risk leukemia admitted to an academic medical center.
Authors: Ashley Freeman, William A Wood, Alexandra Fox, Laura C. Hanson
Journal: Journal of Clinical Oncology (2016)

13 Background: Despite high mortality for certain patients with hematologic malignancies, integration of palliative care (PC) and documentation of advance care planning (ACP) is lacking. Our primary objective was to determine the frequency of PC consultation and ACP for inpatients with poor-risk leukemia at our institution. Our secondary objectives were to describe the content of goals of care (GOC) discussions and to characterize PC and end-of-life quality measures. Methods: Chart reviews were conducted for patients with poor risk leukemia (acute leukemia ≥ 65 years or relapsed leukemia &gt; 18 years) admitted to the University of North Carolina from October 1, 2015 to March 31, 2016. The following was abstracted from the chart: demographic data, disease characteristics, presence of a PC consultation, frequency and content of ACP (written advance directive, documented GOC discussion, identified surrogate decision maker), PC quality measures (assessment of pain, dyspnea, nausea, constipation), and end-of-life quality measures (chemotherapy within 14 days of death, ICU stay within 30 days of death, hospice referral less than 3 days prior to death). Results: Thirty-eight subjects were identified. Fifty percent of patients were over age 65 with a new diagnosis of acute leukemia and 50% had relapsed leukemia. The majority of patients (66%) reported pain and 45% reported dyspnea on admission. Sixteen percent of patients died within 30 days of discharge. Eleven percent of patients received PC consultation and 16% had all elements of ACP documented in the chart. GOC discussions without a surrogate decision maker were documented for 37%; content included discussion of values (11%), prognosis (37%), treatment choices (21%), life sustaining preferences (16%), and hospice (21%). Conclusions: In this descriptive study of inpatients with poor-risk leukemia, we found that despite a poor prognosis and high symptom burden, only 11% of patients received PC consultation and 16% had all elements of ACP present in the chart. While our data are limited by documentation, we believe this represents missed opportunities for the delivery of high-quality care.
Phase II study of 5-FU/LV/Irinotecan in combination with regional hyperthermia (RHT) in 5-FU/LV refractory patients with advanced colorectal cancer
Authors: M. Krych, L. H. Lindner, S. Abele, S. Abdel-Rahman, W. Fahn, V. Milani, S. Braun, B. Stockheim, V. Heinemann, R. D. Issels
Journal: Journal of Clinical Oncology (2005)

3724 Background: In 5FU/LV refractory pts the addition of Irinotecan as 2nd line treatment creates response rates of 22% and leads to a progression free survival of 6.3 months (e.g. Ducreux et al. 1999). Based on the rationale that hyperthermia augments the efficacy of chemotherapeutic agents this study was undertaken to determine the therapeutic potential of a combined thermochemotherapy regimen using 5FU/LV/Irinotecan for this subgroup of pts. Methods: Between 06/01 and 03/04, 15 pts with locally advanced, not resectable (6 pts) or metastatic (9 pts) colorectal cancer were enrolled. Eligible pts had progressed under a previously given 5-FU/LV based chemotherapy. One cycle of thermochemotherapy consisted of continuous infusion of 2000 mg/m2 5-FU over 24h plus 500 mg/m2 LV and 80 mg/m2 Irinotecan weekly in combination with regional (RHT, 42.5°C) or part body (PBH, 40.8°C) hyperthermia for 60 minutes (endoluminal thermometry, power range 800 -1200 W, electromagnetic system BSD 2000, BSD Medical corporation, Salt Lake City, UT) for 6 weeks followed by a 2 week interval. Results: 8 male and 7 female pts (median age 62 yrs, range 34–73 yrs) received a total of 27 cycles. Response evaluation showed 2 CR (confirmed with PET scan), and 3 PR, resulting in a objective response rate of 33%. 4 of 15 pts showed PD after two cycles. After a median observation time of 15 months (9–33 months) the median time to progression was 8 months (1–28 months) and the median overall survival was 12 months (2–28 months). The major common toxicity was diarrhea (with 20% grade 3). Toxicity profile for chemotherapy was mild and manageable, except of grade 3 nausea (3 pts) and a hospitalization due to a non-neutropenic infection (1 pt). HT was well tolerated and only one patient was early withdrawn from therapy due to treatment related pain. Conclusion: The addition of HT appears not to increase the toxicity of the 5FU/LV/Irinotecan therapy. This combined approach might gain additional benefit for 5FU/LV refractory pts. The response rate is promising and warrants further investigation of hyperthermia (RHT, PBH) in a randomized trial. No significant financial relationships to disclose.
Caveolin-1: Oncogenic role in breast cancer? Clues from molecular profiling.
Authors: Rebecca Feldman, Zoran Gatalica, Sandeep K. Reddy, Michael Castro, Jasgit C. Sachdev
Journal: Journal of Clinical Oncology (2015)

