Genetic predisposition for medication-related osteonecrosis of the jaws: a systematic review.

The purpose of this study was to assess whether genetic variation is a predictor for the development of medication-related osteonecrosis of the jaws (MRONJ) in patients receiving bisphosphonate therapy for various conditions. A systematic review based on the PRISMA guidelines was performed. A search strategy was developed. Comprehensive searches of major databases were conducted for studies published January 2003 through July 2018. The PICOS strategy was used to develop the inclusion criteria. The analysis in each study was performed primarily using single nucleotide polymorphism (SNP) frequency mean values and odds ratios between cases and controls. A total of 3301 patients were enrolled in the 15 included studies (two genome-wide association studies, n = 1877; 10 candidate gene studies, n = 1195; three whole genome/whole exome studies, n = 229). Multiple myeloma was the most prevalent primary disease (54.8%). Zoledronate was prescribed in 68.8% of patients. No one SNP was definitively identified as a risk factor for the development of MRONJ. To date, studies have failed to show a single gene as a risk factor for MRONJ. Heterogeneity of case and control populations may be contributory. Next generation sequencing studies may help elucidate the role and interplay of genetic events in the development of MRONJ.

Correction: Pomalidomide, bortezomib, and low-dose dexamethasone in lenalidomide-refractory and proteasome inhibitor-exposed myeloma.

Following the publication of this article, the authors noted that the pomalidomide dose for the additional SC cohort in Fig. 1 was incorrectly listed. The correct dose for pomalidomide in the additional SC cohort should be the maximum tolerated dose of 4 mg/day, not 2 mg/day as listed in the original Fig. 1. The authors apologize for any inconvenience caused.

Pomalidomide, bortezomib and low-dose dexamethasone in lenalidomide-refractory and proteasome inhibitor-exposed myeloma.

This phase 1 dose-escalation study evaluated pomalidomide, bortezomib (subcutaneous (SC) or intravenous (IV)) and low-dose dexamethasone (LoDEX) in lenalidomide-refractory and proteasome inhibitor-exposed relapsed or relapsed and refractory multiple myeloma (RRMM). In 21-day cycles, patients received pomalidomide (1-4 mg days 1-14), bortezomib (1-1.3 mg/m2 days 1, 4, 8 and 11 for cycles 1-8; days 1 and 8 for cycle ⩾9) and LoDEX. Primary endpoint was to determine the maximum tolerated dose (MTD). Thirty-four patients enrolled: 12 during escalation, 10 in the MTD IV bortezomib cohort and 12 in the MTD SC bortezomib cohort. Patients received a median of 2 prior lines of therapy; 97% bortezomib exposed. With no dose-limiting toxicities, MTD was defined as the maximum planned dose: pomalidomide 4 mg, bortezomib 1.3 mg/m2 and LoDEX. All patients discontinued treatment by data cutoff (2 April 2015). The most common grade 3/4 treatment-emergent adverse events were neutropenia (44%) and thrombocytopenia (26%), which occurred more frequently with IV than SC bortezomib. No grade 3/4 peripheral neuropathy or deep vein thrombosis was reported. Overall response rate was 65%. Median duration of response was 7.4 months. Pomalidomide, bortezomib and LoDEX was well tolerated and effective in lenalidomide-refractory and bortezomib-exposed patients with RRMM.

A novel Bruton's tyrosine kinase inhibitor CC-292 in combination with the proteasome inhibitor carfilzomib impacts the bone microenvironment in a multiple myeloma model with resultant antimyeloma activity.

