tbuckley/cabot-search huggingface dataset:
Phase II trial of bortezomib in <i>KRAS G12D</i> mutant lung cancers.
Authors: Anna Maria Litvak, Alexander E. Drilon, Natasha Rekhtman, Maria Catherine Pietanza, Jamie E. Chaft, Kaitlin Woo, Paul K. Paik, Mark G. Kris, Gregory J. Riely
Journal: Journal of Clinical Oncology (2015)

e19002 Background: KRAS mutations are the most common oncogenic drivers in lung cancers without any approved targeted therapy. Preclinical evidence suggests that KRAS mutations are highly dependent on the NF-kB pathway. Bortezomib, a proteasome inhibitor, has been shown to downregulate the NF-kB pathway and lead to objective responses in patients with KRAS G12D in early phase clinical trials. In this single-institution, phase II study we assessed the efficacy and safety of subcutaneous bortezomib in KRAS mutant lung cancers. Methods: Patients with advanced KRAS G12D mutant lung cancers were eligible. Bortezomib was administered at 1.3mg/m2/dose subcutaneously on days 1, 4, 8, and 11 of a 21 day cycle until disease progression or unacceptable toxicity. The primary objective was radiographic response rate (RECIST version 1.1). The secondary endpoints were progression free survival (PFS) and overall survival (OS) determined from the date of first bortezomib treatment. Simon two-stage minimax design was used (H0= 10%, H1= 30%, power = 90%). Results: Sixteen patients with KRAS G12D mutant lung adenocarcinomas were treated on study: 38% never smokers, 31% former smokers ≤ 15 pack years, and 69% with invasive mucinous adenocarcinomas. Patients received treatment for a median of 2 months (range 1-12). One patient had a partial response with a 66% reduction in disease burden (6% observed rate, 95% CI 0.2 to 30.2%). Of the 6 patients (40%) with stable disease, 2 remained on study for over 5 months. The median PFS was 1 month (95% CI 1-6). The median OS was 13 months (95% CI 6-NA). The median OS from date of diagnosis of metastatic disease was 39 months (95% CI 35-NA). The most common treatment-related toxicities of any grade were fatigue (50%), diarrhea (38%), nausea (31%), and rash (31%). Treatment-related peripheral neuropathy occurred in 25% of patients (3 patients with grade 1, 1 patient with grade 2). Conclusions: In patients with KRAS G12D mutant lung cancers, bortezomib was associated with modest anti-tumor activity and durable disease control in a small subset of patients. Further investigation into predictive biomarkers for the efficacy of bortezomib should be pursued. Without a clear biomarker, no further study of bortezomib in KRAS- mutant lung cancers is warranted. Clinical trial information: NCT01833143.
A retrospective analysis of eye disorders induced by chemotherapy including S-1 for gastrointestinal cancer.
Authors: Masataka Yagisawa, Michio Nakamura, Chika Matsuda, Taichi Murai, Kazufumi Itaya, Takayuki Sone, Yuta Koike, Ayana Endo, Yoko Tsukuda, Yuji Ono, Atsushi Nagasaka, Shuji Nishikawa
Journal: Journal of Clinical Oncology (2017)

