tbuckley/cabot-search huggingface dataset:
Phase 1/2a, open-label, dose-escalation and safety study of APC-100 in men with advanced prostate cancer.
Authors: Christos Kyriakopoulos, Elisabeth I. Heath, Jens C. Eickhoff, Jill Kolesar, Mulusew Yayehyirad, Thomas Moll, Glenn Liu
Journal: Journal of Clinical Oncology (2015)

234 Background: Normal human prostate epithelium and prostate carcinoma exhibit high levels of oxidative stress, which is thought to play a role in the pathogenesis of prostate cancer. APC-100 (2,2,5,7,8-Pentamethyl-6-chromanol) is an oxidative stress modulator that reduces reactive oxygen species (ROS) in prostate cancer cells and inhibits growth of cultured androgen-dependent and independent human prostate cancer cells. We aimed to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), adverse events (AEs), clinical activity and pharmacokinetic (PK) parameters of APC-100 in men with castrate-resistant prostate cancer (CRPC). Methods: This open label phase 1/2a study utilizes a time-to-event reassessment method (TITE-CRM) design. Patients (pts) in cohorts of 3 were treated with escalating doses of APC-100 (900mg-2400mg) orally once daily continuously in 150 mg capsules. Cycles were 28 days. All patients were evaluable with PSAs and imaging studies. Results: Twenty pts (median age 72 [range 54-87]) with metastatic and non-metastatic CRPC were enrolled in the dose escalation cohort. Pts remained on study for a median of 12 weeks (range 4-36) and received therapy for a median of 3 cycles (range 1-9). One possible DLT (elevated ALT) was seen at dose level 1 and the patient was taken off study. No other DLTs at least possibly related to therapy were seen and no dose reductions were required. Most frequent AEs at least possibly related to therapy included nausea (grade 1 in 6 pts) and elevated transaminases (grade 1-3 in 5 patients). After enrolment of 20 pts the MTD was not reached, however the maximal feasible dose was exceeded due to the number of capsules required. Five of the 20 patients had stable disease per PSA and/or RECIST 1.1 as their best response. The median progression free survival (PFS) for the cohort was 2.8 months (range 1-8). Conclusions: APC-100 appears to be well tolerated with the MTD not reached. Limited PK assessment supports the need for alternative formulation to allow dose escalation to doses necessary to achieve exposures required for response. Once MTD is established, future studies will explore the activity of APC-100 as a therapeutic and chemopreventive intervention. Clinical trial information: NCT01436214.
Stratification of patients with colorectal cancer of UICC stage II using prognostic mutations signatures obtained by deep amplicon sequencing of cancer genes.
Authors: Andre Rosenthal, Karsten Ridwelski, Frank Marusch, Matthias Pross, Rene Mantke, Thomas Manger, Jörg Pertschy, Thomas Buthut, Klaus Gellert, Robert Gruetzmann, Holger Engelhardt, Peter Nartschik, Rainer Koll, Karin Kretschmar, Karl-Heinz Kretschmar, Bernd Drescher, Katrin Stecker, Ricado Raspe, Susanne Klaßen, Hans-Peter Adams
Journal: Journal of Clinical Oncology (2013)

377 Background: Assignment of patients (pts) with UICC-stage II colorectal cancer (CRC) to adjuvant therapy remains controversial. The clinical utility of histo-pathological parameters (pT 4 , L+, V+) as well as tumor RNA expression signatures like Oncotype Dx Colon Cancer Assay, ColoPrint, or Predictor C is low given their positive predictive value (PPV) of 0.13, 0.22, 0.19, and 0.33, respectively, when adjusted to an incidence of 10% for occurrence of metastatic disease (mets) within 3 years after diagnosis. Methods: We applied deep amplicon sequencing of 48 well-known cancer genes to DNA samples of primary tumors from 173 pts with UICC-stage II CRC using the Illumina MiSeq technology. Patients were selected from a prospective, multicenter clinical diagnostic study named MSKK. More than 6,500 patients with CRC have been recruited into this study conducted by 39 hospitals in Germany. 79 of the 173 pts had progression of disease events within 3 years after R0 resection including 40 pts with mets, 12 pts with local recurrences, and 27 pts with secondary malignancies. 94 pts remained progression-free. Results: Deep sequencing revealed a total of 2,221 sequence variations (SV) including missense, stop, InDel, noncoding, nonsense SV. 401 SV were in COSMIC, 750 SV in normal tissue. The remaining 1471 SV served as basis for development of SV-signatures (SVS) for prediction of progression events in a classical double-nested bootstrap approach in order to generate second order unbiased estimates of performance of SVS, namely sensitivity(S + ), specificity (S - ), PPV, and negative predictive value (NPV). The best SVS for prediction of metastases contained SV in less than 15 genes and has a S + of 0.41, S - of 0.93, PPV of 0.40, and NPV of 0.93 (incidence of metastasis: 10%). The best SVS for prediction any progression event has a S + of 0.33, S - of 0.93, PPV of 0.54, and NPV of 0.84 (incidence for any progression = 20.5%). Conclusions: This deep sequencing based prognostic tissue test with a PPV of 40% and a NPV of 93% represents a milestone over prognostic tests based on RNA expression. The increased PPV leads to more patients being treated correctly with adjuvant therapy.
Grand Rounds--Hammersmith Hospital: A case of laboratory acquired brucellosis
Authors: P R Arlett
Journal: BMJ (1996)

