tbuckley/cabot-search huggingface dataset:
Survival benefit and complications of primary tumor resection (PTR) in patients with stage IV colorectal cancer (CRC) in the era of modern chemotherapy: A systematic review and meta-analysis.
Authors: Shahid Ahmed, Rabia K Shahid, Punam Pahwa, Selliah Kanthan, Bruce Reeder, Sunil Yadav, Amer Sami, Kamal Haider, Anne Leis
Journal: Journal of Clinical Oncology (2013)

3580 Background: Although there is evidences that PTR in advanced CRC may improve outcome, most studies were conducted during the period of monotherapy with 5-fluorouracil. Limited data is available regarding potential benefits and risk of PTR in patients with stage IV CRC treated with modern chemotherapy (MC). A recent phase II study suggested that outcomes are not compromised by leaving the primary colon tumor intact in such patients (JCO.2012;30:3223). Purpose:To compare survival of patients with advanced CRC who underwent PTR with patients without resection in the era of MC. The review also aims to determine post-operative mortality and non-fatal complications rates, primary tumor complications rate (PTCR), non-resection surgical procedures rate (NSPR) and quality of life (QOL). Methods: A literature search was conducted by using CENTRAL (2012), Medline (1946-2012), and EMBASE (1947-2012). Studies involving patients with stage IV CRC who underwent PTR were selected with restriction to publication dates from 2000, English language and human studies. Screening, evaluation of relevant articles and data abstraction was done in duplication and agreement was assessed. Articles that met the inclusion criteria were assessed for quality by using Ottawa-Newcastle score. Data was collected and synthesized as per protocol. Results: Of total of 3,379 reports, 10 retrospective studies were selected with patients population of 2,655. Among 2,655 patients, 1616 (61%) underwent PTR with a median overall survival of 18.7 months (range: 11-30.7) compared with 12.9 months (range: 5.8-22) in the control. The HR for survival was in 0.68 (95% CI: 0.56-0.83) favoring the PTR. Mean 30 days post-operative mortality rate in the PTR group was 3.9% (95% CI: 0-11). Mean PTCR and NSPR in the control group were 27.4% (95% CI: 16.4-38.5) and 27% (95% CI: 12.5-41.6) respectively. No study provided QOL. Conclusions: The retrospective data favors PTR in advanced CRC in the era of modern chemotherapy. Future prospective randomized trials are warranted to confirm the findings.
A first-in-human phase I study of CZ48, a lactone ring protected oral camptothecin, in patients with advanced solid tumors.
Authors: Devalingam Mahalingam, Montaser F. Shaheen, John Sarantopoulos, Steven Weitman, Beppino C. Giovanella, Zhisong Cao, Douglas Coil, Constantine Markides, Lucy Liu, Claire F. Verschraegen
Journal: Journal of Clinical Oncology (2013)

2578 Background: CZ48, the 20-O-propionate ester of camptothecin (CPT), is a prodrug of CPT first described by Cao et al. in 1998. The side-chain is enzymatically cleaved in tissues. This gives rise to CPT, a potent inhibitor of topoisomerase I. Methods: An open-label, single-arm, dose-escalation Phase I study was performed to determine the maximum tolerated dose (MTD) of CZ48 in patients with advanced solid tumors. Initial dosing started qd po 80mg/m 2 , advancing to 2560mg/m 2 for 21 consecutive days, followed by 7 days rest. Dosing was restarted in cohorts of 3 patients tid po at 18mg/m 2 and escalated to 1g/m 2 on a 5 days on, 2 days off schedule for 28 days. Patients were prescreened by measuring CPT levels in plasma following a single pilot dose of CZ48. Dose was doubled until occurrence of at least Grade 2 adverse event, at which time 3+3 patient cohorts with a dose escalation of 33%-100% were implemented. DLT in 2/6 patients defined the MTD as the preceding DLT dose. PK parameters were measured prior to dosing, days 1-5, and day 28 of Cycle 1. Results: Poor absorption led to initial qd dosing reaching 2560mg/m 2 with no signs of DLT. Subsequent tid dosing showed improved plasma levels and arrival at DLT. 34 patients were treated across 8 dose levels from 18 to 1000 mg/m2. The most frequent study-related adverse effects were cystitis, vomiting, diarrhea and fatigue. Grade IV toxicities observed were febrile neutropenia, anemia, and thrombocytopenia. Preliminary PK data in the qd dosing showed poor correlation between dose and C max or AUC, while PK in tid patients showed slightly improved correlation between dose and both CZ48 AUC (Pearson's correlation coefficient ϱ=0.476, p&lt;0.01) and CZ48 C max (ϱ =0.51, p&lt;0.01). Evidence of clinical activity with stable disease ≥ 6 months was observed in 2 heavily pre-treated colon and one breast cancer patient. Conclusions: The MTD of tid po CZ48 administered 5 days on, 2 days off of 28-day cycle is between 750 mg/m 2 and 576 mg/m 2 . Overall toxicity is relatively mild, with DLT being cystitis and myelosuppression. Even with tid dosing, PK values correlate poorly to dose. A new formulation with 3-5 fold higher preclinical absorption values is being considered for introduction into the trial. Clinical trial information: NCT00947739.
BMA condemns failure to deliver rescue funding to GPs
Authors: Gareth Iacobucci
Journal: BMJ (2017)