20 Background: Eye disorders (EDs) are common adverse events in patients received S-1 chemotherapy. Although there are some retrospective reports about EDs induced by S-1 mono therapy (mono) as adjuvant chemotherapy (Adj) in gastric cancer (GC), there are few reports about S-1 induced EDs in other gastrointestinal cancer (GIC). So we conducted this retrospective cohort study to investigate the incidence of S-1 induced EDs in GIC and the association with several clinicopathological factors, such as primary site, treatment setting, regimen, and duration. Methods: All the patients received S-1 chemotherapy for GIC in our institution from January 2008 to May 2016 were identified through medical records review extracted by our hospital data warehouse. We analyzed the incidence of S-1 induced EDs by reviewing all the medical records and the association between ED incidence and several clinicopathological factors using a chi-square test or a Fisher's exact test and logistic regression. Results: Two hundred eighty three GIC patients were analyzed on this study. Patients characteristics were as follows; male/female 170/113, GC/colorectal cancer (CRC)/pancreatic cancer (PC)/biliary cancer (BC) 119/67/57/32, non-Adj/Adj 263/20, S-1 mono/S-1 combination therapy (combo) 130/153. The overall incidence rate with EDs such as epiphora, gum, photophobia, nephelopsia was 15.2% (n = 43). The median time to onset of EDs was 109 days (range 5-1100). The each of ED incidence was 16.5% (n = 28) and 13.3% (n = 15) in male and female (p = 0.503), 14.8% (n = 39) and 20.0% (n = 4) in non-Adj and Adj setting (p = 0.520), 13.8% (n = 18) and 16.3% (n = 25) in S-1 mono and combo (p = 0.619), respectively. The incidence of EDs in GC, CRC, PC, and BC were 15.1% (n = 18), 17.9% (n = 12), 17.5% (n = 10), and 9.4% (n = 3) (p = 0.635), respectively. Conclusions: We found that the incidence of EDs induced by S-1 chemotherapy for GIC was relatively high regardless of cancer site, treatment regimen, setting and duration. Further accumulation of data as prospective cohort study is necessary to confirm the incidence of S-1 induced EDs. Clinical trial information: UMIN000024160.
Minority accrual on a prospective study targeting a diverse U.S. breast cancer population: An analysis of Wake Forest CCOP research base protocol 97609.
Authors: James John Urbanic, Doug Case, Michelle Joy Naughton, Jennifer J. Hu, Gina Enevold, Bettina Beech, Kathryn E Weaver, Suzanne Danhauer, Steve Rapp, Vivian Sheidler, Mara Vitolins, Glenn Lesser, Edward G. Shaw
Journal: Journal of Clinical Oncology (2013)

6564 Background: Clinical trial accrual rates are lower among minority patients. Wake Forest CCOP RB protocol 97609 designed to accrue 400 non-Hispanic White (NHW) and 600 minority patients to a study evaluating potential genomic single nucleotide polymorphisms as markers for breast radiosensitivty. Methods: Accrual data evaluated from 24 participating CCOPs and numerous CTSU sites. Race / ethnicity self-reported by participants (NHW, non-Hispanic Black, Hispanic/Latino, Asian /Pacific Islander, or American Indian/Alaskan Native) based on ACS reporting criteria. Results: 752 participants accrued in 14.5 mths (11/11-1/13); 402 NHW and 350 minorities. NHW accrual goal reached, 5.9 months (period 1; avg 68.4 participants /month) compared with 54 minority participants (period 1; avg 9.2 participants / month). This 7.4 ratio NHW to minority accrual is higher than expected given incidence. During 8.6 months following closure NHW enrollment (period 2), 296 minority participants accrued (avg 34.3 participants/month). An almost 4-fold increase in minority accrual raises question of accrual disparity. 19 CCOPs open in period 1 and 24 CCOPs in period 2. CTSU contributed both periods, more CTSU sites were added during period 2. Excluding all CTSU sites and five CCOPs open only in period 2, the avg minority accrual:6.8 patients / month period 1 and 10.6 patients / month period 2. The average time of accrual was 4.0 months period 1 and 8.6 months period 2 due to variable opening dates at sites. Taking time into account, the avg minority accrual rate was 0.60 patients / month / site in period 1 and 0.56 patients / site / month in period 2. CCOP minority accrual rates in period 1 vs. 2 increased 11 / 19 sites, decreased 6 / 19, and remained the same in 2 / 19, p = .33. Conclusions: Despite closure of enrollment of NHWs into this study with a specific goal to accrue a large minority population, there was no increase in the rate of minority accrual. The initial appearance of an accrual bias can be attributed to the addition of sites and variable lengths of accrual time at sites. It is unknown whether overall lower minority accrual rate compared to NHWs is participant-, provider-, or population-based. Clinical trial information: NCT01407770.
Addressing the Physician Shortage
Authors: Darrell G. Kirch, Kate Petelle
Journal: JAMA (2017)

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Public health interventions are highly cost saving, review finds
Authors: Jacqui Wise
Journal: BMJ (2017)

For every £1 invested in public health an average of £14 will subsequently be returned to the wider health and social care economy, a systematic review of the evidence has demonstrated.

The authors said that their findings, published in the Journal of Epidemiology and Community Health ,1 suggest that cuts to public health services are short sighted and represent a false economy.

