Pralatrexate in Combination with Oxaliplatin in Advanced Esophagogastric Cancer: A Phase II Trial with Predictive Molecular Correlates.

The purpose of our study was to evaluate the efficacy of a combination of pralatrexate plus oxaliplatin in advanced esophagogastric cancer (EGC), analyze the impact of polymorphisms in folate metabolism pathway genes on toxicity and efficacy of pralatrexate, and to evaluate microRNA profile of tumor epithelium as a predictive biomarker. This was a two-stage trial with a safety lead in cohort and a primary endpoint of overall response rate (ORR). Patients received biweekly intravenous oxaliplatin (85 mg/m2) and pralatrexate (Dose level 1 [D1], 120 mg/m2; dose level-1 [D-1] 100 mg/m2). Single-nucleotide polymorphisms (SNP) in genes encoding proteins involved in pralatrexate metabolism were evaluated in germline DNA. microRNA profiling of the tumor epithelium was performed. ORR was 26%. Dose-limiting toxicities were observed in 2 of 4 patients at D1 and none at D-1. The T>C polymorphism in DHFR rs11951910 was significantly associated with lower progression-free survival (PFS; P ≤ 0.01), whereas the presence of the SLC19A1 rs2838957 G>A polymorphism was associated with improved PFS (P = 0.02). Presence of the GGH rs3780130 A>T and SLC19A1 rs1051266 G>A polymorphisms were significantly associated with better overall survival (OS; P = 0.01), whereas GGH rs7010484 T>C polymorphism was associated significantly with reduced OS (P = 0.04). There was no correlation between epithelial microRNA expression profile with disease progression or response. We conclude that the combination of oxaliplatin and pralatrexate is safe, is well tolerated, and has modest efficacy in advanced EGC. Pharmacogenomic analysis may be relevant to the use of pralatrexate in combination with platinum agents.

Natural History and Predictors of Parastomal Hernia after Robot-Assisted Radical Cystectomy and Ileal Conduit Urinary Diversion.

PURPOSE: We investigated the prevalence of and variables associated with parastomal hernia and its outcomes after robot-assisted radical cystectomy and ileal conduit creation for bladder cancer. MATERIALS AND METHODS: We retrospectively reviewed the records of patients who underwent robot-assisted radical cystectomy at our institution. Parastomal hernia was defined as the protrusion of abdominal contents through the stomal defect in the abdominal wall on cross-sectional imaging. Parastomal hernia was further described in terms of patient and hernia characteristics, symptoms, management and outcomes. The Kaplan-Meier method was used to determine time to parastomal hernia and time to surgery. Multivariate stepwise logistic regression was done to evaluate variables associated with parastomal hernia. RESULTS: A total of 383 patients underwent robot-assisted radical cystectomy and ileal conduit creation. Of the patients 75 (20%) had parastomal hernia, which was symptomatic in 23 (31%), and 11 (15%) underwent treatment. Median time to parastomal hernia was 13 months (IQR 9-22). Parastomal hernia developed in 9%, 23% and 32% of cases at 1, 2 and 3 years, respectively. Patients with parastomal hernia had a significantly higher body mass index (30 vs 28 kg/m2, p = 0.02), longer overall operative time (357 vs 340 minutes, p = 0.01) and greater blood loss (325 vs 250 ml, p = 0.04). On multivariate analysis operative time (OR 1.25, 95% CI 1.21-3.90, p <0.001), a fascial defect 30 mm or greater (OR 5.23, 95% CI 2.32-11.8, p <0.001) and a lower postoperative estimated glomerular filtration rate (OR 2.17, 95% CI 1.21-3.90, p = 0.01) were significantly associated with parastomal hernia. CONCLUSIONS: Symptoms develop in approximately a third of patients with parastomal hernia and 15% will require surgery. The risk of parastomal hernia plateaued after postoperative year 3. Longer operative time, a larger fascial defect and lower postoperative kidney function were associated with parastomal hernia.

Systemic Therapy in Advanced Cutaneous Squamous Cell Carcinoma (CSCC): The Roswell Park Experience and a Review of the Literature.

