A genomic-augmented multivariate prognostic model for the survival of natural-killer/T-cell lymphoma patients from an international cohort.

With lowering costs of sequencing and genetic profiling techniques, genetic drivers can now be detected readily in tumors but current prognostic models for Natural-killer/T cell lymphoma (NKTCL) have yet to fully leverage on them for prognosticating patients. Here, we used next-generation sequencing to sequence 260 NKTCL tumors, and trained a genomic prognostic model (GPM) with the genomic mutations and survival data from this retrospective cohort of patients using LASSO Cox regression. The GPM is defined by the mutational status of 13 prognostic genes and is weakly correlated with the risk-features in International Prognostic Index (IPI), Prognostic Index for Natural-Killer cell lymphoma (PINK), and PINK-Epstein-Barr virus (PINK-E). Cox-proportional hazard multivariate regression also showed that the new GPM is independent and significant for both progression-free survival (PFS, HR: 3.73, 95% CI 2.07-6.73; p < .001) and overall survival (OS, HR: 5.23, 95% CI 2.57-10.65; p = .001) with known risk-features of these indices. When we assign an additional risk-score to samples, which are mutant for the GPM, the Harrell's C-indices of GPM-augmented IPI, PINK, and PINK-E improved significantly (p < .001, χ2 test) for both PFS and OS. Thus, we report on how genomic mutational information could steer toward better prognostication of NKTCL patients.

PD-L1 Expressing Recurrent Clear Cell Carcinoma of the Vulva with Durable Partial Response to Pembrolizumab: A Case Report.

BACKGROUND: The optimal treatment and molecular landscape of recurrent clear cell carcinoma of the vulva (VCCC) are unknown. No reported data exist regarding the efficacy of anti-programmed death 1 (PD-1) immune checkpoint inhibition in VCCC. We report on a patient with chemotherapy-refractory recurrent VCCC, who was found to have high tumor programmed death-ligand 1 (PD-L1) combined positive score (CPS), and subsequently experienced a durable partial response (PR), after treatment with off-label fifth-line pembrolizumab. CASE PRESENTATION: A forty-year-old Filipino woman presented to our center with recurrent VCCC that had progressed on multiple prior lines of cytotoxic chemotherapy. She had a large 25 cm fungating left groin tumor causing marked lower limb lymphedema, pain and limited mobility. PD-L1 CPS by immunohistochemistry was 45. She was treated with off-label pembrolizumab monotherapy and had a dramatic clinical, biochemical and radiological partial response. The progression-free survival of this patient's VCCC after treatment with pembrolizumab, defined as the time from initiation of pembrolizumab until disease progression (by Response Evaluation Criteria in Solid Tumors (version 1.1)), was 8 months. While receiving pembrolizumab, she was diagnosed with concurrent secondary myelodysplastic syndrome with excess blasts (MDS-EB), thought to be related to her prior exposure to multiple lines of cytotoxic chemotherapy. This eventually progressed to acute myeloid leukemia (AML), leading to her demise. Overall survival from time of initiation of pembrolizumab till death was 16 months. CONCLUSION: Pembrolizumab was active in this patient with chemotherapy-refractory VCCC which harbored high PD-L1 CPS. Further studies to determine the role of immune check-point blockade in the treatment of VCCC are warranted.

Phase I Trial of Expanded, Activated Autologous NK-cell Infusions with Trastuzumab in Patients with HER2-positive Cancers.

PURPOSE: Natural killer (NK) cells exert antibody-dependent cell cytotoxicity (ADCC). We infused expanded, activated autologous NK cells to potentiate trastuzumab-mediated ADCC in patients with HER2-positive malignancies. PATIENTS AND METHODS: In a phase I trial, patients with treatment-refractory HER2-positive solid tumors received trastuzumab, with or without bevacizumab, and autologous NK cells expanded by 10-day coculture with K562-mb15-41BBL cells. Primary objectives included safety and recommended phase II dose determination; secondary objectives included monitoring NK-cell activity and RECIST antitumor efficacy. RESULTS: In 60 cultures with cells from 31 subjects, median NK-cell expansion from peripheral blood was 340-fold (range, 91-603). NK cells expressed high levels of CD16, the mediator of ADCC, and exerted powerful killing of trastuzumab-targeted cells. In the 22 subjects enrolled in phase I dose escalation, trastuzumab plus NK cells were well tolerated; MTD was not reached. Phase IB (n = 9) included multiple cycles of NK cells (1 × 107/kg) and addition of bevacizumab. Although no objective response was observed, 6 of 19 subjects who received at least 1 × 107/kg NK cells at cycle 1 had stable disease for ≥6 months (median, 8.8 months; range 6.0-12.0). One patient, the only one with the high-affinity F158V CD16 variant, had a partial response. Peripheral blood NK cells progressively downregulated CD16 postinfusion; paired tumor biopsies showed increased NK cells, lymphocytic infiltrates, and apoptosis posttreatment. CONCLUSIONS: NK-cell therapy in combination with trastuzumab was well tolerated, with target engagement and preliminary antitumor activity, supporting continued assessment of this approach in phase II trials.

