tbuckley/cabot-search huggingface dataset:
Evaluation of outcomes following centralization of cystectomy services in the United Kingdom.
Authors: Prashant Patel, Felicity Evison, Henry Goodfellow, Richard Bryan, Nicholas David James
Journal: Journal of Clinical Oncology (2014)

286 Background: NICE-Improving Outcomes in Urological cancers (2002) recommended that providers in UK carry out a cumulative total of at least 50 radical cystectomies or prostatectomies per year. Surgeons should perform ≥5 cystectomies per year and 30-day mortality rates of 3.5% or less must be achieved. We evaluated this effect of centralisation on cystectomy outcomes over the past decade. Methods: The Health Episode Statistic (HES) database for cystectomies in England over a period of 2001 to 2012 for patients with bladder cancer was interrogated. Banded provider volumes (&lt;10, ≥10 to &lt; 16, ≥16) and surgeon volumes (&lt;5, ≥5 to &lt;8, ≥8) with respect to age, sex, Charlsons’ comorbidity index, deprivation index are presented with outcomes related to 30, 60, 90 day mortality; length of stay (LOS); re-admission; complications; operation specific re-intervention; and overall survival related outcome data is analysed. Results: 14,693 cystectomies for bladder cancer were performed over the study period. 85.5% providers (35% of all cystectomies) and 70.9% Surgeons (40% of all cystectomies) were performing less than the recommend standard prior to the NICE 2002 recommendations. A decade later 50% providers (3.5% of all cystectomies) and 42% surgeons continue to perform less than the recommended standard but only 12.5% of all cystectomes were carried in non-compliant centres/surgeons. The 30-day mortality rate fell from 3.7% to 2.4%. There was no difference in age, sex or deprivation scores amongst the bands for providers/surgeons. However, high volume providers and surgeons operated on patients with higher comorbidity scores but achieved shorter LOS. No difference in complications was seen amongst the bands, but re-intervention rates were higher amongst low volume surgeons. Mortality (early and overall) was lower in high volume provider and surgeons when compared to low bands. Conclusions: The UK data suggests 87.5% cystectomies are carried out in a compliant centre indicative of centralisation. The 30-day mortality rates have fallen. Overall mortality is lower in high volume providers and surgeons despite these groups with higher co-morbidity scores reflective of improved service provision through centralisation.
Cancer in young adults: Characteristics of a cohort of Brazilian patients.
Authors: C. S. Souza, A. V. Melo Mendes, S. D. Simon
Journal: Journal of Clinical Oncology (2011)

1537 Background: The increasing incidence of cancer in young adults has been well documented in recent years. Lymphoma, melanoma, testicular cancer, female genital tract, thyroid, central nervous system (CNS), breast, leukemia and bone and soft tissue sarcomas make up 95% of total cancer in this age group. Malignancies in this population have a high cure rate, demonstrating need for awareness and care optimization. Studies on cancer in young people are scarce, especially in developing countries. This study aims to describe the malignancies in young adults among the population of two Brazilian University hospitals. Methods: We collected data regarding sex, age, histology and primary site of tumors from cancer patients diagnosed between 18 and 30 years of age, from January 2000 to January 2010. Records were derived from the central cancer registries of Hospital São Paulo (HSP) and Instituto de Oncologia Pediátrica, teaching hospitals of the Federal University of Sao Paulo, Brazil. Results: There were 261 documented cases of cancer. There were 160 males (61%) and 101 females (39%). Among the young male population, the most common tumors were bone sarcomas (28.3%), testicular cancer (17.6%) and hematologic malignancies (16.3%). Distribution varied among young female cancer patients: bone sarcomas (23.5%), hematologic malignancies (17.6%) and CNS tumors (12.7%). When analyzed by pathology, male predominance was sarcomas (36.4%), germ cell tumors (24.5%) and gliomas (10.0%) and female was sarcomas (31.3%), gliomas (14, 7%) and non-Hodgkin lymphomas (7.8%). This distribution is markedly different from older patients, where tumors of epithelial origin are much more frequent. Survival curves will be presented, evidencing a high success rate in the treatment of cancer in young adults. Conclusions: The high prevalence of bone neoplasms and low incidence of melanoma and thyroid cancer found in this study are in disagreement with other series of cancer in young adults, collected mostly in developed countries. It may reflect ethnic and environmental differences between the different populations. Young adults with cancer have a unique distribution of non-epithelial tumors and need an optimized and individualized care in order to achieve high cure rates.
Quality of published studies supporting off-label and accelerated approval oncology indications.
Authors: K. R. Carson, Y. Chia, J. Sekhar, R. R. Coeytaux, J. L. Wheeler, C. L. Bennett, A. P. Abernethy
Journal: Journal of Clinical Oncology (2010)