take the contraceptive pill.These relatives have at least one family member with venous thrombosis who carries the mutation.Should we offer them screening?Perhaps they should first be told about the benefits and risks of knowing and asked about the acceptability of other forms of contraception.The advice to be screened might be firmer if other first degree family members are found to have had deep vein thrombosis at young ages or without clear risk factors (which would suddenly make the family into one with a tendency to multiple thrombosis), or if the index patient is a homozygote or carries combined thrombogenic defects.The clinical situation of the patient and the other family members will continue to direct the doctor's advice, rather than the mere presence or absence of a mutation.
Oncologic outcomes following radical resection with intraoperative electron radiation therapy in patients with recurrent colorectal cancer.
Authors: O. H. Llaguna, M. O. Meyers, M. B. Smith, K. B. Stitzenberg, A. M. Deal, B. H. O'Neil, S. A. Bernard, A. Z. Wang, J. E. Tepper, B. F. Calvo
Journal: Journal of Clinical Oncology (2011)

508 Background: Of the 40,000 rectal cancer patients treated annually, up to 15% will experience a local recurrence (LR). Resection only series for LR report 30–60% positive margin rates. For this reason our institution utilizes intra-operative electron radiation therapy (IOERT) in patients undergoing resection of locally advanced rectal cancer recurrences (LA-RRC). The purpose of this study was to evaluate the oncologic outcomes of patients treated for a LA-RRC with resection and IOERT Methods: Under IRB approval a prospective database of patients with LA-RRC undergoing resection and IOERT from April 2001 to January 2010 was analyzed. Demographic, clinical, and pathologic variables were collected. The Kaplan-Meier method estimated 5-year overall survival (OS) and Fisher's Exact test's explored associations for developing a LR. Results: Fifty patients (32 male, mean age 58 ± 11) underwent resection and IOERT (median dose 1500 cGy, energy 9 MeV). Primary procedures included pelvic exenteration (n = 17), APR (n = 10), LAR (n = 7), isolated pelvic/retroperitoneal tumor (n = 7), para-aortic lymphadenectomy (n = 7), and partial colectomy (n = 2). 56% (n = 28) required multi-visceral resections including partial/total cystectomy (n = 14), small bowel resection (n = 10), vaginectomy (n = 6), hysterectomy (n = 3), oophorectomy (n = 3), nephrectomy (n = 2), and other (n = 4). 34 pelvic sidewall resections and 12 partial sacrectomies were required. Margins were R0 in 37 (74%) and R1 in 13 (26%). Median LOS was 10 days and there were no peri-operative deaths. Five-year OS was 32% with a 19-month follow-up of survivors. 32% (n = 16) developed a pelvic LR, of which 2 were isolated and 14 were in the setting of distant metastasis. No difference was noted in OS (p = 0.5) or LR (p = 0.3) in patients with R0 vs. R1 resections. Initial T (p = 0.1), N (p = 0.2), and stage (p = 0.7) were not found to be associated with LR. Conclusions: This study reveals that resection combined with IOERT provides good local control and reasonable long-term survival in patients with LA-RRC. The similar OS and LR following an R0 and R1 resections could be interpreted as a measure of the beneficial effect of IOERT on microscopic disease. No significant financial relationships to disclose.
Reducing variability in operating room utilization.
Authors: Craig S. Owen, John C. Frenzel, Garrett L. Walsh
Journal: Journal of Clinical Oncology (2012)

