tbuckley/cabot-search huggingface dataset:
Salvage chemotherapy with carboplatin plus weekly docetaxel in patients (pts) with castration- and docetaxel-resistant prostate cancer (DRPC): Associations of patient and disease characteristics with overall survival (OS).
Authors: Christoph W. Reuter, Michael A. Morgan, Viktor Grünwald, Christoph A. J. von Klot, Axel S. Merseburger, Philipp Ivanyi, Martin Fenner, Arnold Ganser
Journal: Journal of Clinical Oncology (2014)

75 Background: Our recent data suggest that carboplatin is effective in combination with docetaxel (DC) in docetaxel-resistant prostate cancer (DRPC). Platinum(II)-complexes interfere with steroid biosynthesis lowering testosterone levels by inhibiting the cholesterol side chain cleavage enzyme (CYP11A1), 3β-hydroxysteroid dehydrogenase (HSD3B1,2) and 17α hydroxylase/C17,20-lyase (CYP17A1). Methods: Docetaxel failure/resistance was defined according to the Prostate Cancer Working Group (PCWG2 2007) criteria. Treatment consisted of at least two cycles of carboplatin AUC5 iv for 30 min on day one every 4 weeks (q4w), docetaxel 35 mg/m2 iv for one hour on days 1, 8, and 15 plus prednisone 2x5mg/day orally after receiving informed consent until disease progression or occurrence of intolerable adverse effects. Efficacy measures were done following PCWG2 recommendations. Free testosterone levels were measured before (n=59) and during DC chemotherapy (n=52). Results: Of the 82 pts treated since February 2005, 95.1% had bone, 42.7% had lymph node, 26.8% liver, and 18.3% lung involvement. At the current analysis, the median follow-up time was 15.6 months. The objective response rate was 40.8% and the disease control rate 63.3% in the 49 pts with measureable disease. Response of prostate-specific antigen (greater than or equal to 50%) was observed in 3 out of /82 (47.6%) pts. Median progression-free survival (PFS) was 6.9 months (CI 95% 6.0, 7.8) and median OS was 18.0 months (CI 95% 12.7, 23.3). The most common reversible grade 3/4 toxicity was leukopenia/neutropenia (42.7/37.8%). Median free testosterone (fT) was 0.745 pg/ml before and less than 0.18 pg/ml during DC treatment (nadir levels, p=0.009; detection limit less than 0.18 pg/ml) and median serum androgene (T+DHT=TA) was 0.19 ng/ml and below the detection limit of less than 0.05 ng/ml (p&lt;0.001). In multivariate analyses, lactate dehydrogenase, PSA response, and fT and TA nadir levels were associated with longer OS (p&lt;0.05). Conclusions: These data suggest that carboplatin plus weekly docetaxel may be an important second-line treatment option for DRPC patients by inhibiting the testosterone biosynthesis.
Clinical significance of tumor markers as prognostic factors in patients with metastatic gastric cancer receiving first-line chemotherapy.
Authors: J. Jo, M. Ryu, D. Koo, B. Ryoo, H. J. Kim, J. Lee, H. Chang, T. W. Kim, K. D. Choi, G. H. Lee, H. Jung, K. C. Kim, J. H. Yook, S. T. Oh, B. S. Kim, J. Kim, Y. Kang
Journal: Journal of Clinical Oncology (2011)

4035 Background: Although tumor markers are known to be associated with tumor burden and/or aggressive biology, any association of such markers with patient survival has not previously been determined in patients with metastatic or recurrent gastric cancer. Methods: Of 3,107 patients with metastatic or recurrent gastric cancer who initiated palliative chemotherapy in Asan Medical Center between January 2000 and December 2008, 1,178 were assayed for expression of three serum tumor markers, CA 19-9, CA 72-4, and CEA, prior to initiation of first-line chemotherapy. We retrospectively analyzed the relationships between tumor marker concentrations and clinicopathologic features, and treatment outcomes in such patients. Results: Elevated serum concentrations of CA 19-9 (>37 U/mL), CA 72-4 (>4 U/mL), or CEA (>6 ng/mL) were observed in 38.1%, 56.2%, and 33.1% of patients, respectively. Univariate analysis showed that serum positivity of all the 3 markers, CA 19-9 (p=0.001), CA 72-4 (p=0.001), and CEA (p=0.030) were associated with poor survival. However, upon multivariate analysis, only CA19-9 (HR 1.22; 95% CI, 1.08-1.37, p<0.001) was independently associated with poor survival outcome, in addition to the following clinical factors determined in previous study for gastric cancer prognostic model (Koo, et al): ECOG PS ≥ 2, no previous gastrectomy , peritoneal metastasis, bone metastasis , lung metastasis, serum alkaline phosphatase (ALP) > 120 IU/L, serum albumin < 3.3 g/dL, and total serum bilirubin > 1.2 mg/dL. In good risk group by the prognostic model, survival difference in the positivity of CA 19-9 was more significant (p < 0.001), while serum positivity of CA 19-9 did not provide clinical significance for moderate and poor groups. Conclusions: The postivitiy of serum CA 19-9 for patients with metastatic or recurrent gastric cancer at the time of first line chemotherapy, especially in good prognostic group is an independent negative prognostic factor.
EML4-ALK-negative mucinous bronchioalveolar/adenocarcinoma (BAC/AC) of the lung in a 15-year-old female patient with CPAM.
Authors: A. Abdolmohammadi, M. E. Fallat, V. V. Balasa, G. H. Kloecker
Journal: Journal of Clinical Oncology (2011)