The …
<sup>11</sup>C-coline-positron emission tomography/computerized tomography (C-PET/CT) for tumor localization of locally recurrent prostate cancer after radiation therapy
Authors: D. Sahi, C. Ohlmann, D. Pfister, U. Engelmann, A. Heidenreich
Journal: Journal of Clinical Oncology (2007)

15519 Background: Radical salvage prostatectomy (sRPE) represents one local secondary treatment option with curative intent in patients failing radiation therapy for localized PCA. C-PET/CT is an innovative imaging technique for the evaluation of PCA. It was the purpose of our study to assess the sensitivity of C-PET/CT to predict local intra- and extraglandular extent of PCA and the presence of lymph node involvement. Methods: 45 patients with biopsy-proven locally recurrent PCA scheduled for sRPE underwent preoperative C-PET/CT. All patients underwent retropubic sRPE with extended pelvic lymphadenectomy. The prostatectomy specimens were processed according to the Stanford protocol and pathohistological results were compared to C-PET/CT findings. Intraglandular location of cancer nodules = 5mm was correlated with PET/CT findings. Results: A total of 45 patients underwent sRPE; mean preop. serum PSA was 7.8 (2–24) ng/ml; mean biopsy Gleason score was 5.6 (4–9). A mean of 19 (10 - 32) lymph nodes were removed. Pathohistology showed stage pT1–2pN0 in 27 (60%), stage pT3a/b and pTxpN1 PCA in 9 (20%) and 9 (20%) of patients, respectively. Positive surgical margins were identified in 5 (11%) patients. C-PET/CT identified 1, 2, 3 or more than 3 intraprostatic cancer nodules in 23 (51.1%), 13 (28.9%) and 9 (20%) patients, respectively. Correlation of prostate biopsy findings with PET/CT findings demonstrated a sensitivity of 90% for PET/CT. There was a low sensitivity for PET/CT detecting lymph node metastases. A positive uptake was identified in 14 (31.1%) patients; pathohistology revealed positive lymph nodes in 9 patients with only 4 patients exhibiting positive 11 C-choline uptake and 5 patients having demonstrated a negative preoperative PET/CT scan. Conclusions: C-PET/CT is a valuable imaging modality for the detection of locally recurrent prostate cancer after radiation therapy. Due to its high sensitivity it might replace prostate biopsy prior to sRPE and it might be of additional value in patients with a negative biopsy but a high suspicion of local recurrence. The value of PET/CT for the identification pN1 disease is of modest value and not reliable. No significant financial relationships to disclose.
Predictors of long-term response to abiraterone acetate with prednisone and cabazitaxel after first-line docetaxel in patients with metastastic castration-resistant prostate cancer (mCRPC): Subgroup analysis of a prospective observational study.
Authors: Nuria Sala, María José Méndez-Vidal, Alvaro Pinto, Javier Puente, Angel Rodriguez Sanchez, Jose Miguel Cuevas Sanz, Sergio Vazquez-Estevez, Jacobo Muñoz del Toro, Pedro Ruiz, Angela Garcia, Aranzazu Gonzalez del Alba
Journal: Journal of Clinical Oncology (2017)

227 Background: Recently treatment options for mCRPC have increased considerably. It remains unclear if there is any predictive factor to recognize which patients (pts) could obtain the most benefit in second line (2L) mCRPC. Recent data have been published addressing long-term predictive factors in a retrospective cohort in 2L 1 . We aim to reproduce it in this prospective study. Methods: The CAPRO study is a prospective multicenter national observational descriptive study. The primary endpoint was to describe the management in 2L mCRPC pts after DOC in routine clinical practice. To characterize which factors are associated with a better response in 2L mCRPC, we performed a multivariant analysis in the subgroup of pts with a long-term response (long-term responders (LTR): pts receiving abiraterone acetate + prednisone (AA) or Cabazitaxel (CB) for &gt; 12 mo). Results: 150 patients were recruited (Jul 2013-Jan 2015). We identified 36 LTR (29/100 with AA: (29%) and 7/44 (15.9 %) with CB as 2L. No statistical differences in the number of LTR treated with AA vs CB (p = 0.095) were observed. LTR group (before starting 2L): median age 77.2 (51-87) median PSA 56.7 ng/dL (5.3-2627 ng/dL), alkaline phosphatase 92.5 IU/L (44-630 IU/L) and LDH 221.5 IU/L (147-445 IU/L). At median follow-up of 7.8 mo (IQR 4.2- 12.8), median PFS (clinical and/or radiological) was significantly longer in LTR AA group (not yet reached) vs LTR CB group 18.14 [95% CI 12.67-23.6]; HR 0·29 [95% CI 0,092 – 0,918; p = 0.025]. In a multivariate analysis two factors were significantly associated with LTR in 2L mCRPC: Gleason score &lt; 7 (OR: 0.22 95% CI 0.065-0.745, p = 0.015) and normal LDH ( &lt; 250 IU/L) (OR: 0.235, 95% CI 0.093-0.595, p = 0.002). No differences in safety profile between LTR vs non LTR of AA group and CB group were found. Conclusions: In this final subgroup analysis we observed Gleason score &lt; 7 and LDH &lt; 250 IU/L are predictors of long term response in 2L mCRPC. Median PFS in LTR treated with AA was significantly longer than LTR treated with CB. These findings need to be validated in further larger prospective studies.
Herniated Thoracic Spleen Mimicking Lung Metastasis on 68Ga-Labeled Prostate-Specific Membrane Antigen PET/CT in a Patient With Prostate Cancer
Authors: Dharmender Malik, Rajender K. Basher, Apurva Sood, Sudheer Kumar Devana, Anish Bhattacharya, Bhagwant Rai Mittal
Journal: Clinical Nuclear Medicine (2017)