The BMA has urged NHS England to remedy the “scandalous” failure to deliver resilience funding to struggling general practices that was due be deployed by the end of this financial year.

NHS England had promised to deliver £16m (€18.5m; $20m) by the end March,1 to support practices that had been worst affected by rising demand from patients, restricted funding, and staff shortages, as part of a four year £40m resilience package set out in its General Practice Forward View .2

But recent data shared by NHS England showed that more than £11m of funding had not been spent as at February 2017, said Chaand …
Outcomes of severe sepsis in very elderly (age &gt;80 years) patients with metastatic cancer.
Authors: Zahra Touqir, Shagufta Shaheen, Shivanck Upadhyay, Creticus Petrov Marak, Gagan Kumar, Achuta Kumar Guddati
Journal: Journal of Clinical Oncology (2013)

9558 Background: With better treatment and prolonged life expectancy of cancer patients, more elderly patients with metastatic cancer are being treated aggressively for sepsis. There has been philosophical debate about how aggressive the treatment should be for very elderly patients with metastatic disease admitted to intensive care unit with severe sepsis. The data with regards to the outcome of severe sepsis in those above 80 years with metastatic disease is very limited. Methods: Using the Healthcare Cost and Utilization Project - Nationwide Inpatient Sample 2007-2008, patients older than 80 years, discharged with severe sepsis were identified using ICD-9-CM codes. Those with metastatic disease were identified using ICD-9-CM codes 196-199. The outcomes studied were mortality and discharge disposition. We also examined the rates of invasive mechanical ventilation, blood transfusion, use of central venous catheter, tracheostomy and dialysis. The outcomes were compared to those who did not have cancer. Chi square test was used to compare the variables. Significance was defined as p value &lt;0.05. Results: There were 458,443 discharges with severe sepsis in patients aged ≥80 years. Of these 3.3% had metastatic disease. The in-hospital mortality was significantly higher in those with metastatic disease (43.7% vs. 33.3%, p&lt;0.001). The discharge disposition of the very elderly is shown in the Table. The rates of invasive mechanical ventilation, tracheostomy, use of central venous lines and dialysis were similar in both the groups. Blood transfusions were observed to be higher in metastatic group. Conclusions: Resource utilization in elderly with severe sepsis is similar regardless of the presence of metastatic disease. However, the mortality is significantly higher in those with metastatic disease. Of the survivors, only a fraction reaches home with independent functioning. Involvement of palliative care services at an early stage and addressing code status promptly during the beginning of each hospitalization may help relieve resource and financial burden to health care providers. [Table: see text]
K-ras mutation for prediction of response to chemotherapy plus autophagy inhibition in NSCLC.
Authors: Biren Saraiya, Joseph Aisner, Sujani Ganga Surakanti, Janice M. Mehnert, Eileen White, Robert S. DiPaola
Journal: Journal of Clinical Oncology (2014)