e21007 Background: Congenital pulmonary airway malformation (CPAM) is a rare developmental anomaly. BAC is associated with CPAM type I and has been reported in the pediatric population. There are few reports about the oncogenic mutations in these NSCLC. Fusion of the echinoderm microtubule-associated protein-like 4 (EML4) gene with the signaling portion of the receptor tyrosine kinase of the anaplastic lymphoma kinase (ALK) gene is a potential driver of oncogenesis in a minority of patients with NSCLC. Activating mutations of the K-RAS oncogene may represent an adverse prognostic factor in resectable lung adenocarcinomas. Activating mutations in the TK domain of EGFR gene can result in deregulation of this pathway and play a role in promoting neoplasia. Methods: We report a case of a 15-year old female patient with an invasive mucinous adenocarcinoma arising from a CPAM type I. An oncogenic analysis was ordered to assist in the management. Results: The lobectomy specimen revealed multifocal intralobar BAC/AC without evidence of lymph node involvement. The invasive adenocarcinoma was evident within a diffuse mucinous bronchioalveolar carcinoma and was acinar predominant 80%, papillary 10%, and lipidic 10%. The results of mutation analyses were negative for EGFR and ELM4-ALK and positive for K-RAS mutation. Conclusions: K-RAS mutation was present in this mucinous BAC/AC arising from a CPAM. Mutant K-RAS in NSCLC portends a poorer prognosis. A similar case (K-RAS positive, EGFR negative) was recently reported. An EML4-ALK mutation was not found in our case. This is the first report about an ELM4-ALK mutation analysis in a young patient with BAC/AC arising within a type I CPAM. Although ELM4-ALK mutations are detected more frequently in non-smoking, younger patients with AC, the pathogenesis of this rare CPAM associated BAC/AC needs further elucidation to guide practical management.
A phase I trial of sequential 2-weekly doublet therapy (SDT) of gemcitabine (G) in combination with carboplatin (C) followed by pemetrexed (P) in combination with gemcitabine in chemo-naive patients with stage IIB/IV non-small-cell lung cancer (NSCLC)
Authors: J. P. Steele, G. S. Patel, P. Wells, A. Reeves
Journal: Journal of Clinical Oncology (2008)

19110 Background: Current evidence suggests that patients with non-small-cell lung cancer with inoperable locally-advanced or stage IV disease should be treated with a platinum-based combination. Most data suggest that at least one additional drug is used. In order to improve response rates we combined two of the most important additional drugs - Pemetrexed and Gemcitabine - with Carboplatin in a rolling schedule administered every 14 days. Methods: Patients with stage IIIB or IV NSCLC, ECOG performance status 0 or 1, with previous radiotherapy, but not chemotherapy treatment, were eligible. Patients received G (1000mg/m2)/C (AUC4) on day 1 and G/P (400mg/m2) on day 15 of a 4 weekly cycle, at dose level -1. P was increased to 500mg/m2 at dose level 1, C to AUC 5 at dose level 2, and G to 1200mg/m2 at dose level 3. All patients received vitamin B12, folic acid and steroid prophylaxis. Results: 20 patients have been enrolled into this trial: mean age 66 (range 39–78), and male: female ratio 16:6, of whom, 16 are evaluable for toxicities. 3 patients died before receiving chemotherapy and one withdrew from study. The regime is well tolerated, with only one dose limiting toxicity (DLT) of raised transaminases (1 patient, recovered with treatment delay). Grade 3 toxicities include anaemia (18%), thrombocytopaenia (6%), neutropaenia (6%), constipation (6%), transaminitis (12%), and thrombotic events (12%, 1 TIA and 1 DVT). The CT response rate was 31% (4/13 patients) with 2 patients still undergoing follow-up at dose level 3. Dose escalation upto level 3 has been achieved with minimal DLT and additional patients are currently being treated on this expanded cohort to confirm the safety of this dose and obtain efficacy data Conclusions: This two-weekly sequential doublet treatment for non-small-cell lung cancer combines three of the most important drugs currently available. The treatment has proved to be generally well-tolerated with some response at lower drug levels. Updated efficacy and toxicity data at higher doses will be presented. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Lilly Oncology Lilly Oncology Lilly Oncology
Foxp3 expression in patients with non-small cell lung cancer.
Authors: H. Kalofonos, F. D. Dimitrakopoulos, H. Papadaki, A. G. Antonacopoulou, A. E. Kottorou, C. D. Scopa, A. Gotsis, A. Mouzaki
Journal: Journal of Clinical Oncology (2011)