We report a case of clinically asymptomatic patient of prostate cancer who was previously subjected to radical prostatectomy presenting with a rising serum prostate-specific antigen level of 6.6 ng/mL. Whole-body PET/CT with Ga-labeled prostate-specific membrane antigen ligand was performed to assess for disease recurrence, which revealed an intense tracer uptake in a soft tissue mass in left hemithorax mimicking lung metastasis; which later turned out to be splenic tissue.
First-salvage treatment in patients with recurrent or refractory advanced germ-cell cancer after cisplatin-based chemotherapy: A database of the German Testicular Cancer Study Group.
Authors: Karin Oechsle, Lars Arne Berger, Anja Lorch, Marcus Hentrich, Hans-Georg Kopp, Thomas Christoph Gauler, Joerg Beyer, Maike De Wit, Friedemann Honecker, Carsten Bokemeyer
Journal: Journal of Clinical Oncology (2013)

4559 Background: About 20-30% of patients (pts) with advanced germ-cell cancer (GCC) relapse after cisplatin-based chemotherapy. This database evaluates first salvage treatment and the prognostic categories at first relapse according to the International Prognostic Factors Study Group (= IPFSG; JCO 2010). Methods: A total of 144 pts (78% nonseminoma) with relapsed or refractory GCC undergoing 1 st salvage treatment with either conventional (CD-CX) or high-dose chemotherapy with autologous stem cell support (HD-CX) from 16 German centers were retrospectively analysed. Results: Subgroups according to the IPFSG prognostic categories, were: very low risk in 9/144 (6%), low risk in 26/144 (18%), intermediate risk in 78/144 (54%), high risk in 27/144 (19%), and very high risk in 4/144 pts (3%). 1 st salvage treatment consisted of HD-CX in 96 (67%) and CD-CX in 48 pts (33%). Treatment response was CR/PR- in 60%, PR+/SD in 33%, and PD in 7%. After a median follow-up (mFU) of 21 months (mos) (range, 0 – 193), 53% of all pts had relapsed and 30% had died resulting in a median progression-free survival (PFS) of 7 mos ( 95% CI 0-16) and overall survival (OS) of 47 mos ( 95% CI 21-73). At subsequent relapses, 25/48 pts (52%) received HD-CX as &gt; 2 nd -salvage treatment. For the total cohort, PFS rate after 2 years was 35%, and OS rate after 5 years was 53%. Stratification according to IPFSG prognostic categories significantly correlated with PFS (p=0.001) and OS (p=0.004) after 1 st salvage treatment. Even among high-risk and very high risk (n=31, mFU 12 mos) a PFS of 37 % at 2 years and an OS of 60 % at 2 years was observed, after 1 st or 2 nd salvage treatment, which might be due to patient selection and short follow-up. Conclusions: IPFSG prognostic categories highly correlated with observed PFS and OS after first salvage treatment in this cohort of pts with refractory or relapsed GCC. First salvage treatment with CD- or HD-CX resulted in overall 5 year-OS rates of about 50% across all prognostic categories. Even pts with high and very high risk achieved 2 year-OS rates of about 60% with salvage HD-CX at first or subsequent relapses.
Neutrophil lymphocyte ratio (NLR) as a clinical biomarker predictive of outcomes with immune checkpoint inhibitor therapy in genitourinary cancers.
Authors: Ghayathri Jeyakumar, Naresh Bumma, SeongHo Kim, Craig Landry, Heejin Kim, Cynthia Silski, Stacey Suisham, Brenda Dickow, Elisabeth I. Heath, Joseph A. Fontana, Ulka N. Vaishampayan
Journal: Journal of Clinical Oncology (2017)