134 Background: Caveolin-1 (CAV1) is the structural component of caveolae, compartments within the plasma membrane that sequester signaling molecules, thus facilitating molecular “hot spots”. The role of CAV1 in breast cancer is an active area of investigation. We sought to understand the clinical and pathological characteristics of CAV1 positive tumors (CAV 1+) through a retrospective analysis of molecularly-profiled breast cancer patients. Methods: 2,728 breast cancer patients molecularly profiled with a commercial assay (Caris Life Sciences) were evaluated retrospectively for expression of various biomarkers by immunohistochemistry (IHC) and in situ hybridization. JMP statistical analysis tool was used to ascertain distributional differences. Results: Using a threshold of 2+ and 30%, 121/2728 (4%) of patients exhibited CAV1 over-expression by IHC. To observe clinicopathologic differences in the CAV1 + and CAV1- tumors, distribution by age, metastatic disease, and triple negative histology (TNBC) were analyzed. Average age for both groups was 55. 39% vs. 54% were metastatic and 74% vs. 26% were TNBC (p = 0.0001) among CAV1+ and CAV1- groups, respectively. To evaluate the potential oncogenic associations of CAV1, we evaluated the relationship between CAV1+ and various oncogenic pathways. Positive EGFR protein expression and presence of EGFR gene amplification, as well as cKIT over-expression associated with CAV1+ (all p-values &lt; 0.001), whereas HER2 expression and amplification were associated with CAV1- (p = 0.001 for both). In addition, higher Ki67, p53 and TOP2A expression by IHC were observed in CAV1+ patients compared to the CAV1- subgroup (90% vs. 66%, 50% vs. 36%, 84% vs. 65% ; all p-values &lt; 0.0001). Biomarker expression differences that did not meet statistical significance: ERCC1, MGMT, PDGFRA, RRM1, SPARC, TS and TOPO1. Conclusions: The majority of CAV1+ breast cancers are comprised of triple negative, higher proliferative tumors, with aberrant p53 expression as well as expression of other growth factor signaling proteins. This data supports the potential role of CAV1 in fostering molecular hubs for signaling and CAV-1 being a potential target for future therapeutic investigation in TNBC.
Age-dependent shift in macrophage polarisation causes inflammation-mediated degeneration of enteric nervous system
Authors: Laren Becker, Linh Nguyen, Jaspreet Gill, Subhash Kulkarni, Pankaj Jay Pasricha, Aida Habtezion
Journal: Gut (2017)

