Discoidin Domain Receptor 2 Expression as Worse Prognostic Marker in Invasive Breast Cancer.

Discoidin domain receptor 2 (DDR2) is arising as a promising therapeutic target in breast carcinoma (BC). The ability of DDR2 to bind to collagen promotes protumoral responses in cancer cells that influence the tumor microenvironment (TME). Nonetheless, the interrelation between DDR2 expression and TME modulation during BC progression remains poorly known. For this reason, we aim to evaluate the correlation between intratumoral expression of DDR2 and the infiltration of the main TME cell populations, cancer-associated fibroblasts (CAFs), and tumor-associated macrophages (TAMs). First, collagen and DDR2 expression levels were analyzed in human invasive BC samples. Then, DDR2 status correlation with tumor aggressiveness and patient survival were retrieved from different databases. Subsequently, the main pathways, cell types, and tissues correlated with DDR2 expression in BC were obtained through bioinformatics approach. Finally, we studied the association of DDR2 expression with the recruitment of CAFs and TAMs. Our findings showed that, together with the expected overexpression of TME markers, DDR2 was upregulated in tumor samples. Besides, we uncovered that altered TME markers were linked to DDR2 expression in invasive BC patients. Consequently, DDR2 modulates the stromal reaction through CAFs and TAMs infiltration and could be used as a potential worse prognostic factor in the treatment response of invasive BC.

Commentary on Current Trends in Rising Drug Costs and Reimbursement Below Cost.

PURPOSE: To quantify prescription drug price increases over a span of 3 years (2012-2015), as well as extrapolate current reimbursement rates expected by independent retail pharmacies. In addition, we investigate potential reasons for these increasing drug costs. DESIGN: Descriptive analysis. METHODOLOGY: National average drug acquisition costs (NADAC) data published by the Centers for Medicare & Medicaid Services were examined. Specifically, December 2012, 2013, and 2014, and July 2015 NADAC files were analyzed to identify generic and branded products with the highest percentage price increases. Percentage price differences were also calculated for 17 first-in-class drugs and their "me-too" competitors. The margin and margin percentage were calculated for claims adjudicated through four major payers. RESULTS: The top 50 generic drug price increases ranged from 474% to over 18,000% from December 2012 to July 2015. The top 50 branded drug price increases ranged from 63% to 391% during the same time period. The percentage price difference for the first-in-class drugs versus their me-too analogues ranged from -2.3% to 61,259%. The margin for generic drug claims adjudicated ranged from -$237.11 to-$1,105.96. The margin for branded drug claims adjudicated ranged from $272.42 to $360.17. CONCLUSION: Several potential reasons for the surge in prescription drug prices include manufacturer competition, industry consolidation, and capitalization on me-too drugs. This increase has compelled PBMs, health plan sponsors, and retail pharmacies to find novel ways to turn a profit, often at the expense of the consumer. Although there are no immediate solutions, legislation regulating PBM functions and the use of therapeutic interchange programs may offer health plans some assistance in managing drug costs.

Effect of the methylenetetrahydrofolate reductase C677T polymorphism on patients with cisplatin/gemcitabine-treated stage IV non-small-cell lung cancer.

Single nucleotide polymorphisms (SNPs) in the metabolic pathways of S-adenosylmethionine have been related to global hypomethylation and a lower number of hypermethylated CpG islands of tumor suppressor genes. Hypermethylation of checkpoint and DNA repair genes has been shown to be indicative of chemosensitivity. In the present study, we have examined the SNP of methylenetetrahydrofolate reductase (MTHFR) C677T, which affects DNA methylation patterns and is linked to elevated plasma homocysteine levels in 208 patients with gemcitabine/cisplatin-treated stage IV non-small-cell lung cancer (NSCLC). No differences in response rate were observed according to the MTHFR genotype. However, time to progression was 7.4 months for 68 patients with CC genotype, 5.5 months for 108 patients with heterozygous CT genotype, and 5.2 months for 28 patients with TT genotype. These findings can lead us to distinguish different outcome patterns among patients with stage IV NSCLC whose similar clinical prognostic factors would otherwise indicate similar outcomes. Carriers of the MTHFR 677T allele could benefit from supplementation with folic acid and vitamin B12. The Spanish Lung Cancer Group has undertaken a phase III randomized trial to elucidate this concept.

Preradiation chemotherapy with VM-26 and CCNU in patients with glioblastoma multiforme.