321 Background: With a fixed number of operating rooms, as well as complexity of cases and volumes continuing to rise, it became important for MD Anderson to more effectively utilize the OR resources that are available. Methods: The initial intervention (4 years ago) was the development of a mechanism for effectively measuring and reporting both In-Block Utilization and Total OR Utilization. Through a systematic process of measuring and reporting OR utilization by day of week, all services began to pay closer attention to their data/utilization and began to engage in the process. The “OR Capacity” application was created, which enabled stakeholders to view overall booked capacity of the OR, as well as at the service level. This created complete transparency for all services to see how effectively they were using their block allocation by day of week, as well as across the month. Results: Reports produced monthly reflect each services overall In-Block Utilization, Total OR Utilization, as well as both of these metrics by case day of week. By viewing this data across all services, it provides transparency of utilization and where possible block swaps between services may occur. At the beginning of fiscal year 2009, the variability by case day of week of In-Block Utilization was 16% and 33% for Total OR Utilization. This wide variability was difficult for perioperative stakeholders to manage. Through a systematic approach of measuring, monitoring, and reporting, the most current data reflects the variability by case day of week of In-Block Utilization and Total OR Utilization has decreased to 3% and 9% respectively. Conclusions: By creating an application that provides transparency of OR capacity, as well as clear policies and procedures for block reallocation and how the measurement and reporting of block utilization would occur, we have demonstrated how a complex and multi-factorial issue of effective block utilization across the days of the week can be solved. This has required a multi-disciplinary team of individuals to work through and understand the issues, develop interventions, as well as the mechanisms to provide sustainable and ongoing monitoring and reporting of the utilization by case day of week. Without strong leadership, this effort would not have been possible.
Suitability of clear cell renal cell carcinoma to heat shock proteins-inhibitors.
Authors: Matteo Brunelli, Francesco Massari, Chiara Ciccarese, Stefano Ferrero, Giacomo Gazzano, Alessandra Modena, Emilio Bria, Giampaolo Tortora, Silvano Bosari, Guido Martignoni
Journal: Journal of Clinical Oncology (2014)

480 Background: Heat shock proteins (HSP) HSP27 and HSP90 are expressed in response to a wide variety of insults, thus allowing the cell to adapt to stress. In cancer cells, both HSP27 and HSP90 may participate to carcinogenesis, suggesting these chaperones as an appealing target for cancer therapeutics. The role of HSP in the development and progression of renal-cell carcinomas (RCCs) remains to be defined. We sought to evaluate a series of clear cell RCCs. Methods: 388 RCCs with clear cell histology available on 10 tissue microarrays were recruited. Each case was represented by 3 neoplastic cores. All these cases were stratified according to the Mayo Clinic SSIGN (Size, Staging, Grading, Necrosis) score into five prognostic groups with increasing worse prognosis (1 to 5). Immunostainings for HSP27 and 90 were performed. A mean score number from the three cores was set per case (percentage x intensity). Results were detailed per number of scorable cases per SSIGN category (1 to 5). Results: 117 and 122 RCCs were respectively available for HSP90 and HSP27 scoring. The remaining samples were lost due to the lack of tissue sections or to the absence of adequate neoplastic cells scorable. HSP90 scored 4,9 in 32 with SSIGN1, 3,5 in 41 SSIGN2, 4,8 in 11 SSIGN3, 4,2 in 22 SSIGN4 and 5 in 3 SSIGN5 patients. HSP27 scored 4,6 in 33 with SSIGN1, 3,1 in 43 SSIGN2, 2,6 in 11 SSIGN3, 3,6 in 24 SSIGN4 and 2,7 in 3 SSIGN5 patients. A significant trend of increasing value for HSP90 has been observed when comparing cases tabled SSIGN1-2 versus SSIGN3-5 (4,2 to 4,6 mean values) (p=0.05); a minor stratification has been observed for HSP27 (3,8 to 3,9) (p=0.08). Conclusions: In conclusion, HSP90 and HSP27 are variable immunoexpressed in a subset of clear cell RCCs, with a trend to higher prognostic SSIGN score. At light of new emerging targeted-therapies in kidney cancer, we report an increasing suitability of these patients to therapies that target the pathways of heat shock protein molecules. Additional learning of the HSP role in clear cell RCCs carcinogenesis is required to guide future therapeutic developments.
Marker driven systemic treatment of inoperable cholangiocarcinomas: Panitumumab and combination chemotherapy in KRAS wild-type tumors.
Authors: L. H. Jensen, J. Lindebjerg, J. Ploen, T. Hansen, A. K. M. Jakobsen
Journal: Journal of Clinical Oncology (2011)