e18059 Background: Lung cancer is rarely cured by the current therapeutic approaches. Although numerous studies have implicated Foxp3 positive T regulatory cells in cancer pathogenesis, the role of Foxp3 in lung cancer pathogenesis remains unknown. Methods: We determined Foxp3 expression, using immunohistochemistry in 44 NSCLC tissue specimens, 20 samples from adjacent non neoplastic lung parenchyma and 5 normal lung tissue specimens. Immunohistochemical reactivity was graded on a scale of 0–3 according to intensity of staining and percentage of immunopositive cells. Foxp3 expression in cancer cells was categorized in three groups (high vs median vs low) using as a cut-off point the 33rd and 66th percentile. The total score for each slide was the sum of the intensity and distribution (between 0 and 6). Statistical analysis was performed with SPSS 17.0. Results: Nuclear Foxp3 immunostaining was detected in al tissues assessed. Foxp3 expression levels were higher in neoplastic cells than in adjacent non neoplastic tissue and normal lung parenchyma. Moreover, Foxp3 expression in tumor cells correlated with lymphocytic Foxp3-immunopositivity and the presence of lymph node metastasis. Furthermore, Foxp3 lymphocytic expression was negatively associated with the age of the patients. Conclusions: Foxp3 is overexpressed in NSCLC cells and tumor infiltrating lymphocytes. Moreover, tumor Foxp3 expression correlates with lymph node metastasis while lymphocytic Foxp3 levels may be age-related.
Discovering new drugs to target microsatellite instable (MSI) colorectal cancer (CRC) using the Connectivity Map (CMap)
Authors: E. Vilar, B. Mukherjee, G. Rennert, S. B. Gruber
Journal: Journal of Clinical Oncology (2008)

11087 Background: MSI tumors represent approximately 15% of CRC. Several preclinical and clinical studies have identified differences in response to 5-Fluorouracil and Irinotecan between Microsatellite Stable (MSS) and MSI tumors. CMap is a systems biology tool which enables researchers to match a gene expression signature defining a biologic state of interest with a database containing expression data obtained from different cell lines after being exposed to a panel of 164 small molecules. Our objective was to identify new compounds to target MSI tumors using CMap and to evaluate these candidates in the preclinical setting. Methods: We have used gene expression data generated from MSI tumors included in the Molecular Epidemiology of Colorectal Cancer study and from 2 signatures published previously (Watanabe et al and Koinuma et al). In addition, an aggregated signature was generated from the common genes found to be up and downregulated through the 3 signatures. The most active compounds selected for cytotoxicity assays fulfilled the following criteria: ≥2 negative scores in the global analysis using the CMap; ≥50% negative scores; and compounds highly ranked in terms of a summary measure obtained from aggregating p-values across the different signatures. CRC cell lines showing MSI due to mutations in mismatch repair (MMR) genes, MSI due to hypermethylation of the promoter of MLH1, and MSS were selected to perform cytotoxicity experiments. Cells were seeded in 96-well plates and exposed to 7 different concentrations of drug over 5 days. Results: 17-Allyamino-Geldamycin (17- AAG), which targets hsp90, and Trichostatin, which acts through HDAC inhibition, are novel small molecules predicted to preferentially target MSI CRC based on expression profiles and the CMap. Cell lines with hypermethylation of MLH1 were more sensitive to 17-AAG than MSS and MSI cell lines harboring mutations in MMR genes. No differences in IC50 concentrations were observed for Trichostatin between any groups. Conclusions: We report the application of CMap systems biology tool for discovering new small molecules to specifically target MSI CRC. Further investigation of 17-AAG in combination with standard chemotherapeutic agents is warranted for MSI colorectal cancers. No significant financial relationships to disclose.
Systematic review of interventions to facilitate advance care planning (ACP) in cancer patients.
Authors: Bryan Chan, Hao-Wen Sim, Camilla Zimmermann, Monika K. Krzyzanowska
Journal: Journal of Clinical Oncology (2016)