e19069 Background: Autophagy (ATG) preserves growth potential during cellular stresses and may promote chemotherapy resistance. K-ras deficient mouse models depend on ATG for tumor growth. Hydroxychloroquine (HCQ) inhibits ATG in in vitro and in vivo models, and may thus enhance chemotherapy effect. Methods: We conducted phase II studies of q 21 day chemotherapy up to 6 cycles with paclitaxel 200 mg/M2 with carboplatin AUC=6, and bevacizumab (Bev) (per Bev criteria) 15mg/Kg, together with daily p.o. HCQ at 200 mg bid (25 patients), and 600 mg bid (2 patients, ongoing); then followed by daily p.o. HCQ and Bev (per Bev criteria) as maintenance for up to one year. Results: We entered 27 patients (16M/11F) median PS=1, Median age = 70. Overall we saw 0 CR, 14 PR, 5 SD, 6 PD, and 2 TE. Median TTP = 7+ months, OS = 10+ months. Neutropenia, grade 3 and 4 was the predominant toxicity. Among 9 patients with prospectively assayed k-ras status: k-ras wild-type showed 1PR and 2PD; k-ras mutant showed 4 PR, 1 SD, 1 PD, and 1 TE. We are currently obtaining tissue, where available, for retrospective k-ras assay for those cases not assayed. Conclusions: ATG inhibition may augment chemotherapy response, preliminary data suggest a predictive role of k-ras in response to this regimen, and the retrospective kras assay may thus be helpful. Study continues at higher HCQ levels to reach free drug levels of HCQ. Clinical trial information: NCT01649947.
Evaluation of the diagnostic accuracy of cervical biopsy and determination of associated risk factors for positive margin status in recurrent cervical dysplasia after leep or conization.
Authors: Diana Peta-gay English, Monica Pasternak, Janelle Warmington, Elena Ratner, Dan-Arin Silasi, Masoud Azodi, Peter E. Schwartz, Alessandro Santin, Thomas J. Rutherford
Journal: Journal of Clinical Oncology (2014)

5609 Background: Severe dysplasia on a cervical biopsy is often followed by an excisional procedure such as a loop electrosurgical excisional procedure (LEEP) or cone biopsy. The objective of this study was to determine the prevalence and associated risk factors for positive surgical margins on cold knife conization or LEEP as well as the recurrence of dysplasia after these procedures. Secondary objective was to determine the correlation of cervical biopsy revealing CIN II with degree of dysplasia found on final pathology. Methods: This is a descriptive analytical study of 118 patients who underwent a LEEP or cone biopsy during a 12 year period (1999-2011) by trained gynecologic oncologists at our institution. Medical records were reviewed from a prospectively maintained pathology database. Cases were identified through a search performed for all patients in this period with a CIN II diagnosis. All pathology specimens were reviewed by one of four board specialized gynecologic pathologists. The need for cervical biopsy was determined based on pap results according to the ASCCP guidelines. Univariate analysis was performed with the chi-square test and the Student's t-test. Results: Of the 118 patients, 29 cases had a positive cone/LEEP margin (24.6%). Of the patients with positive margins, 48.2 % of these patients were considered to be immuno-compromised due to factors such as chronic steroid use and smoking, chemotherapy or HIV positivity. Recurrence of abnormal pap smears within 2 years of an excisional procedure was 19% in the margin negative group and 31% in the margin positive group (P <0.0001). The positive predictive value of cervical biopsy for determining CIN II on an excisional procedure was 94.1%. Conclusions: Positive surgical margins on LEEP/cone biopsy is not uncommon and increases the risk for abnormal cervical cytology in the subsequent years post-procedure. Cervical biopsies when performed by trained physicians correlate well with final pathology on cone biopsy/LEEP. Risk factor assessment continues to be important in following patients after cervical excisional procedures.
BRCA1 and telomere dysfunction-implications for malignant transformation.
Authors: Rinat Yerushalmi, Orit Uziel, Lital Zuriano, Einat Beery, Jardena Nordenberg, Ido Lubin, Shulamith Rizel, Shlomit Perry, Yonatan Adel, Metsada Pasmanik-Chor, Hagai Yavin, Daniel Shepshelovich, Irit Ben-Aharon, Dan Frumkin, Meir Lahav
Journal: Journal of Clinical Oncology (2015)