AIMS AND BACKGROUND: The objective of the study was to evaluate the efficacy of combined chemoradiation in patients with newly diagnosed glioblastoma multiforme. The main end points were time to progression and overall survival. METHODS: Thirty-one patients with glioblastoma multiforme underwent surgery whenever possible and then received intravenous VM26 (120 mg/m2) and oral CCNU (120 mg/m2) for three cycles followed by radiotherapy (60 Gy). RESULTS: Surgery consisted of a complete resection in 39% of patients, partial resection in 35% and a biopsy in 26%. Sixteen patients had clinical or radiological evidence of progression during or after chemotherapy. Hematologic toxicity was mild. Forty-five percent of patients received the scheduled dose of radiation. The outcome was disappointing, with a median time to progression of 18 weeks and median survival of 37.17 weeks. CONCLUSIONS: The survival of patients with glioblastoma multiforme remains disappointing. Multimodal therapy does not seem to modify the evolution of the tumor. Stratification according to prognostic factors might detect a potential benefit of other therapeutic approaches.

[Prognostic and predictive factors of patients with cancer of unknown origin treated with a paclitaxel-based chemotherapy]. / Factores pronósticos y predictivos en pacientes con cáncer de origen desconocido tratados con un esquema de quimioterapia con paclitaxel.

BACKGROUND AND OBJECTIVE: Taxane-based combinations appear to be promising for the treatment of carcinoma of unknown primary site (CUPS). PATIENTS AND METHOD: Patients with CUPS not corresponding to any favourable subset were treated with paclitaxel, carboplatin and etoposide. Interaction between various factors with survival was analyzed. A regression model was applied to identify factors with independent prognostic significance. RESULTS: 48 patients were included and 15 responses were observed with a median overall survival of 7.4 months. In the multivariate analysis, performance status and hypoalbuminemia were negatively associated with overall survival. CONCLUSIONS: Some patients can achieve complete response and prolonged survival. This treatment cannot be recommended for patients with a regular performance status. A better knowledge of prognostic factors and a definition of more subgroups with favourable outcome are needed.

FOLFOX in patients aged between 76 and 80 years with metastatic colorectal cancer: an exploratory cohort of the OPTIMOX1 study.

BACKGROUND: Patients older than 75 years of age are usually excluded from metastatic colorectal cancer randomized studies. The OPTIMOX1 study evaluated FOLFOX7, a simplified (s) leucovorin (LV) and 5-fluorouracil (5FU) regimen (sLV5FU2) with high-dose oxaliplatin, in a new oxaliplatin stop-and-go strategy. An exploratory cohort of patients aged 76 to 80 years was included in the study. METHODS: In all, 620 previously untreated patients were randomized between FOLFOX4 until progression (arm A), or FOLFOX7 for 6 cycles, maintenance without oxaliplatin for 12 cycles, and reintroduction of FOLFOX7 (arm B). RESULTS: A total of 37 patients aged 76 to 80 years were included, 20 in arm A and 17 in arm B. The overall response rate (ORR) was 59.4%, comparable to younger patients (59%). Median progression-free survival (PFS) was 9.0 months and median overall survival (OS) was 20.7 months. These results did not differ from that in younger patients < or =75 years in the OPTIMOX1 study with PFS 9.0 months (P = .63) and OS 20.2 months (P = .57). They experienced slightly more grade 3 of 4 toxicity than younger patients: 65% versus 48% (P = .06), mainly with more neutropenia (41% vs 24%, P = .03) and neurotoxicity (22% vs 11%, P = .06). Tolerability, however, was manageable and no toxic death occurred in this elderly population. CONCLUSIONS: The efficacy of FOLFOX-based treatment was maintained in patients >75 years with both FOLFOX regimens. The oxaliplatin stop-and-go management strategy performed well in this population.

Metastatic non-small-cell lung carcinoma successfully treated with pre-operative chemotherapy and bilateral adrenalectomy.

Metastatic non-small-cell lung cancer is a common condition with a dismal prognosis. Although palliative chemotherapy improves survival and quality of life, nearly all patients die of progressive disease. Metastatic involvement of adrenal glands is not rare, but usually reflects widespread dissemination. Selected patients with single adrenal metastasis may be cured with surgery, although the level of evidence comes from single cases reports and short retrospective series. Here we report a patient with bilateral adrenal metastases from previously resected non-small-cell lung cancer, who remains free of disease four years after pre-operative chemotherapy and bilateral adrenalectomy.