21 Background: ACP refers to the process of consideration, documentation and communication of preferences for future care. ACP is crucial for patients (pts) with advanced cancer as it can guide substitute decision makers (SDM) and health care providers (HCP) to align care with preferences, thus improving quality of end-of-life care. Methods: We performed a systematic review of MEDLINE, EMBASE, CINAHL, PsycINFO and Cochrane (Systematic Review and Clinical Trial) databases (1995 to 2015) to identify interventions that facilitate ACP for cancer pts (documentation or discussion of advance directives, SDM or code status). We extracted data on study design, setting, subject numbers, interventions and outcomes. Study quality was assessed using a modified Downs and Black checklist. Results: Of the 64,196 unique citations identified, 10 studies met inclusion criteria for testing interventions using a pre-post or controlled trial design (median sample size 134, range 48-9105). Interventions were categorized based on target audience: health system (n = 4), pts and caregivers (n = 3) or HCP (n = 3). Types of interventions included: introduction of ACP facilitators (n = 4), reminders or prompts (n = 2), and HCP training, videos, website or pt screening (n = 1 each). Heterogeneity in study design, outcome measures and small sample sizes limited study quality and precluded meta-analysis. Prompts such as medical record or email reminders were most consistently associated with improved ACP documentation. System changes incorporating the use of ACP facilitators also improved ACP documentation in 3 out of 4 studies. Interactive HCP training significantly improved confidence to initiate ACP discussions which has been identified as a barrier to timely ACP. Pilot trials showed no significant increase in ACP with educational videos/websites directed at pts. Passive HCP education and one-off reminders were also ineffective. Conclusions: The complexity of ACP is reflected in the multitude of interventions that have been evaluated but none are ready for wide-scale adoption. Further studies of interventions such as prompts and ACP facilitators are needed to inform the best approach to improve ACP uptake in cancer pts.
Embedding palliative care into care coordination.
Authors: Finly Zachariah, Mariela Gallo, Matthew Loscalzo, Laura E. Crocitto
Journal: Journal of Clinical Oncology (2014)

62 Background: The Institute of Medicine (IOM) identified care coordination as a key strategy with potential to improve the safety and effectiveness of implemented care by deliberately organizing patient care activities and sharing information among all participants concerned. Palliative care maximizes quality of life for patient and family in serious illness and can be provided early and concurrently with curative therapies. At City of Hope National Medical Center (COH), we developed a pilot program for bladder cancer patients undergoing cystectomy to provide the benefits of care coordination and palliative care. Methods: 72 patients underwent cystectomy at COH from 2011-2013, the average case mix index was 3.51, the average length of stay (LOS) was 10.65 days, the LOS index was.92, Cost index 1.61, 30-day readmission rate 32.14%, and the most common causes for readmission were infection and dehydration. Based on comparative data, the urology service supported development of a novel pathway by a multidisciplinary team. The goals of the pathway are to facilitate navigation through the healthcare system, integrate tablet-based bio-psycho-social screening to proactively address patient and caregiver needs and goals, optimize medications to improve symptom management and recovery, empower patients with teach-back education, have anticipated interventions for likely readmission reasons, and develop effective collaboration amongst multidisciplinary providers across settings. The metrics include LOS, readmission rates, patient and family satisfaction, advanced directives on file, and cost index. Results: Hospital leadership and provider buy in was obtained, a daily rounding multidisciplinary team was created, change champions were identified, staff engagement increased, and COH and community agency staff were equipped with needed skills and support. Care model diagrams and clinical pathway orders were developed. Education materials were revised and updated. The pilot launched in April of 2014. Conclusions: We believe that a care coordination model with early integration of palliative care will improve the effectiveness of care delivered to our bladder cancer patients. A six-month retrospective review will be done to assess metric achievement.
Prevalence and clinicopathologic features of hereditary nonpolyposis colorectal cancer (HNPCC) syndrome in Chinese American patients in south Brooklyn, New York.
Authors: Ying-Yi Xiao, Yan Yu Sun, Jatin Karsandas Desani, Bradley Clark, Khin Than Win, Yiwu Huang, Yiqing Xu
Journal: Journal of Clinical Oncology (2014)