Objective The enteric nervous system (ENS) undergoes neuronal loss and degenerative changes with age. The cause of this neurodegeneration is poorly understood. Muscularis macrophages residing in close proximity to enteric ganglia maintain neuromuscular function via direct crosstalk with enteric neurons and have been implicated in the pathogenesis of GI motility disorders like gastroparesis and postoperative ileus. The aim of this study was to assess whether ageing causes alterations in macrophage phenotype that contributes to age-related degeneration of the ENS. Design Longitudinal muscle and myenteric plexus from small intestine of young, mid-aged and old mice were dissected and prepared for whole mount immunostaining, flow cytometry, Luminex immunoassays, western blot analysis, enteric neural stem cell (ENSC) isolation or conditioned media. Bone marrow derived macrophages were prepared and polarised to classic (M1) or alternative (M2) activation states. Markers for macrophage phenotype were measured using quantitative RT-PCR. Results Ageing causes a shift in macrophage polarisation from anti-inflammatory ‘M2’ to proinflammatory ‘M1’ that is associated with a rise in cytokines and immune cells in the ENS. This phenotypic shift is associated with a neural response to inflammatory signals, increase in apoptosis and loss of enteric neurons and ENSCs, and delayed intestinal transit. An age-dependent decrease in expression of the transcription factor FoxO3, a known longevity gene, contributes to the loss of anti-inflammatory behaviour in macrophages of old mice, and FoxO3-deficient mice demonstrate signs of premature ageing of the ENS. Conclusions A shift by macrophages towards a proinflammatory phenotype with ageing causes inflammation-mediated degeneration of the ENS.
Frequency of insulin-like growth factor 1 (IGFR-1) expression and correlation with clinical and selected molecular parameters in advanced non-small cell lung cancer (NSCLC) patients (pts)
Authors: M. Batus, M. J. Fidler, S. Basu, J. S. Coon, L. Buckingham, K. Kaiser-Walters, S. E. McCormack, P. D. Bonomi
Journal: Journal of Clinical Oncology (2008)

22080 Background: The epidermal growth factor receptor (EGFR) signaling pathway has become an important target in lung cancer with the success of EGFR tyrosine kinase inhibitors (TKI). The IGFR-1 signaling pathway has also been implicated in oncogenesis and cancer cell survival. The aim of the study was to determine the correlation of IGFR-1 expression with both clinical features of previously treated advanced NSCLC pts and molecular markers in the EGFR pathways in pts treated with gefitinib. Methods: Consecutive Expanded Access Trial pts with >1 week gefitinib were included for analysis. 83 pts had tissue evaluated for IGFR-1 immunohistochemistry (IHC). IGFR-1 positivity was defined as presence of any staining. 81 patients were evaluated for EGFR protein expression by IHC; EGFR gene copy number, and chromosome 7 copy number (c7) by fluorescence in situ hybridization (FISH), FISH positivity as defined by Cappuzzo et al, JNCI, 2005. Results: 78 pts had tissue with both IGFR-1 expression and FISH analyses available: median age 66, 36(46.2%) men, 48(61.5%) with adenocarcinoma, 12(15.4%) never smokers, and 71(91.0%) with performance status(PS) of 0. The response rate (including CR and PR) to gefitinib was 15.38%. Median progression free survival was 3.0 months. Median overall survival was 7.3 months. Positive IGFR-1 score (> 0) was seen in 71.08% of tissue samples. Positive IGFR-1 was marginally associated with smoking (p<0.1). No significant association was found between IGFR-1 score and age, gender, histology, or PS. There was a significant association between IGFR-1 positivity and the following parameters: EGFR IHC (p=0.002), c7 (p=0.03), and EGFR gene amplification (p-0.01). Conclusions: IGFR-1 expression is relatively frequent in NSCLC. In this group of NSCLC pts, IGFR expression by IHC did not correlate with clinical parameters. The significant correlations between IGFR expression by IHC and increased EGFR protein expression, EGFR gene amplification and c7 polysomy, suggest that combining an IGFR inhibitor with an EGFR TKI might improve outcomes in selected NSCLC pts. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration AstraZeneca AstraZeneca
Safety and efficacy of resin 90Y-microspheres in 548 patients with colorectal liver metastases progressing on systemic chemotherapy.
Authors: Andrew S. Kennedy, David Ball, Steven J. Cohen, Michael Cohn, Douglas M. Coldwell, Alain Drooz, Edward Ehrenwald, Samir Kanani, Steven C. Rose, Charles W. Nutting, Fred M Moeslein, Michael Savin, Sabine Schirm, Samuel G. Putnam, Navesh K Sharma, Eric Wang
Journal: Journal of Clinical Oncology (2013)

