Survival and Prognostic Factors in Patients With Solid Pseudopapillary Neoplasms of the Pancreas.

OBJECTIVES: Prognostic factors for solid pseudopapillary neoplasms (SPN) of the pancreas have been incompletely defined in the literature. We aimed to use the National Cancer Database to describe survival and characterize prognostic factors in patients with pancreatic pseudopapillary neoplasms. METHODS: We identified 304 patients with pancreatic SPN diagnosed between 2004 and 2012 using the National Cancer Database. All patients were included in the survival analysis. Kaplan-Meier method, χ, and log-rank tests were used for statistical analysis. Cox proportional hazard regression model was used for multivariate analysis. RESULTS: The median age at diagnosis was 36.5 years. Eighty-five percent of patients were female, 69% were white, and 25% were black. Metastases were observed in 5% of patients. Median tumor size was 5.1 cm. Ninety-two percent of patients underwent primary tumor resection. At 60 months, 98% of patients who underwent resection were alive, and 40% who did not undergo resection were alive. On multivariate analysis, female sex, resection of primary tumor, and absence of metastasis were correlated with improved survival. CONCLUSIONS: Patients with SPN who undergo resection have an excellent survival at 5 years. Surgery should be considered in all patients with this diagnosis.

Exceptional response to everolimus in a novel tuberous sclerosis complex-2 mutation-associated metastatic renal-cell carcinoma.

Everolimus, an oral inhibitor of the mammalian target of rapamycin (mTOR) pathway, is currently approved for treatment of advanced renal-cell carcinoma (RCC) after failure of initial treatment with the tyrosine kinase inhibitors. Patients with tuberous sclerosis complex (TSC) syndrome can also develop RCC primarily mediated through mTOR signaling. However, the efficacy and duration of response of mTOR inhibition in patients with TSC-associated RCC is not well known. Herein, we describe a case of a patient with TSC2-associated metastatic RCC with mutations H1620R and Y1650C who has had an exceptional response to everolimus in the frontline setting and continues to derive benefit from mTOR inhibition 2 yr into therapy. Furthermore, the alteration H1620R in exon 37 resulting in a missense mutation is likely deleterious given our findings and previous analyses of the TSC2 gene. Further studies of somatic mutations in extended responders to mTOR inhibitors will help personalize therapy for these patients. It also emphasizes the value of targeted therapies based on genomic analyses.

Characteristics and long-term outcomes of head and neck squamous cell carcinoma after solid organ transplantation.

INTRODUCTION: Immunosuppression after solid organ transplant prevents graft rejection, but leads to increased incidence of various malignancies including head and neck squamous cell carcinoma (HNSCC). Outcomes of patients with post-transplant HNSCC are unknown. MATERIALS AND METHODS: We retrospectively identified patients who developed HNSCC after solid organ transplant between 1995 and 2010. Adults with pathology-proven HNSCC and adequate follow up were included. Median overall survival and progression free survival were analyzed using the Kaplan-Meier method. The prognostic effect of variables was studied with Cox proportional hazards models. RESULTS: Thirty-three patients met study inclusion criteria. The median time to diagnosis of HNSCC after transplant was 5.9years. The primary site was oral cavity in 15 patients, oropharynx in 10, larynx in 3, hypopharynx in 2, parotid in 2 and unknown in 1 patient. Eighty-eight percent underwent upfront surgical resection. Of those, sixty-six percent received adjuvant therapy. Six percent of patients had definitive chemoradiation. Treatment was well tolerated and did not lead to graft rejection. The 5-year overall survival rate was 45% and 37% for localized and locally advanced disease respectively. Seventy-five percent of patients with oropharyngeal tumors were HPV-positive and they had better outcomes (5-year overall survival rate of 67%). In multivariate analysis, age ≥60years was a negative predictor of survival (HR 2.7; 95% CI, 1.1-6.5; P=0.03). CONCLUSIONS: Patients with post-transplant HNSCC have relatively poor survival and high risk of locoregional and distant recurrence. HPV- positive oropharyngeal tumors continue to have better outcomes in this population.

Expression of PD-1 and PD-L1 in Anaplastic Thyroid Cancer Patients Treated With Multimodal Therapy: Results From a Retrospective Study.