6059 Background: We evaluated the quality of published studies supporting a sample of accelerated approval (AA) and off-label (OL) oncology drug indications, since AA/OL indications represent a substantial proportion of anticancer therapies prescribed. Methods: Using an established systematic literature review approach, we screened 1695 publications supporting 19 OL indications for 8 drugs; 66 phase II or III trials were identified. 28 phase II or III trials for 24 AA indications for 19 drugs were identified using FDA approval data. Study quality was graded using the Downs instrument, designed to assess quality of randomized or nonrandomized studies (score range 0 to 32). Mean quality scores were compared by t-test. Factors associated with study quality were analyzed using linear regression. Results: Mean quality score for AA studies was 16.8 (SD = 3.35), while mean score for OL studies was 16.1 (SD = 2.31) (p = 0.246). Multivariate analysis evaluated influence of the following on mean study score: sponsor (pharmaceutical v. other), orphan indication (< 200,000 cases/year vs. ≥ 200,000), multicenter vs. single, and phase III vs. phase II. Only orphan indication (β – 2.193, p = 0.007) and phase III design (β 4.505, p < 0.001) were significant in multivariate analysis, with orphan indications having a lower mean quality score than nonorphan (16.1 vs. 18.5), and phase III having a higher mean quality score than phase II (20.8 vs. 16.1). Conclusions: Mean quality scores for trials supporting OL and AA indications were lower than mean scores previously reported in oncology trials (20 or 21); the majority of AA and OL studies were nonrandomized. There was no difference in the quality of publications supporting AA vs. OL indications. This may reflect publication space limitations, or limitations of the Downs instrument. It may also suggest that efforts are required to improve quality of reporting, as well as the evidence basis supporting OL and AA indications and their reimbursement. Review of characteristics of higher-quality phase II studies would facilitate creation of phase II reporting tools similar to CONSORT guidelines for randomized trials. No significant financial relationships to disclose.
Pharmacologic Blockade of αvβ1 Integrin Ameliorates Renal Failure and Fibrosis In Vivo
Authors: Yongen Chang, Wei Ling Lau, Hyunil Jo, Kazuyuki Tsujino, Leslie Gewin, Nilgun Isik Reed, Amha Atakilit, Ane Claudia Fernandes Nunes, William F. DeGrado, Dean Sheppard
Journal: Journal of the American Society of Nephrology (2017)

Activated fibroblasts are deemed the main executors of organ fibrosis. However, regulation of the pathologic functions of these cells in vivo is poorly understood. PDGF receptor β (PDGFR β ) is highly expressed in activated pericytes, a main source of fibroblasts. Studies using a PDGFR β promoter–driven Cre system to delete α v integrins in activated fibroblasts identified these integrins as core regulators of fibroblast activity across solid organs, including the kidneys. Here, we used the same PDGFR β -Cre line to isolate and study renal fibroblasts ex vivo . We found that renal fibroblasts express three α v integrins, namely α v β 1, α v β 3, and α v β 5. Blockade of α v β 1 prevented direct binding of fibroblasts to the latency-associated peptide of TGF- β 1 and prevented activation of the latent TGF- β complex. Continuous administration of a recently described potent small molecule inhibitor of α v β 1, compound 8, starting the day of unilateral ureteral obstruction operation, inhibited collagen deposition in the kidneys of mice 14 days later. Compound 8 also effectively attenuated renal failure, as measured by BUN levels in mice fed an adenine diet known to cause renal injury followed by fibrosis. Inhibition of α v β 1 integrin could thus hold promise as a therapeutic intervention in CKD characterized by renal fibrosis.
A phase II study of intravenous azacitidine alone in patients with myelodysplastic syndromes: NCT0038495
Authors: R. A. Walgren, C. Dao, F. Kreisel, P. Westervelt, C. N. Abboud, T. Graubert, A. F. Cashen, G. L. Uy, F. Gao, J. F. Dipersio, R. Vij
Journal: Journal of Clinical Oncology (2008)

