Diagnostic challenges of renal medullary carcinoma and the role for cytologic assessment: Case report and literature review.

BACKGROUND: Renal medullary carcinoma (RMC) is a diagnostically challenging, aggressive primary renal malignancy associated with abysmal survival. Delays in diagnosis contribute to most patients having diffusely metastatic disease at the time of initial presentation. METHODS: We present the case of a 13-year-old African American male with sickle cell trait who presented with a renal mass and hematuria. Evaluation included imaging, fluid cultures, and cytologic assessment. RESULTS: Patient was diagnosed with RMC based on cytologic assessment of sub-centimeter fluid collections aspirated from the left kidney at the time of cortical biopsy for suspected renal mass. The additional fluid aspiration in conjunction with renal biopsy was an atypical but crucial step in early diagnosis. CONCLUSION: Cytomorphologic evaluation of fluid biospecimens is not currently part of the standard work-up for patients with renal masses but, when available, can provide crucial information that reduces time to diagnosis. Prompt symptom recognition and treatment initiation may improve patient outcomes.

Maintenance DFMO Increases Survival in High Risk Neuroblastoma.

High risk neuroblastoma (HRNB) accounts for 15% of all pediatric cancer deaths. Despite aggressive therapy approximately half of patients will relapse, typically with only transient responses to second-line therapy. This study evaluated the ornithine decarboxylase inhibitor difluoromethylornithine (DFMO) as maintenance therapy to prevent relapse following completion of standard therapy (Stratum 1) or after salvage therapy for relapsed/refractory disease (Stratum 2). This Phase II single agent, single arm multicenter study enrolled from June 2012 to February 2016. Subjects received 2 years of oral DFMO (750 ± 250 mg/m2 twice daily). Event free survival (EFS) and overall survival (OS) were determined on an intention-to-treat (ITT) basis. 101 subjects enrolled on Stratum 1 and 100 were eligible for ITT analysis; two-year EFS was 84% (±4%) and OS 97% (±2%). 39 subjects enrolled on Stratum 2, with a two-year EFS of 54% (±8%) and OS 84% (±6%). DFMO was well tolerated. The median survival time is not yet defined for either stratum. DFMO maintenance therapy for HRNB in remission is safe and associated with high EFS and OS. Targeting ODC represents a novel therapeutic mechanism that may provide a new strategy for preventing relapse in children with HRNB.

Neuroblastoma in Africa: A Survey by the Franco-African Pediatric Oncology Group.

PURPOSE: Neuroblastoma is a sympathoadrenal lineage neural crest-derived tumor. It is the third most common childhood malignancy in the Western world. Studies from the United States show that black patients with neuroblastoma have a greater proportion of high-risk neuroblastoma with poorer prognosis compared with white patients. In Africa, there are few published data on the epidemiology and management of neuroblastoma. The primary aim of this study was to assess the diagnostic and therapeutic resources available for the management of neuroblastoma within the Franco-African Pediatric Oncology Group (GFAOP). METHODS: A survey was conducted in the pediatric oncology centers of the GFAOP. Participating GFAOP centers were Abidjan, Algiers, Bamako, Dakar, Lubumbashi, Lomé, Ouagadougou, Rabat, Tananarive Antananarivo, and Tunis. Questionnaires were sent out by e-mail to the principal investigators at each participating GFAOP center in December 2013. RESULTS: Ten (62%) of 16 GFAOP centers responded to the questionnaire. Neuroblastoma represented only 3% to 5% of childhood cancers in the sub-Saharan African centers, with the exception of Antananarivo, where it represented 7.5%. In contrast, in the northern African centers of Tunis, Rabat, and Algiers, neuroblastoma accounted for 30%,10%, and 7% of childhood cancer, respectively. At initial diagnosis, 50% to 80% of patients had metastatic neuroblastoma in eight of 10 centers. CONCLUSION: Based on this survey, neuroblastoma seems to be less common in sub-Saharan Africa. The proportion of patients with metastatic neuroblastoma seems to be higher than reported in Western countries.