OBJECTIVES: Treatment of locally advanced unresectable or metastatic cutaneous squamous cell carcinoma (mCSCC) is suboptimal with a paucity of robust data on systemic therapy. This retrospective study aimed to evaluate the efficacy and outcomes of patients with locally advanced unresectable or mCSCC treated with systemic therapy. METHODS: Records of patients with CSCC treated with systemic therapy from January 2001 to January 2011 were reviewed. Response was assessed using WHO criteria. Descriptive results were assessed using Wilcoxon rank-sum test for ordinal responses and Pearson χ test for categorical responses. Survival was calculated by the Kaplan-Meier method. RESULTS: Of 28 patients identified, 25 patients (M:F=18:7), median age 66 years (range, 39 to 85 y), had the required data for final analysis. Partial response was 44% and stable disease (SD) was 24%. The median progression-free survival (PFS) and overall survival (OS) were 5.5 months (2.3, 13.2) and 10.9 months (5.3, 21.3) respectively; 3-year OS was 22%. Patients with WHO response had improved PFS (20.8 mo; 4.4, NR) and OS (37.5 mo; 10.3, NR) compared with patients with SD/PD (PFS 2.7 mo; OS 5.9 mo). Use of platinum-based therapy significantly improved PFS and OS, whereas taxanes and cetuximab had no impact in this small cohort. There was no difference in PFS or OS with multiagent versus single-agent therapy. CONCLUSIONS: Platinum-based therapy remains as one of the standard options in advanced CSCC management. Agents to improve response rates are needed and future trials should address the use of novel targeted and new chemotherapy combinations in CSCC.

Semiquantitative visual approach to scoring lung cancer treatment response using computed tomography: a pilot study.

OBJECTIVE: Our objective was to compare a newly developed semiquantitative visual scoring (SVS) method with the current standard, the Response Evaluation Criteria in Solid Tumors (RECIST) method, in the categorization of treatment response and reader agreement for patients with metastatic lung cancer followed by computed tomography. MATERIALS AND METHODS: The 18 subjects (5 women and 13 men; mean age, 62.8 years) were from an institutional review board-approved phase 2 study that evaluated a second-line chemotherapy regimen for metastatic (stages III and IV) non-small cell lung cancer. Four radiologists, blinded to the patient outcome and each other's reads, evaluated the change in the patients' tumor burden from the baseline to the first restaging computed tomographic scan using either the RECIST or the SVS method. We compared the numbers of patients placed into the partial response, the stable disease (SD), and the progressive disease (PD) categories (Fisher exact test) and observer agreement (kappa statistic). RESULTS: Requiring the concordance of 3 of the 4 readers resulted in the RECIST placing 17 (100%) of 17 patients in the SD category compared with the SVS placing 9 (60%) of 15 patients in the partial response, 5 (33%) of the 15 patients in the SD, and 1 (6.7%) of the 15 patients in the PD categories (P < 0.0001). Interobserver agreement was higher among the readers using the SVS method (kappa, 0.54; P < 0.0001) compared with that of the readers using the RECIST method (kappa, -0.01; P = 0.5378). CONCLUSIONS: Using the SVS method, the readers more finely discriminated between the patient response categories with superior agreement compared with the RECIST method, which could potentially result in large differences in early treatment decisions for advanced lung cancer.

Invasive filamentous fungal infections in allogeneic hematopoietic stem cell transplant recipients after recovery from neutropenia: clinical, radiologic, and pathologic characteristics.

Invasive filamentous fungal infection (IFFI) is an important cause of mortality in allogeneic hematopoietic stem cell transplant (HSCT) recipients. We reviewed 22 consecutive cases of IFFI in allogeneic HSCT recipients at Roswell Park Cancer Institute. IFFI was diagnosed after neutrophil recovery in 21 patients (95%). All had received corticosteroids within 1 month prior to IFFI diagnosis. Fourteen (64%) presented with dyspnea, and only 7 (32%) were febrile. Aspergillus species were isolated in 18 (82%) cases. Thirty day mortality after IFFI diagnosis was associated with a higher mean daily dose of corticosteroids (P=0.02) and receiving OKT3 (P=0.01) within 1 month prior to IFFI diagnosis and serum creatinine>2 mg/dl at the time of diagnosis (P=0.004). Histopathologic material from biopsy or autopsy was available in 15 patients (68%). In 8 (53%), the predominant lung histopathology was an acellular coagulative necrosis and hyphal angioinvasion was observed in some of these cases. These findings have generally been observed in neutropenic patients but not in non-neutropenic HSCT recipients. The predominance of coagulative necrosis in our series may reflect the high doses of corticosteroids used to treat graft-versus-host disease (GVHD), which may have disabled leukocyte trafficking and hyphal killing.

CT venography in suspected pulmonary thromboembolism.