e12512 Background: Telomere maintenance is crucial for malignant transformation. Being a part of the DNA repair machinery, BRCA1 may be implicated in telomere biology. We explored the role of BRCA1 in telomere maintenance in 1) BRCA1/2 mutation carriers and in 2) in vitro system by silencing its expression in HB-2 breast epithelial cells. Methods: Telomere length and telomerase activity were measured by Southern blot and Q-TRAP assay respectively; its gene expression by Q-PCR. The shelterin proteins' binding to telomeres was evaluated by the ChIP assay and their cellular levels by Western blot. DNA damage was indicated by following the levels of gH2AX. Pyro-sequencing was employed to decipher the methylation status of the sub-telomeric regions. Telomeres G-strand overhang length was measured by the G-tail assay. Total gene expression was evaluated by Affymetrix whole exome microarrays. Similar methods were employed to study theses parameters in the BRCA1/2 carriers. Results: The results in both systems were similar and complementary. BRCA1/2 mutation causes perturbation of telomere length homeostasis and shortening of the single stranded telomere overhang. The intercellular telomere length variability increased as well as number of telomere free chromosomal ends. All these changes resulted in an increased DNA damage status of the cells. Telomerase activity, inducibilty and hTERT expression remained unchanged. The binding of two shelterin proteins to telomeres changed significantly; TRF1 binding increased fourfold while TIN2 was reduced tenfold. The methylation of the sub-telomeric regions in chromosomes 5 and 10 changed significantly and this change was more pronounced during malignant transformation. The levels of DNMT1 were significantly reduced. The silencing of BRCA1 resulted in expression of a distinct set of genes, some of which may relate to pre-disposition to malignancy. Conclusions: These results suggest that BRCA1 has a role in telomere length homeostasis in breast epithelial cells. Its silencing results in loss of telomere protection leading to DNA damage. These findings suggest that abnormalities in telomere biology caused by BRCA1/2 mutation may play a role in the propensity to malignant transformation in carriers.
Association of elevated alpha-1 antitrypsin with advanced clinicopathologic features of hepatocellular carcinoma.
Authors: Reham Abdel-Wahab, Manal Hassan, Robert A. Wolff, Sahin Lacin, Humaid Obaid Al-Shamsi, Kanwal Pratap Singh Raghav, Ahmed S Shalaby, James C. Yao, Ahmed Omar Kaseb
Journal: Journal of Clinical Oncology (2017)

289 Background: Alpha-1 Antitrypsin (A1AT) is a circulating liver derived protease inhibitor. There is an evolving evidence that elevated level of A1AT stimulate tumor cell proliferation, and invasion in different cancers. Despite A1AT well-known involvement in hepatic fibrosis, its role in hepatocellular carcinoma (HCC) pathogenesis is not well characterized. The current study aimed to investigate the association between A1AT and clinicopathologic features and prognosis of patients with HCC. Methods: Between 2001 and 2014, total of 766 HCC patients from MD Anderson Cancer Center were enrolled. Under IRB approval, baseline patients’ clinical characteristics were retrieved from medical records. The normal level of plasma A1AT was defined based on the Mayo clinic reference value (1 – 1.9 mg/ml). Survival analysis included Kaplan Meier statistic and Cox regression analysis. Multivariate Hazard Ratio (HR) and 95% Confidence interval (CI) were estimated to determine the independent effect of A1AT on HCC prognosis. Results: The mean and standard deviation of plasma A1AT level was 2.7 ± 0.98 mg/mL. All patients were categorized into 2 groups: group 1 (N = 156) with normal serum level ( ≤ 1.9) and group 2 (N = 610) with higher values ( &gt; 1.9). Median survival (months), 95% CI were 24.4 (18.02 – 30.7) and 11.6 (9.6 – 13.6) in group 1 and 2 respectively, (P &lt; .0001). Patients in group 2 experienced poor clinical characteristics than group 1. The estimated multivariate HR (95% CI) for A1AT is 1.4 (1.1 – 1.7) after adjustment for age, sex, race, cirrhosis, AFP, TNM staging, and treatment exposure. Conclusions: High plasma level of A1AT is associated with higher α-feto protein, advanced TNM and Barcelona clinic liver cancer (BCLC) staging and poor survival of HCC patients. Recent preliminary studies suggested that changes in glycosylaion of production of A1AT by HCC cells correlates with the microenvironment inflammatory and proteolytic activities, which are probably linked to advanced clinicopathologic features and poorer survival. Future excremental studies are warranted to understand the mechanistic pathways of potential A1AT involvement in HCC initiation and progression.
Extranodal natural killer T-cell lymphoma, nasal-type—A new staging system from CSWOG—A multicenter study.
Authors: Tongyu Lin, Huangming Hong, Chaoyong Liang, He Huang, Chengcheng Guo, Ying Tian, Tingzhi Liu, Mengping Zhang, Xueying Li, Xiaohong Fu, Zhao Wang, Xiaojie Fang, Xiaoting Lin, Shanshan Li, Jia Tian Lin, Raj Shrestha Prem, Sheng Ye, Jiqun Yi, Yanhong Deng, Jian Xiao
Journal: Journal of Clinical Oncology (2014)