441 Background: HNPCC is a hereditary disorder that predisposes to colorectal and other cancers before 50 years old and in multiple generations, with a prevalence of 2 to 5% in Caucasians. It is associated with mutations in DNA mismatch repair genes (MMR). The gold standard for diagnosis is genomic DNA sequencing. Immunohistochemical staining (IHC) is sensitive to predict but not diagnostic for HNPCC, as acquired hypermethylation of MLH1 promoter can present with negative IHC staining. We aimed to study the prevalence and clinicopathological features of HNPCC in Asian patients. Methods: IHC for 4 MMR protein expressions on tumor specimens, commercial MLH1 methylation studies and genomic sequencings were performed on eligible and selected patients diagnosed of colon, gastric or endometrial cancers. Results: 117 patients were identified (2000 to 2012), 55 M and 62 F, ranges from 23 to 92 years old. Seven cases of MMR deficiency were found: 5 with colon cancer (81 patients), 2 with gastric cancer (31 patients) and 0 with endometrial cancer (5 patients). Among the 81 colon cancer patients, 20 had cancer younger than 50 years old; and among them, 3 cases of MMR deficiency were confirmed by DNA sequencing. One patient was found to have a unique previously unreported suspected deleterious mutation. The other 2 patients had MLH1 promoter hypermethylation indicating acquired abnormality. 31 patients had gastric cancer, and 2 cases of MMR deficiency were found, including 1 MLH1 promoter hypermethylation and another isolated PMS2 deficiency by IHC. Conclusions: The prevalence of HNPCC in Chinese colon cancer patients in South Brooklyn is 3.7% (3/81). All cases were found in patients younger than 50 years old with a prevalence of 15% (3/20). Hypermethylation in MLH1 can be seen in both colon and gastric cancers. The screening in Chinese Americans for HNPCC is as important as in Caucasian population, and should be done also in Asian gastric cancer patients as well.
Efficacy of lanreotide 30 mg as symptomatic treatment in patients with inoperable bowel obstruction due to peritoneal carcinomatosis: A randomized double-blind, placebo-controlled study.
Authors: P. Mariani, J. Blumberg, L. Chauvenet
Journal: Journal of Clinical Oncology (2011)

242 Background: Somatostatin analogues in previous open label studies improved symptoms due to bowel obstruction in patients with peritoneal carcinomatosis. This study assessed the efficacy and safety of lanreotide microparticles 30 mg as treatment of clinical symptoms in inoperable patients. Methods: Eighty cancer patients with inoperable digestive obstruction of malignant origin (mean age 62.3 years, 82.5% female) were randomized to receive one intramuscular injection either of lanreotide microparticles 30 mg (N=43) or placebo (N=37). The primary location of cancer was mostly genital (ovary 37.5%, uterus 13.8%) or digestive (colon 16.3%, stomach 11.3%, pancreas 6.3%). Most patients were fed by central parenteral route (80%) and were severely impaired (63.8% ECOG 3 or 4). The primary endpoint was the response rate at day 7 (responders defined as patients with ≤ 1 vomiting episode per day or no vomiting recurrence after removal of the NGT, for at least 3 consecutive days) assessed in a diary card in the intention to treat (ITT) population. Per protocol (PP) population mainly excludes concomitant treatment and inclusion criteria deviations defined during a blinded data review meeting. Results: In the ITT analysis, 41.9% of lanreotide 30mg treated patients were responders versus 29.7% for placebo. This difference was not statistically significant (odds ratio (OR) = 1.75 (95% CI [0.68; 4.49], p = 0.24, logistic regression). The predefinedPP (n= 49) sub group analysis did show a statistically and clinically significantly higher response rate in the lanreotide group (OR 3.60 (95% CI [1.03, 12.62], p = 0.045). There was no significant difference between the 2 treatment groups in secondary efficacy endpoints assessment but there were significant differences in favor of lanreotide in well-being using a visual analogue scale at D3 (p = 0.04), D6 (p = 0.04) and D7 (p = 0.01). No drug-related serious adverse event (SAE) or unexpected event was reported. Conclusions: Lanreotide 30 mg may decrease clinical symptoms and improve well-being in patients with inoperable bowel obstruction due to peritoneal carcinomatosis. [Table: see text]