Bruton's tyrosine kinase (Btk) modulates B-cell development and activation and has an important role in antibody production. Interestingly, Btk may also affect human osteoclast (OC) function; however, the mechanism was unknown. Here we studied a potent and specific Btk inhibitor, CC-292, in multiple myeloma (MM). In this report, we demonstrate that, although CC-292 increased OC differentiation, it inhibited OC function via inhibition of c-Src, Pyk2 and cortactin, all involved in OC-sealing zone formation. As CC-292 did not show potent in vitro anti-MM activity, we next evaluated it in combination with the proteasome inhibitor, carfilzomib. We first studied the effect of carfilzomib on OC. Carfilzomib did not have an impact on OC-sealing zone formation but significantly inhibited OC differentiation. CC-292 combined with carfilzomib inhibited both sealing zone formation and OC differentiation, resulting in more profound inhibition of OC function than carfilzomib alone. Moreover, the combination treatment in an in vivo MM mouse model inhibited tumor burden compared with CC-292 alone; it also increased bone volume compared with carfilzomib alone. These results suggest that CC-292 combined with carfilzomib augments the inhibitory effects against OC within the bone microenvironment and has promising therapeutic potential for the treatment of MM and related bone disease.

Low incidence of CNS relapse with cranial radiotherapy and intrathecal methotrexate in acute lymphoblastic leukemia.

OBJECTIVES: To assess the incidence of isolated central nervous system (CNS) relapses in patients of acute lymphoblastic leukemia (ALL) treated with a protocol containing cranial irradiation and intrathecal methotrexate as CNS directed therapy. DESIGN: Prospective non randomized study. SETTING: Department of Medical Oncology, Tata Memorial Hospital. SUBJECTS: 623 children of ALL on MCP 841. METHODS: CNS relapse was diagnosed, if upon examination of the CSF, more than 50 cells/microliter were observed, or a count of 5 cells which were unequivocally lymphoblasts. RESULTS: The incidence of isolated CNS relapse was 1.75% with the use of this treatment. Age, sex, white blood cell count, platelet count, lactic dehydrogenase and immunophenotyping were not significantly related to isolated CNS relapse. CONCLUSION: A low incidence of isolated CNS relapse demonstrates the adequacy of the presymptomatic CNS therapy.

Infection analysis in acute lymphoblastic leukemia: a report of 499 consecutive episodes in India.

The use of empirical antibiotic combinations in the treatment of febrile neutropenic patients has decreased complication-related mortality in cancer patients. We have analyzed retrospectively 499 consecutive episodes of fever in 432 patients with acute lymphoblastic leukemia over a 5-year period. We have compared various antibiotic combinations used empirically in our study. Of the febrile episodes, 92% were neutropenic. The most common site of clinical documentation was the lung. The most common pathogen isolated in our setting was Pseudomonas aeruginosa (27.27%). The overall response rate to first-line empirical antibiotic combination was seen in 61.92%, the best results being with ceftazidime and amikacin combination (65.69%). A uniform antibiotic policy resulted in a decrease in mortality, with the number of deaths decreasing significantly in the 1989 to 1991 era (P = 0.00000003). The other contributing factors were an improvement in the supportive care with a reduction in length of hospital stay during induction. Our fungal isolates demonstrated 11 patients with documented fungal infection with a positive outcome in 8 patients.

Melanotic neuroectodermal tumor of infancy: report of a case with ganglionic differentiation.

Melanotic neuroectodermal tumor of infancy (MNTI) is a rare but well-documented lesion of neuroectodermal derivation. Maturation of the neural elements has been reported only occasionally. We report a case of MNTI of the maxilla showing maturation of neural elements to ganglionic cells.

Response with combined modality treatment in childhood rhabdomyosarcoma.

Children diagnosed with rhabdomyosarcoma at the Tata Memorial Hospital during the period January 1986-December 1988 were studied. All were treated with combination chemotherapy incorporating vincristine, Adriamycin, and cyclophosphamide given sequentially in repeated cycles over 18 months, along with local radiotherapy. Of 24 patients, 18 patients had advanced-stage disease at onset. All patients have been followed up for 18 months or more. Of the 11 patients with group III disease, six are in complete remission; of the six patients with group IV disease, two patients are in complete remission. These results are clearly better than those achieved in the past, where surgery was employed as the primary modality of therapy with chemoradiotherapy given only for patients with group IV disease.