7097 Background: 5-Azacytidine (Aza) has been shown to provide a survival benefit in the treatment of myelodysplastic syndromes (MDS). While Aza was first approved for subcutaneous (SC) administration, SC injection site reactions are not uncommon, especially in thrombocytopenic patients. Aza is FDA approved for short intravenous (IV) infusion for 7 days and is anticipated to be efficacious from pharmacokinetic profiling, but prospective efficacy data for this route are lacking. In addition, the 7 day treatment course presents logistic problems in an outpatient setting. Methods: To determine the efficacy of short IV infusion Aza, an open-label, single-arm, single-center phase II study of IV Aza in MDS, defined by FAB classification was undertaken. Subjects previously treated with Aza or decitabine were ineligible. Treatment consisted of Aza 75 mg/m2 given as a 20 minute IV infusion once daily on Days 1–5 of a 28-day cycle. Response was evaluated by modified IWG 2006 criteria. Patients failing to achieve a CR after 2 cycles were eligible for an increased dose of 100 mg/m2. Patients must have demonstrated at least a hematologic improvement to continue on study beyond 6 cycles. Study endpoints include determination of complete response (CR) and partial response (PR) rates. Results: Accrual began 8/17/06 with a target of 21 subjects. Eighteen subjects (median age 71.4 yr, range 53–82) have completed ≥ 1 cycle (median 3, range 1–9). Subjects consist of 4 RA, 10 RAEB, 2 RAEB-t, and 2 CMML, and IPSS risk of 1 Low, 5 Int-1, 10 Int-2, and 2 High. One subject achieved a CR and 2 have achieved a PR. Another 2 achieved an erythroid response, and 1 had stable disease. Nine subjects remain on study, 5 withdrew due to progressive disease, and 4 deaths have occurred on study (2 sepsis, 1 pneumonia, 1 MI). No deaths were attributed to Aza. Common adverse events (grades 1–4) include nausea (44%), emesis (39%), fatigue (44%), and hematologic toxicities (44%). Hematologic toxicities have resulted in transient treatment delays (≤ 4 weeks) and dose reductions but have not prevented subsequent treatment on study. Conclusions: This prospective study of IV AZA is approaching target accrual. Preliminary results demonstrate that IV AZA when administered over a 5 day period is safe and effective in patients with MDS. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Genzyme AnorMED, Bayer, Celgene, Genzyme, MGI Pharma, Novartis, Pfizer, Pharmion Pharmion
Clinical outcomes in pancreatic adenocarcinoma (PAC) associated with a known BRCA mutation.
Authors: M. A. Lowery, Z. K. Stadler, E. Ludwig, E. Salo-Mullen, D. R. D'Adamo, P. J. Allen, R. C. Kurtz, D. P. Kelsen, E. M. O'Reilly
Journal: Journal of Clinical Oncology (2011)

268 Background: BRCA1 and -2 germ-line mutations are associated with increased risk of PAC; approximately 5% of all cases of PAC are estimated to be due to an inherited genetic mutation (Lynch, HT, et al. Pancreatology, 2001;1(5):466-471). Other BRCA-associated cancers have demonstrated increased sensitivity to platinum chemotherapy and PARP inhibitors (PARPi) with improved clinical outcomes compared to sporadic cases (J Clin Oncol, 2008 Dec 1;26(34):5530-6). Outcomes in BRCA-associated pancreatic cancer are unknown. Methods: Patients with a known BRCA1 or -2 mutation and a diagnosis of PAC were retrospectively identified from the MSKCC Familial Pancreas Cancer Registry and via institutional database review. Outcomes and clinical characteristics were reviewed. 7 patients (1 male) with BRCA2 mutation and PAC, 4 patients (1 male) with BRCA1 mutation and PAC, were identified. Two further cases of BRCA mutation and cholangiocarcinoma were identified. Results: See Table for patient demographics. Treatment for advanced disease included a PARP inhibitor (PARPi) in 2 cases; both pts had a radiologic partial response (PR) to therapy. Five patients received platinum-based chemotherapy for advanced disease, 4 of whom had a PR. Median survival for all patients was 27.6 months. Conclusions: The use of platinum- containing chemotherapy, radiation therapy, and PARPi to target the BRCA-associated defective DNA repair mechanism is deserving of further investigation in these patients. PARPi have demonstrated promising efficacy in patients with BRCA-mutated breast and ovarian cancer and are undergoing prospective evaluation in PAC. Genetic testing in patients presenting with a personal history or strong family history of BRCA associated cancers may help to guide choice of therapy. [Table: see text] No significant financial relationships to disclose.
Treatment of metastatic penile cancer in the adjuvant setting with ifosfamide, paclitaxel, and cisplatin: A single institution experience.
Authors: Aine O'Reilly, Margaret O'Keeffe, Paul Aherne, Nicholas J. Mayer, John P. Sweeney, Derek G. Power
Journal: Journal of Clinical Oncology (2013)