Increased CTLA-4(+) T cells and an increased ratio of monocytes with loss of class II (CD14(+) HLA-DR(lo/neg)) found in aggressive pediatric sarcoma patients.

BACKGROUND: There is little information regarding the composition of peripheral blood immunity in sarcoma patients and even less in the context of pediatric sarcomas. We describe the immune status using flow cytometry of peripheral blood in patients with osteosarcoma and Ewing sarcoma and demonstrate excessive CD14 in tumor tissues. METHODS: Peripheral blood from patients with OS and ES was collected at diagnosis or relapse, and used for immune phenotyping of 74 different leukocyte phenotypes. Blood from young adult healthy volunteers was collected as controls. Tumor tissues were analyzed by immunohistochemistry. RESULTS: Nineteen patients (average age = 14 y) and 16 controls (average age = 25y) were enrolled on study. Of the 74 phenotypes, 14 were different between sarcoma patients and HV. Sarcoma patients' leukocytes contained a higher percentage of granulocytes (67 % sarcoma vs. 58 % HV; p = 0.003) and fewer lymphocytes (20 % sarcoma vs. 27 % HV; p = 0.001). Increased expression of CTLA-4 was seen in both T cells in sarcoma patients as compared to HV (p = 0.05). Increased CD14(+) HLA-DR(lo/neg) immunosuppressive monocytes were seen in sarcoma patients (p = 0.03); primarily seen in OS. Increased tumor necrosis factor receptor II expression was seen on CD14(+) cells derived from sarcoma patients as compared to HV (p = 0.01). Massive infiltration of CD14(+) cells was seen in OS (>50 % of cells in the majority of tumors) compared to ES (<10-25 % of cells). In contrast, both OS and ES had limited T cell infiltration (generally <10 % of cells). CONCLUSIONS: Pediatric sarcoma patients exhibit several immune phenotypic differences that were exacerbated in more severe disease. These phenotypes have the potential to contribute to immune suppression and may indicate potential targets for immune therapies.

VEGF blockade enables oncolytic cancer virotherapy in part by modulating intratumoral myeloid cells.

Understanding the host response to oncolytic viruses is important to maximize their antitumor efficacy. Despite robust cytotoxicity and high virus production of an oncolytic herpes simplex virus (oHSV) in cultured human sarcoma cells, intratumoral (ITu) virus injection resulted in only mild antitumor effects in some xenograft models, prompting us to characterize the host inflammatory response. Virotherapy induced an acute neutrophilic infiltrate, a relative decrease of ITu macrophages, and a myeloid cell-dependent upregulation of host-derived vascular endothelial growth factor (VEGF). Anti-VEGF antibodies, bevacizumab and r84, the latter of which binds VEGF and selectively inhibits binding to VEGF receptor-2 (VEGFR2) but not VEGFR1, enhanced the antitumor effects of virotherapy, in part due to decreased angiogenesis but not increased virus production. Neither antibody affected neutrophilic infiltration but both partially mitigated virus-induced depletion of macrophages. Enhancement of virotherapy-mediated antitumor effects by anti-VEGF antibodies could largely be recapitulated by systemic depletion of CD11b(+) cells. These data suggest the combined effect of oHSV virotherapy and anti-VEGF antibodies is in part due to modulation of a host inflammatory reaction to virus. Our data provide strong preclinical support for combined oHSV and anti-VEGF antibody therapy and suggest that understanding and counteracting the innate host response may help enable the full antitumor potential of oncolytic virotherapy.

Gemcitabine, docetaxel, and bevacizumab in relapsed and refractory pediatric sarcomas.

BACKGROUND: The outcome for patients with relapsed and refractory pediatric sarcomas remains dismal. Novel agents are needed to improve overall survival in these patients. OBSERVATIONS: We present 3 patients with relapsed/refractory sarcomas treated with gemcitabine, docetaxel, and bevacizumab in 3-week cycles. The combination was well tolerated with minimal toxicity. Two patients had a partial response and the third patient had stable disease for >6 months. CONCLUSIONS: These results are limited by small patient numbers but this strategy should be evaluated in prospective clinical trials.