453 Background: Immune checkpoint inhibitors (ICI) have been approved in genitourinary cancers (GU) such as renal cell carcinoma (RCC) and urothelial carcinoma (UC). There is an unmet need to determine factors predictive of response, to guide therapeutic selection in these cancers. We evaluated NLR as a predictor of response, progression free survival (PFS), and overall survival (OS) in patients treated with ICI. Other known prognostic clinical factors assessed were age, race, and smoking status and for RCC the prognostic score per MSKCC (Memorial Sloan Kettering) and Heng criteria. Methods: Regulatory approval was obtained. A retrospective chart review of RCC and URC patients at Karmanos Cancer Institute, treated with ICI based therapy was conducted. Data was collected on demographics, smoking status, prognostic scoring, NLR pretherapy, and post 4 doses of ICI. Correlation with clinical PFS and OS was conducted by univariable and multivariable analyses. Log-rank test was used to compare PFS and OS. Results: 57 pts were evaluated with median age 62 yrs (range, 24-85). 11 (19%) were African American (AA) and 31 (54%) were smokers. Pretherapy NLR&lt;4 and ≥4 was seen in 38 (67%) and 19 (33%) pts respectively. 13 (31%) RCC pts were treated with &gt; 1 VEGF therapy and 24(57%) pt were treated for &gt; 6 mths and 14/15 UC pts were pretreated. RCC pts treated with &gt; 6 mths and &gt; 12 mths of VEGF therapy had a shorter PFS (HR =2.31, p= 0.028; HR = 2.075, p= 0.051 respectively). AA had shorter PFS and OS with ICI in RCC but not in UC (HR=3.72, p=0.001; HR= 40.8; p=0.001; HR=0.49, p=0.5; HR=0.85, p=0.88, respectively). Conclusions: Pretherapy NLR ≥4 was a statistically significant predictor of shorter PFS and OS with ICI therapy in RCC. NLR is an easily applicable clinical predictive factor that can help guide therapy, after validation of these findings in a larger population dataset. [Table: see text]
Evaluation of driver mutations involving in RAS-RAF/PI3K-mToR pathway in gastric signet ring cell carcinoma.
Authors: Baorui Liu, Jia Wei, Nandie Wu, Lixia Yu, Zhengyun Zou, Yang Yang
Journal: Journal of Clinical Oncology (2015)

e15077 Background: Signet ring cell carcinoma (SRCC) accounts for one thirds of gastric cancer (GC). Previous studies have confirmed that SRCC has a worse prognosis than other forms of GC. Trastuzumab was recently approved for the treatment of advanced HER2-positive GC patients as the encouraging result of ToGA study. However, the incidence of HER2 positivity in SRCC was merely 1%, leaving a significant proportion of patients whose clinical options can only limited to chemotherapy. Furthermore, no molecular profiling specific to SRCC has been explored until now. Methods: We assessed the mutation status of driver mutations in KRAS, NRAS, BRAF, PIK3CA by sanger sequencing in 5 GC cell lines and 400 SRCC samples. Correlation between drug sensitivity of MEK and mTOR inhibitors and gene mutations status was evaluated in 5 GC cell lines. Gene mutations status was also analyzed for association with patients’ overall survival. Results: The frequency of KRAS mutations in codon 12, 13 and 61 was 15%. G12V and G12D mutant KRAS alleles account for 80% of all KRAS mutant alleles. No mutant KRAS allele in codon 61 was observed. NRAS mutations of codon 12 or 13 were detected in1.75% of samples. Frequency of BRAF mutation in codon 15 was 1.73%, PIK3CA mutations in exon 9 or exon 20 was 2.27%, respectively. No correlation was found between patients’ overall survival and gene status. GC cell line AGS with KRAS mutation was hypersensitive to MEK inhibitor compared with other four wild-type GC cell lines. Conclusions: KRAS mutation rate is higher in SRCC than other types of GC. GC with such oncogenic KRAS mutations might be suitable for targeted therapy with MEK inhibitors.