340 Background: Surgery alone rarely results in long-term disease-free control in patients with N2 or N3 (stage III or IV) metastatic penile cancer. Five-year overall survival rarely exceeds 40% in this group of patients. Ifosfamide, paclitaxel, and cisplatin chemotherapy (ITP) has been reported in the neoadjuvant setting in a phase II trial. The evidence supporting adjuvant chemotherapy after inguinal lymph node dissection (LND) is poor. We report our experience of ITP chemotherapy given in the adjuvant setting after bilateral inguinal LND for stage III and IV penile cancer Methods: In our regional cancer center we performed a retrospective analysis of a prospectively maintained database of all patients between May 2008 and February 2012 who received adjuvant chemotherapy for regional metastatic penile cancer. Results: Four patients received chemotherapy in the adjuvant setting. One patient completed 4 cycles of cisplatin and 5-Fluorouracil after bilateral inguinal LND (pT1N2). There is no evidence of disease recurrence at 20 months post completion of chemotherapy. Three patients received adjuvant chemotherapy with paclitaxel 175 mg/m 2 on day 1; ifosfamide 1,200 mg/m 2 on days 1-3; and cisplatin 20 mg/m 2 on days 1-3 (ITP). All pts received 4 X 3 weekly cycles with no significant toxicity. The first two patients underwent inguinal LND for pT3N2 (stage IIIB) disease followed by 4 cycles of ITP. In both patients surveillance imaging showed no evidence of disease recurrence 28 and 50 months, respectively, post completion of chemotherapy. The third patient underwent inguinal LND for pT1bN3 (stage IV) disease followed by 4 cycles of ITP. Surveillance imaging at 6 months post completion of chemotherapy showed no evidence of local or distant recurrence. Conclusions: Multimodality treatment of regional metastatic penile cancer offers the best chance of long-term disease-free and overall survival. The ITP regimen is relatively nontoxic and well-tolerated. We propose that this regimen should be further investigated in the adjuvant or peri-operative settings.
Intermediate-risk prostate cancer treated with external beam radiotherapy (EBRT): A risk group with heterogeneous behavior.
Authors: Constanza Pérez de la Puente, Federico Losco, Carolina Chacon, Juan Pablo Sade, Gonzalo H. Giornelli, Matias Chacon, Reinaldo D. Chacon
Journal: Journal of Clinical Oncology (2016)

145 Background: In men with intermediate-risk prostate cancer (IR-PC) treated with low dose EBRT, the addition of androgen deprivation therapy (ADT) prolongs overall survival. Zumsteg proposes a subdivision for de IR-PC group: favorable or unfavorable. Purpose: retrospective evaluation of EBRT efficacy according to IR-PC subgroups (favorable or unfavorable). Methods: From the institutional radiotherapy department database, from 2000 to 2011, 95 men with IR-PC were identified and subdivided as follows: Favorable Risk (FR) – Gleason 3+4 or less and positive prostate biopsies (ppb) not exceeding 50% and only one intermediate-risk factor excluding 4+3; Unfavorable risk (UR) – Gleason 4+3 or at least 2 intermediate-risk factors or at least one intermediate risk factor and ppb &gt;50%. Results: 95 patients were included in the analysis, mean FUP 6.2 years. 32.6% (31) had &gt;50% ppb, 14.7% (14) had Gleason 4+3, 38.9% (37) had 2 intermediate-risk factors. 42.1% (40) were FR and 57.9% (55) were UR. Median EBRT dose: 79.8Gy. Only 25% of FR patients received some hormonal therapy treatment. There were no differences in time to Prostatic Specific Androgen (PSA) nadir (FR 12 vs UR 13 months; p= .50), biochemical relapse free survival (RFS) (FR 60 vs US 58 months; p= .80), or doubling time PSA (FR 12 vs UR 11 months; p= .19). Biochemical relapse (BR) and local relapse (LR) rates were lower for FR (BR: FR 27.5 vs UR 38.2%, p= .17; LR: FR 5 vs UR 14.5%, p= .40). Local RFS (FR 13.6 vs UR 9.6 years; p= .11) and distant RFS (FR 13.1 vs UR 12.4 years; p= .65) were longer for FR patients. Conclusions: Short course ADT is the standard treatment in IR-PC patients when EBRT is indicated, especially if they have UR features. In our study IR-PC group had heterogeneous outcomes and, in spite the study limitations, FR patients had a trend for better prognosis even with a very low use of ADT. If Favorable IR-PC patients may avoid ADT morbidity should be answered by a randomized trial.
Evaluation of early clinical experience of a novel prognostic proteomics prostate cancer biopsy test.
Authors: Sibgat Choudhury, Bruce J. Trock, Rene Benson Skone, Julie Nardone, James Dunyak, Michail Shipitsin, Jonathan I Epstein
Journal: Journal of Clinical Oncology (2015)