Pulmonary embolism (PE) and deep venous thrombosis (DVT) are a continuum and are difficult to diagnose clinically. Combined CT venography and pulmonary angiography (CTVPA) is a single examination that combines multidetector CT pulmonary angiography (CTPA) and CT venography (CTV) of the abdomen, pelvis, and lower extremities, providing "one-stop shopping" for venous thromboembolism without additional venipuncture or i.v. contrast, and it adds only a few additional minutes to scanning time. CTVPA rapidly and accurately examines the deep veins, reveals the presence, absence, and extent of deep venous thrombosis, serves as a baseline, and helps guide patient management. Multiple investigators have reported a high degree of accuracy when CTV is compared with venous ultrasound. There are some pitfalls in image interpretation, especially with regard to mixing artifacts, and there are continuing controversies as to exactly which parts of the abdomen, pelvis, and legs should be scanned routinely, the ideal timing of CTV acquisition relative to contrast injection, and the slice thickness and gap, if any, that should be used.

Combined CT venography and pulmonary angiography: a comprehensive review.

The combination of computed tomographic (CT) venography and pulmonary angiography (CTVPA) was initially described in 1998 as a single comprehensive noninvasive imaging examination for suspected thromboembolic disease. It allowed the identification of pulmonary embolism as well as deep venous thrombosis (DVT) in the abdomen, pelvis, thighs, and calves. The venographic portion of CTVPA has now been studied by multiple researchers and has been shown to be an accurate imaging study for the thigh veins in comparison with lower extremity sonography. In contrast to sonography, however, CTVPA readily and rapidly permits evaluation of the inferior vena cava, the pelvic veins, the calf veins, and all of the superficial venous system. Complex venous anatomy can be surveyed, an additional sonographic study is not required, and only a few extra minutes and images are required over and above CT pulmonary angiography. A review of 957 recent cases of suspected pulmonary embolism examined with CTVPA revealed an overall 10.5% frequency of DVT, with a nearly equal distribution of thrombosis at the common femoral, superficial femoral, popliteal, and deep calf veins. Although a variety of protocols for CTVPA may be implemented, including a contiguous helical acquisition, obtaining 5- or 10-mm-thick images every 4 cm provides a high degree of accuracy and decreases overall radiation dose.

Rituximab in combination with CHOP or fludarabine in low-grade lymphoma.

Non-Hodgkin's lymphoma (NHL) is composed of a group of lymphoid malignancies that has been increasing in incidence at an annual rate of 4% to 7% over the last 20 years in both the United States and Europe. The reasons for this rise in incidence in NHL are not yet defined but most likely involve environmental exposures. Low-grade and follicular lymphomas account for approximately 40% of the incidences of NHL in the United States. While patients with intermediate- and high-grade lymphomas are potentially curable with combination chemotherapy, low-grade and follicular lymphomas are still considered to be essentially incurable with standard therapy. Although low-grade lymphomas characteristically respond well to treatment with chemotherapeutic agents, the disease typically follows a course of recurrent relapse and progressively shorter remissions, and ultimately death from lymphoma. Median survival for patients with low-grade lymphoma is 6.2 years from diagnosis and just 5 years from time of first relapse. Therefore, novel therapeutic strategies are urgently needed for these patients. One approach to the development of innovative strategies for treatment of NHL has been the generation of monoclonal antibodies to specific B-cell antigens expressed on NHL cells.

Rituximab in combination with CHOP or fludarabine in low-grade lymphoma.

Non-Hodgkin's lymphoma (NHL) is composed of a group of lymphoid malignancies that has been increasing in incidence at an annual rate of 4% to 7% over the last 20 years in both the United States and Europe. The reasons for this rise in incidence in NHL are not yet defined but most likely involve environmental exposures. Low-grade and follicular lymphomas account for approximately 40% of the incidences of NHL in the United States. While patients with intermediate- and high-grade lymphomas are potentially curable with combination chemotherapy, low-grade and follicular lymphomas are still considered to be essentially incurable with standard therapy. Although low-grade lymphomas characteristically respond well to treatment with chemotherapeutic agents, the disease typically follows a course of recurrent relapse and progressively shorter remissions, and ultimately death from lymphoma. Median survival for patients with low-grade lymphoma is 6.2 years from diagnosis and just 5 years from time of first relapse. Therefore, novel therapeutic strategies are urgently needed for these patients. One approach to the development of innovative strategies for treatment of NHL has been the generation of monoclonal antibodies to specific B-cell antigens expressed on NHL cells. Semin Oncol 29 (suppl 2):36-40. Copyright © 2002 by W.B. Saunders Company.