Allogeneic stem cell transplant in patients with chronic lymphocytic leukemia with 17p deletion: consult-transplant versus consult- no-transplant analysis.

Allogeneic stem cell transplant (alloSCT) can overcome the adverse prognosis of chronic lymphocytic leukemia with 17p deletion (17p- CLL). However, its applicability remains unclear. Since 2007, our leukemia service has referred patients with 17p- CLL for alloSCT at presentation. In this study, the outcomes of these patients were reviewed retrospectively to determine whether they underwent alloSCT and why patients did not undergo alloSCT. Fifty-two patients with 17p- CLL who were referred to the transplant service from 2007 to 2010 were identified. Of these patients, 32 (62%) did not undergo alloSCT, mainly because of treatment- or disease-related complications (n = 15). The 2-year post-referral overall survival rates of the alloSCT and non-SCT groups were 64% and 25%, respectively (p = 0.001). These findings suggest that while alloSCT is an effective therapy in patients with 17p- CLL, pre-SCT complications may preclude a significant proportion of patients from undergoing the procedure.

Case report: cytomegalovirus-induced thrombosis in an immunocompetent patient.

Thrombotic manifestations of cytomegalovirus infection in immunocompetent individuals are rare. However, it has been postulated that cytomegalovirus infection can be both directly cytopathic and capable of inducing antiphospholipid antibodies due to shared "molecular mimicry" between cytomegalovirus virus antigens and antiphospholipid antibodies. The case of a previously well 30-year-old woman with primary cytomegalovirus infection complicated by splenic infarction and massive pulmonary embolus is described. The patient is unusual given the development of thromboses affecting both the arterial and venous circulation, associated with both transient anticardiolipin antibodies and persistently positive anti-ß(2) glycoprotein I antibodies. The temporal relationship between the primary infection and thrombosis was suggestive of a pathogenic role for cytomegalovirus.

Hereditary thrombophilia in an unselected cohort of venous thrombosis patients in Singapore.

AIM: Hereditary thrombophilic markers are commonly screened among patients diagnosed as having venous thromboembolism, but optimal patient selection and the goals of screening may differ between populations. Determining the patterns of hereditary thrombophilia may improve screening strategies. METHOD: An unselected cohort of venous thromboembolism patients in three tertiary institutions in Singapore was prospectively tested for the prevalence of deficiencies of protein C, protein S, antithrombin III, factor V Leiden and prothrombin 20210 gene mutations. RESULTS: Among 384 patients screened, the prevalences of protein S, protein C and antithrombin III were 9.20%, 1.18% and 4.19% respectively. Only one patient was positive for the factor V Leiden mutation and none tested positive for the prothrombin 20210 gene mutation. At least 1 in 9 patients (11.52%, 95% CI 8.20 to 15.93) will test positive for one of the above markers in an unselected group of 269 patients who completed all tests. The exclusion of patients with clinical risk factors did not improve the detection rates, in comparison with those with obvious provoking clinical risk factors (11.72%, 95% CI 7.36 to 18.06 vs 11.29%, 95% CI 6.73 to 18.18). When upper age limits were set for thrombophilia screening by decades, a statistical difference in the likelihood of a positive thrombophilia screen between younger and older patient was seen for patients below 40 (p<0.001). CONCLUSION: In Singapore and countries with similar demographics, hereditary thrombophilia screening should be confined to testing for protein C, protein S and antithrombin III.

Primary cutaneous anaplastic large cell lymphoma of the vulva: a typical cutaneous lesion with an 'atypical' presenting site.

Non-Hodgkin lymphoma of vulva is exceedingly rare and it often poses a diagnostic challenge if their existence is not suspected. We report a patient who has primary cutaneous anaplastic large cell (C-ALCL) with an unusual presentation as a vulvar ulcer. She received a brief course of chemotherapy followed by local irradiation and has remained disease-free more than a year from the time of diagnosis. To our knowledge, primary C-ALCL involving the vulva has never been reported. Despite its typical cutaneous manifestation of C-ALCL, the uncommon presenting site of this entity warrants recognition because of its prognostic and therapeutic implication.