8552 Background: Extranodal NK/T-cell lymphoma, nasal type (ENKTL), is a rare and high aggressive disease with poor prognosis. The Ann Arbor staging system had been unable to define ENKTL staging in specific way. This study conduct a new staging system specified for ENKTL, which can identify poor prognostic patients who need more aggressive therapy. Methods: Based on the primary studied of one single center consecutive patients diagnosed as ENKTL treated with CHOP-like regimens on ASCO meeting 2008, the new staging system was established as stage I: lesions confined within nasal cavity or nasopharynx without local invasiveness (paranasal sinuses or bony or skin invasion); stage II: localized disease with local invasiveness; stage III: localized disease with regional lymph node involvement (cervical lymph nodes); stage IV: disseminated disease (lymph nodes on both sides of diaphragm, multiple extranodal site). We further undertaken two multicenter study, one retrospective analyzed the patients treated with CHOP-like to confirm the new system and the other prospective validate the new system in current treatment modality containing L-asp-based chemotherapy in ENKTL. Results: A total of 821 patients with final diagnosis of ENKTL (ranging 9-90 years old) were included. Among them 588 were retrospective studied between Jan 2000 and Jun 2008, and 233 were prospective studied from Jul 2008 to Dec 2012. The distribution of all patients using the new system compared with Ann Arbor system were stage I: 19.6% vs 56.9%; stage II: 38.1% vs 20.1%; stage III: 17.8% vs 7.2%; stage IV: 24.5% vs 15.8%, respectively. In the retrospective study, the 5-year OS rate of stage I to IV using the new system were 63%, 51%, 38% and 29% compared with 55%, 45%, 15% and 29% using the Ann Arbor system, respectively. For prospective study, the 5-year OS rate of stage I to IV of the new system were 82%, 73%, 67% and 54%, respectively, while stage IV was better than stage III (74% vs 47%) when the Ann Arbor system was adopted. Conclusions: The new staging system with a more balanced distribution and a superior prognostic discrimination as compared with the Ann Abor staging system is more suitable for ENKTL and should be recommended used in the future.
Predictors of long-term responders in patients treated with pazopanib for advanced renal cell carcinoma (aRCC).
Authors: Jinhee Park, Xiaolong Jiao, Thomas Wilson, Sameer Ghate, Qasim Ahmad, Jose Ricardo Perez, Nicholas J. Vogelzang
Journal: Journal of Clinical Oncology (2017)

524 Background: The objective of this study was to characterize the long term responders to pazopanib (PAZ) treatment in aRCC patients treated in a real-world community oncology setting. Methods: This retrospective study used US Oncology’s (USON) iKnowMed electronic health record database (Nov 2009 – Oct 2014), supplemented with chart review. Eligible patients: Age ≥ 18 at first diagnosis of aRCC, treated with PAZ as first-line between 11/1/2009 – 8/31/2012, and had at least 2 office visits during the follow-up period. Patients were excluded if they were enrolled in a clinical trial and diagnosed or treated for other primary cancers during the study period. Long-term responders were defined as patients with progression free survival (PFS) ≥18 months. Predictors of long-term responders to PAZ were assessed using multivariate logistic regression analysis. Results: A total of 153 PAZ patients were included of which, 33 patients (22%) were identified as long-term responders. The median PFS in long-term responders and non-long-term responders was 27.2 months (95% CI: 23.0, 35.2) vs. 6.9 months (95% CI: 5.03-8.55), respectively. Long-term responders were more likely to have Eastern Cooperative Oncology Group (ECOG) score=0 at baseline (42.4% vs. 18.3%, p=0.004), and a history of nephrectomy (81.8% vs. 57.5%, p=0.010) than non-long-term responders. Other patient characteristics including age, gender, or comorbidities did not differ significantly between the two groups even though long-term responders tend to be slightly younger (mean 64.7 vs. 66.2), female (33% vs. 25%), and less likely to have a comorbid condition (36.4% vs. 51.7%) compared to non-long-term responders. In the multivariate analysis, the only predictors of long-term response were ECOG = 0 at baseline (vs. ECOG = 1 (OR: 0.38; 95% CI 0.16-0.89) and vs. ECOG≥2 (OR: 0.07, 95% CI: 0.01-0.54) and history of nephrectomy (OR: 3.33; 95% CI 1.28-8.65). Conclusions: A subset (22%) of PAZ patients had clinically relevant long term responses in a US community oncology setting. ECOG score of 0 and history of nephrectomy were predictors of long term response in PAZ.