4101 Background: Cholangiocarcinoma is a relatively rare cancer with a severe prognosis. Regimens combining cisplatin and gemcitabine are considered standard chemotherapy in non-resectable cases. In Denmark, a combination of gemcitabine, oxaliplatin and capecitabine has been evaluated in phase I and phase II trials. Based on experience with other gastrointestinal tumors, additional effect may be expected when combining chemotherapy and epidermal growth factor receptor (EGFR) antibodies, but only in KRAS wild-type (wt) tumors. The purpose of this phase II trial was to evaluate the efficacy of chemotherapy and the EGFR-inhibitor panitumumab in KRAS wt cholangiocarcinomas. Methods: Main eligibility criteria were performance status <3, age <80 years, evaluable (not necessarily measurable) disease, and KRAS wt. All patients received panitumumab 6 mg/kg, gemcitabine 1,000 mg/m2, and oxaliplatin 60 mg/m2 on day one plus capecitabine 1000 mg/m2 b.i.d. day one to seven on a two weeks cycle. In a two-stage design, the first 18 patients met the criteria for extending inclusion to 46. The primary endpoint was the fraction of progression free survival (PFS) at six months and secondary endpoints were response rate (RR), toxicity, and overall survival (OS). Results: From 10/2008 to 8/2010, 46 patients were included in a single institution. There were 31 women and 15 males. Median age was 66 years (range 37-80). Twenty-five, 16, and 5 patients were in performance status 0, 1, and 2, respectively. The primary endpoint, fraction of PFS at 6 months, was 71.6% (95% CI 56.1%-82.4%, 33 events, intention-to-treat). Forty-two patients had measurable disease and the best response was 1 CR, 13 PR, 21 SD, and 7 patients progressing or dying at or before first assessment after 3 months. Thus, RR was 33% and the disease control rate 83%. Median PFS was 8.3 months (95% CI 6.7-8.7 months) and median OS was 9.8 months (95% CI 7.4-12.5 months). Toxicity was as expected including 8 cases of EGRF related skin adverse events >grade 2. Conclusions: This is the first marker driven phase II trial in inoperable cholangiocarcinoma. The regimen is feasible and will be tested in a randomized trial.
The Role of Obesity, Type 2 Diabetes, and Metabolic Factors in Pancreatic Cancer: A Mendelian Randomization Study
Authors: Robert Carreras-Torres, Mattias Johansson, Valerie Gaborieau, Philip C Haycock, Kaitlin H Wade, Caroline L Relton, Richard M Martin, George Davey Smith, Paul Brennan
Journal: JNCI Journal of the National Cancer Institute (2017)

Risk factors for pancreatic cancer include a cluster of metabolic conditions such as obesity, hypertension, dyslipidemia, insulin resistance, and type 2 diabetes. Given that these risk factors are correlated, separating out causal from confounded effects is challenging. Mendelian randomization (MR), or the use of genetic instrumental variables, may facilitate the identification of the metabolic drivers of pancreatic cancer. We identified genetic instruments for obesity, body shape, dyslipidemia, insulin resistance, and type 2 diabetes in order to evaluate their causal role in pancreatic cancer etiology. These instruments were analyzed in relation to risk using a likelihood-based MR approach within a series of 7110 pancreatic cancer patients and 7264 control subjects using genome-wide data from the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4). Potential unknown pleiotropic effects were assessed using a weighted median approach and MR-Egger sensitivity analyses. Results indicated a robust causal association of increasing body mass index (BMI) with pancreatic cancer risk (odds ratio [OR] = 1.34, 95% confidence interval [CI] = 1.09 to 1.65, for each standard deviation increase in BMI [4.6 kg/m2]). There was also evidence that genetically increased fasting insulin levels were causally associated with an increased risk of pancreatic cancer (OR = 1.66, 95% CI = 1.05 to 2.63, per SD [44.4 pmol/L]). Notably, no evidence of a causal relationship was observed for type 2 diabetes, nor for dyslipidemia. Sensitivity analyses did not indicate that pleiotropy was an important source of bias. Our results suggest a causal role of BMI and fasting insulin in pancreatic cancer etiology.
Radiolabeled anti–prostate-specific membrane antigen (PSMA) monoclonal antibody J591 for metastatic castration-resistant prostate cancer (CRPC).
Authors: N. H. Akhtar, D. M. Nanus, S. Vallabhajosula, J. Osborne, H. Beltran, L. Tyrell, K. Nadeau, A. Saran, G. Mileo, S. J. Goldsmith, N. H. Bander, S. T. Tagawa
Journal: Journal of Clinical Oncology (2011)