Context: Anaplastic thyroid cancer (ATC) is rare and a highly fatal malignancy. The role of programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1) as prognostic and/or predictive markers in ATC is unknown. Objective: Multimodal therapy offers the best chance at tumor control. The objective of this study was to detect potential associations of PD-1/PD-L1 axis variables with outcome data in ATC. Design: Retrospective study of a uniformly treated cohort. Setting: Single institution retrospective cohort study. Patients or Other Participants: Sixteen patients who received intensity-modulated radiation therapy (15 had preceding surgery) were studied. Main Outcome Measure: Patients treated with multimodal therapy were followed and assessed for overall survival (OS) and progression-free survival (PFS). Results: All samples demonstrated PD-1 expression in inflammatory cells whereas tumor cells were primarily negative. PD-L1 was expressed on ATC tumor cells in most samples and showed mainly membranous staining. High PD-1 expression (>40% staining) in inflammatory cells was associated with worse overall survival (OS; hazard ratio, 3.36; 95% confidence interval, 1.00 to 12.96; P < 0.05) and trended toward worse PFS, whereas high PD-L1 expression in tumor cells (>33% staining) trended toward worse PFS and OS. Conclusion: PD-1/PD-L1 pathway proteins are highly expressed in ATC tumor samples and appear to represent predictive markers of PFS and OS in multimodality-treated ATC patients.

Frontline Systemic Therapy With Pemetrexed-Platinum in Nonsquamous Non-Small-Cell Lung Cancer With Asymptomatic Brain Metastases.

The incidence of brain metastases from nonsquamous non-small-lung cancer is increasing as a result of superior imaging techniques for early detection of distant metastases. Although whole-brain radiation therapy and stereotactic radiosurgery along with systemic chemotherapy have shown to be effective in alleviating symptoms and improving outcomes, the approach to patients with asymptomatic brain metastases remains elusive. We explored the literature for a possible role of frontline systemic chemotherapy in asymptomatic brain metastases from nonsquamous non-small-lung cancer and found promising evidence that upfront systemic therapy with pemetrexed-platinum regimens might be a reasonable option for these patients and would forestall the need for upfront brain radiation therapy. More large-scale phase II and phase III clinical trials are needed to further investigate the frontline use of pemetrexed-platinum regimens in this setting.

A case of multiple myeloma with metachronous chronic myeloid leukemia treated successfully with bortezomib, dexamethasone, and dasatinib.

The coexistence of multiple myeloma and chronic myeloid leukemia in a single patient is a very rare event that has been reported very infrequently in the literature. We report a case of a patient who developed chronic myeloid leukemia four years after his diagnosis with multiple myeloma. Historically, no link between the two malignancies has been identified. This synchronous existence complicates the treatment plan for these patients, and there is a lack of evidence on the best therapeutic approach. Our patient was successfully treated with a combination of bortezomib, dexamethasone, and dasatinib, which he tolerated well for eleven months until he eventually succumbed to cardiac complications and pulmonary hypertension leading to his death.

MicroRNAs in brain metastases: potential role as diagnostics and therapeutics.

Brain metastases remain a daunting adversary that negatively impact patient survival. Metastatic brain tumors affect up to 45% of all cancer patients with systemic cancer and account for ~20% of all cancer-related deaths. A complex network of non-coding RNA molecules, microRNAs (miRNAs), regulate tumor metastasis. The brain micro-environment modulates metastatic tumor growth; however, defining the precise genetic events that promote metastasis in the brain niche represents an important, unresolved problem. Understanding these events will reveal disease-based targets and offer effective strategies to treat brain metastases. Effective therapeutic strategies based upon the biology of brain metastases represent an urgent, unmet need with immediate potential for clinical impact. Studies have demonstrated the ability of miRNAs to distinguish normal from cancerous cells, primary from secondary brain tumors, and correctly categorize metastatic brain tumor tissue of origin based solely on miRNA profiles. Interestingly, manipulation of miRNAs has proven effective in cancer treatment. With the promise of reduced toxicity, increased efficacy and individually directed personalized anti-cancer therapy, using miRNA in the treatment of metastatic brain tumors may prove very useful and improve patient outcome. In this review, we focus on the potential of miRNAs as diagnostic and therapeutic targets for the treatment of metastatic brain lesions.

The brain microenvironment negatively regulates miRNA-768-3p to promote K-ras expression and lung cancer metastasis.

The brain microenvironment promotes metastasis through mechanisms that remain elusive. Co-culture of lung cancer cells with astrocytes - the most abundant cell type within the metastatic brain niche - lead to downregulation of miRNA-768-3p which drives K-ras expression and key signaling pathways, enhances cell viability and promotes chemotherapeutic resistance. Vector-based forced expression of miRNA-768-3p complementary sequence or a chemically-engineered miRNA-768-3p inhibitor recapitulated the astrocyte effect to increase tumor cell viability. The miRNA-768-3p inhibitor targeted the K-ras 3'-UTR as demonstrated by increased luminescence from a luciferase reporter and strikingly increased the K-ras protein and the downstream effectors ERK1/2 and B-Raf. miRNA-768-3p was reduced in patient brain metastases compared to normal brain tissue and was lower in patient tissue from brain metastases compared to same-patient primary tumour tissue. The brain microenvironment negatively regulates miRNA-768-3p to enhance K-ras and promote metastasis. We propose that therapeutic replacement of the metastasis suppressor miRNA-768-3p holds clinical promise.