Irinotecan (CPT-11) combined with bolus 5-fluorouracil/leucovorin (Saltz regimen) as first-line chemotherapy of patients with advanced colorectal cancer.

Concerns about the safety of irinotecan (CPT-11) plus bolus 5-fluorouracil (5-FU)/leucovorin (LV) (the so-called Saltz regimen) have been previously reported. This prospective, multicenter, non-randomized study evaluated the anti-tumoral effect and toxicity of the Saltz regimen as first-line chemotherapy of 130 patients with advanced colorectal cancer (CRC). The median numbers of treatment cycles and infusions received per patient were 3 and 12, respectively. Eight (6.1) and 37 patients (28.5%) showed complete and partial responses, respectively [overall response rate=34.6% (95% confidence interval=20.7-48.5%)]. After a median follow up period of 9 months, 70 patients had died. The median progression-free survival and overall survival were 6.78 (0.3-33.8) and 8.26 months (range 0.3-33.8), respectively. The combined CPT-11/5-FU/LV treatment was well tolerated and no toxic deaths were reported. The most common grade 3/4 hematological toxicity was neutropenia (28% of patients and 3% of infusions), but no febrile neutropenia was reported. Delayed diarrhea was the most reported grade 3/4 non-hematological toxicity (21% of patients and 2% of infusions). Other non-hematological toxicities showed very low incidences. During the study five patients died due to factors not associated with disease progression. We conclude that the Saltz regimen administered on an outpatient basis was safe and well tolerated in patients with advanced CRC. Close monitoring of external patients together with an early treatment of toxicity was found to be essential to prevent severe and potentially fatal gastrointestinal or thromboembolic events previously reported with this CPT-11 combined regimen.

Biweekly administration of cisplatin/gemcitabine in advanced nonsmall cell lung cancer.

INTRODUCTION: In an attempt to increase the dose intensity of cisplatin and gemcitabine given to patients with stage IIIB or IV nonsmall cell lung cancer without increasing toxicity, we have studied a biweekly administration schedule. We analyze the safety and efficacy of this treatment. METHODS AND PATIENTS: In this study, cycles of 50 mg/m2 cisplatin with 2500 mg/m2 gemcitabine were given on days 1 and 15 every 28 days. The median age of the 49 patients was 62 years and 23 were in stage IIIB patients (46.9%), whereas 26 (53.1%) were in stage IV. RESULTS: Overall response rate was 38.8%, 52.2% for stage IIIB and 26.9% for stage IV. Median survival was 48 weeks and 1-year survival was 44%, with 66.7% of stage IIIB patients and 13.3% of stage IV patients surviving for 1 year. In the study, 178 cycles were administered, a mean of 4 cycles per patient. The intensity of the 359 administrations reached 91.16% of the planned dosage, although 49 were delayed for 1 week while subjects recovered from the toxicity. There was 1 toxic death and 2 patients experienced vascular toxicity with distal arterial ischemic severe changes in their lower extremities. There were 7 episodes of grade 2 neutropenia, 2 of grade 3, and one of grade 4; however, no cases of febrile neutropenia were seen. The predominant nonhematologic toxic effects were asthenia and nausea/vomiting. CONCLUSION: The schedule of cisplatin and gemcitabine analyzed is active with a good therapeutic index.

Factores pronósticos y predictivos en pacientes con cáncer de origen desconocido tratados con un esquema de quimioterapia con paclitaxel / Prognostic and predictive factors of patients with cancer of unknown origin treated with a paclitaxel-based chemotherapy

FUNDAMENTO Y OBJETIVO: Las combinaciones con taxanos parecen prometedoras en el carcinoma de origen desconocido. PACIENTES Y MÉTODO: Los pacientes con carcinoma de origen desconocido no clasificable en subgrupos especiales fueron tratados con paclitaxel, carboplatino y etopósido. Se analizó la relación de diversas variables con la supervivencia y se aplicó un modelo de regresión logística para detectar variables pronósticas independientes. RESULTADOS: Se incluyó a 48 pacientes. Se consiguieron 15 respuestas y una mediana de supervivencia de 7,4 meses. Según el análisis multivariante, una puntuación de 2 en el estado general y la presencia de hipoalbuminemia influyeron negativamente en la supervivencia global. CONCLUSIONES: Algunos pacientes pueden conseguir supervivencias prolongadas. No puede recomendarse esta combinación para pacientes con estado general regular. Se necesita un mejor conocimiento de los factores pronósticos y la definición de más subgrupos específicos (AU)