e15186 Background: J591 is a monoclonal antibody which selectively binds the external domain of PSMA with no direct effect on PSA expression or secretion. Two phase I trials of radiolabeled (RL)-J591 are published; 2 additional studies have been presented. 90Y is a beta-emitter optimal for tumor lesions 28-42 mm; 177Lu is best suited for 1-3 mm lesions. Methods: With IRB approval, long-term follow-up of four trials and ongoing expansion studies were analyzed for response, overall survival (OS), and imaging. Results: Between 10/00 and 11/10, 137 pts with metastatic CRPC received RL-J591 (108 177Lu-J591 at total doses of 20-90 mCi/m2, 29 90Y-J591 at 5-20 mCi/m2), median follow-up 69.5 months (mo). Median age 70.1 yrs, 40.9% with prior chemo, 47.4% got post-J591 chemo. 86.4% had accurate targeting of lesions on planar imaging. Median Halabi nomogram score was 146 (97-196). OS and PSA declines in Table; more declines at higher doses [p<0.001 for >30% decline, p=0.05 for any decline]; pts receiving 177Lu-J591 tended to have more 30% PSA declines, though the 50 pts with measurable disease had more radiographic responses to 90Y-J591 vs 177Lu-J591 [p=0.04]. All objective responses also had significant PSA declines. Pts with any PSA decline lived longer [p=0.001]; pts with > 30% PSA decline also lived longer [ p=0.055]. In recent era, of 21 pts with baseline and follow up CTC counts (CellSearch), 81% became or remained favorable. Conclusions: With a decade of experience, RL-J591 has demonstrated efficacy, producing PSA declines, which correlate with measurable response and appear to translate into survival benefit. As predicted based on physical properties, 177Lu-J591 appears more effective for lower volume disease, with objective responses in bulky disease only with 90Y-J591. N (%) Median OS (mo) [95% CI] 177Lu-J591 N (%) 90Y-J591 N (%) Treated at MTD N (%) All pts 137 16.6 [13.4, 19.7] 108 29 59 >30% PSA decline 30 (21.9%) 23.7 [19.5, 27.9] 26 (24.1%) 4 (13.8%) 23 (39.0%) No >30% PSA decline 107 (78.1%) 15.8 [12.7, 19.0] 82 (75.9%) 25 (86.2%) 36 (51.0%) Any PSA decline 74 (54.0%) 22.1 [19.7, 25.4] 61 (56.5%) 13 (44.8%) 38 (64.4%) PSA increase 63 (46.0%) 12.1 [7.7, 16.5] 47 (53.5%) 16 (55.2%) 21 (35.6%)
Age, hormone receptor status, ethnicity, and adjuvant radiation therapy as predictive factors for cancer-related death in patients age 70 and older with early-stage pT1a,b N0 breast cancer: An NCI-SEER database analysis.
Authors: Akkamma Ravi, Paul J. Christos, Dattatreyudu Nori, Clifford Chao, Weisi Yan
Journal: Journal of Clinical Oncology (2012)

155 Background: Studies have shown that older women are undertreated for breast cancer. Few data are available on 1) cancer-related death in elderly women age 70 and older with pathologic stage T1a, bN0 breast cancer and 2) on the impact of prognostic factors such as increasing age, hormone receptor status (ER), adjuvant radiation therapy (EBRT), chemotherapy, and ethnicity on cancer-related death. Methods: Patient data from SEER database were extracted. Inclusion criteria: females, age 70 and older, pT1a, bN0 invasive breast cancer, ER positive or negative, adjuvant EBRT or no radiation. Cause-specific survival time recorded for all eligible patients. Log-rank test and multivariate Cox regression analysis used for statistical analysis. Hazard ratios (HR) are presented for cancer-related death. Results: ER negative patients had a greater risk of breast cancer death compared to ER positive patients (adjusted HR = 2.34; p &lt; 0.0001). Stage IB patients had a greater risk of breast cancer death compared to stage IA patients (adjusted HR = 1.26; p = 0.09; trend). Patients with no radiation therapy had a greater risk of breast cancer death compared to patients with radiation therapy (adjusted HR = 1.40; p = 0.003). Older age groups had greater risk of breast cancer death compared to patients age 70-74 (referent category) (adjusted HR’s = 1.41, 1.72, and 3.18 for 75-79, 80-84, and 85+ age groups, respectively) (Table). Race had no effect on survival. Conclusions: Patients age 75 and older with T1a, b N0, ER-negative, breast cancer had increased risk of breast cancer-related death. Adjuvant EBRT showed survival benefit in this elderly patient population. Future randomized studies should focus on adjuvant treatments that will improve cancer-related death in this age group. [Table: see text]