88 Background: Standard clinical and pathological parameters derived from diagnostic biopsy are insufficient to accurately assess final prostate tumor pathology of patients with biopsy Gleason grades 3+3 or 3+4. We developed a novel assay (ProMark) that performs quantitative measurements of 8 protein markers from prostate biopsy FFPE sections. In the validation study, assay risk scores were strongly predictive of final prostate tumor pathology with a C-stat of 0.69 (95%CI = 0.63 – 0.76) (p&lt;0.0001). By design, the train-test (N=381) and validation (N=274) studies were enrichment studies, with a higher % of aggressive disease than in the intended use population. Here we study 293 needle biopsy cases that have come to our CLIA lab for ProMark testing over a four month period. The objective of this study is to establish the ProMark score distribution for these ‘real world’ clinical use patients, and to confirm that this distribution matches our clinical validation study. Methods: To establish prevalence of aggressive disease in the intended use population, we used the Institutional Urology Prostate Cancer Database at Johns Hopkins. Among 9,305 men with biopsy Gleason 3+3 or 3+4 and prostatectomy from 2004-2014 the distribution of favorable (GS&lt;4+3 &amp; organ confined) and unfavorable (GS≥4+3 or non-organ confined) based on surgical pathology is 73.1% vs. 26.9%. The adjusted risk score distribution from the validation trial (N=274) is then compared to the CLIA lab samples (N=293), based on cumulative distributions and binomial confidence intervals. Results: Comparison of the risk score distribution of early clinical data with the population-adjusted validation score distribution shows good agreement based on 95% CIs. Table shows expected and measured frequencies in Low, Intermediate and High risk categories. The K-S test for comparison of distributions has p-value=0.44, supporting equivalence of distribution. Conclusions: The results of our study show that early clinical practice closely matches expectations from controlled clinical studies. [Table: see text]
Highly functional natural killer (NK) cells as predictive biomarkers associated with long response to castration in newly diagnosed metastatic prostate cancer.
Authors: Christine Pasero, Gwenaelle Gravis, Mathilde Guerin, Palma Rocchi, Jeanne Thomassin, Jochen Walz, Naji Salem, Slimane Dermeche, Serge Brunelle, Daniel Olive
Journal: Journal of Clinical Oncology (2014)

95 Background: Immunotherapy is now investigated as a promising alternative treatment for patients (pts) with metastatic prostate cancer (PC). Natural killer (NK) cells are powerful effector cells with antitumoral activity and their role have been explored in solid tumors but not yet in prostate cancer. NK cell cytotoxicity is regulated by a balance between activating and inhibitory receptors. Here, we performed a restrospective study to evaluate the link between NK cells and the time of castration response in newly diagnosed PC patients with metastases. Methods: Newly diagnosed metastatic PC pts were divided according the time of castration response, with an 18-months cutoff value: 18 pts with long castration response (LCR, median = 64.6 months), and 14 pts with short castration response ([SCR] median = 11.2 months), with a median overall survival of 97.7 months and 33.8 months respectively. Circulating NK cells from these patients were studied by flow cytometry to evaluate the expression of activating receptors and the NK cell functionality. Results: We observed thatNK cells from LCR pts express higher levels of the maturation marker CD57 (43.3% vs. 23.3% positive cells, p= 0.002), the receptor CD16 involved in cytotoxicity (29,124 vs. 16,806 MFI, p= 0.02), and the activating receptors NKp46 and NKp30 (17.5 vs. 11.4 RMFI, p= 0.0146 , and 10.9 vs. 6.3 RMFI, p = 0.0128 respectively) than NK cells from SCR pts. This suggests that LCR pts have powerful NK cells. Indeed, NK cells from LCR pts are highly efficient in CD107 functional assay than NK cells from SCR pts (28.9% vs. 19.4%, p =0.002). In vitro blocking experiments show that NKp46 is precisely one of the NK cell receptors involved in the NK-mediated recognition of prostate tumor cells, thus higher expression of NKp46 would help to control PC progression. Conclusions: Together our results show for the first time that efficient NK cells are associated to a long response to castration and prolonged survival in newly diagnosed metastatic PC. NK cell receptors might be useful as predictive biomarkers in metastatic PC, to help in stratification of patients and to design NK cell–based immunotherapeutic strategies for PC.