264 Background: 90 Y-microspheres (radioembolization) are administered via the hepatic artery following failure of one or more lines of fluoropyrimidine-based systemic chemotherapy, with or without biologic agents in colorectal carcinoma metastatic (mCRC) to the liver. Methods: A retrospective review of consecutively treated patients with mCRC from July 2002 to December 2011 at 11 U.S. institutions was conducted. Data on background characteristics, prior chemotherapy, surgery/ablation, radiotherapy, vascular procedures, 90 Y treatment (SIR-Spheres; Sirtex Medical), subsequent adverse events (grade 3+) and survival were documented. Median follow-up was 8.5 mo. (IQR 4.3–15.6). Trends in the occurrence of adverse events for patients receiving 1, 2, or 3+ lines of systemic chemotherapy were evaluated by Fisher’s Exact. Kaplan Meier estimates compared the overall survival of patients across lines of chemotherapy. Results: A total of 548 patients were included; majority were male (61%), Caucasian (66%), mean age 61 years; received median of 2 (range 1–6) lines of chemotherapy prior to 90 Y therapy. Median tumor/liver ratio at 90 Y therapy was 15% (IQR 23%). Median 90 Y activity administered was 1.18 GBq (IQR 0.48). Hospital stay duration was &lt;24 hours for most cases (97.8%). The most common adverse events (grade 3+) following 90 Y therapy included: abdominal pain 6.6% (n=36), GI ulceration 1.8% (10), nausea 1.5% (8), vomiting 1.6% (9), fatigue 6.0% (33), ascites 3.5% (19), hyperbilirubinemia 5.7% (31) and anorexia 1.1% (6). A comparison of 1, 2 and 3+ lines of chemotherapy versus grade 3+ adverse events to 3 months post- 90 Y therapy revealed no significant difference (p&gt;0.05). Corresponding median survivals (95% CI) were 13.0 (10.5–14.6), 9.0 (7.8–11.0) and 8.1 (6.4–9.3) months, respectively (p&lt;0.0001). Conclusions: 90 Y microsphere therapy appears to have a favorable risk/benefit ratio in patients with mCRC who have failed prior systemic chemotherapy. These data show a clinically relevant survival benefit for 90 Y therapy in patients not responding to chemotherapy, including those heavily pre-treated (3+ lines).
An oral androgen receptor PROTAC degrader for prostate cancer.
Authors: Taavi K Neklesa, Lawrence B Snyder, Mark Bookbinder, Xin Chen, Andrew P Crew, Craig M Crews, Hanqing Dong, Deborah A Gordon, Kanak Raina, AnnMarie K Rossi, Ian Taylor, Nicholas Vitale, Jing Wang, Ryan R Willard, Kurt Zimmermann
Journal: Journal of Clinical Oncology (2017)

273 Background: The Androgen Receptor (AR) remains the principal driver of castration-resistant prostate cancer during the transition from a localized to metastatic disease. Most patients initially respond to inhibitors of the AR pathway, but the response is often short-lived. The majority of patients progressing on enzalutamide or abiraterone exhibit genetic alterations in the AR locus, either in the form of amplifications or point mutations in the AR gene. Given these mechanisms of resistance, our goal is to eliminate the AR protein using the PROteolysis TArgeting Chimera (PROTAC) technology. Further, we sought to make an orally bioavailable AR PROTAC. Methods: Medicinal chemistry efforts yielded a small molecule AR PROTAC that simultaneously binds E3-ubiquitin ligase and AR, thus leading to ubiquitination and degradation of AR. This molecule has been characterized in in vitro and in vivo preclinical studies. Results: Our lead oral AR PROTAC degrades 92-98% of total AR in all cell lines tested, with 50% degradation concentration (DC 50 ) &lt; 1 nM. AR degradation suppresses the expression of AR-target gene PSA, inhibits cell proliferation, and induces potent apoptosis in VCaP cells. No activity is observed in AR-null cell lines, such as PC-3. While enzalutamide loses its activity in the presence of elevated androgens, AR PROTAC maintains its antiproliferative activity. Further, AR PROTAC is able to degrade all clinically relevant mutant AR proteins. A robust oral bioavailability is observed across multiple species and overall ADME properties are encouraging. Approximately 95% AR degradation is observed in AR-amplified VCaP xenografts at doses as low as 10 mg/kg. Congruent with AR degradation, a dose responsive tumor growth inhibition is observed in AR-dependent xenograft studies. Conclusions: In summary, we report the first orally bioavailable AR PROTAC that robustly degrades AR in vitro and in vivo.