Blocking FcRn in humans reduces circulating IgG levels and inhibits IgG immune complex-mediated immune responses.

The neonatal crystallizable fragment receptor (FcRn) functions as an intracellular protection receptor for immunoglobulin G (IgG). Recently, several clinical studies have reported the lowering of circulating monomeric IgG levels through FcRn blockade for the potential treatment of autoimmune diseases. Many autoimmune diseases, however, are derived from the effects of IgG immune complexes (ICs). We generated, characterized, and assessed the effects of SYNT001, a FcRn-blocking monoclonal antibody, in mice, nonhuman primates (NHPs), and humans. SYNT001 decreased all IgG subtypes and IgG ICs in the circulation of humans, as we show in a first-in-human phase 1, single ascending dose study. In addition, IgG IC induction of inflammatory pathways was dependent on FcRn and inhibited by SYNT001. These studies expand the role of FcRn in humans by showing that it controls not only IgG protection from catabolism but also inflammatory pathways associated with IgG ICs involved in a variety of autoimmune diseases.

Role of adjuvant radiation in the management of central neurocytoma: Experience from a tertiary cancer care center of India.

BACKGROUND AND OBJECTIVE: Neurocytoma (NC) is a rare benign neuronal tumor. A complete excision remains curative for most of these tumors, but atypical histology and extra-ventricular location often necessitates adjuvant therapy. We intended to explore the clinico-pathological features and treatment outcome in patients of NC in our institute. MATERIALS AND METHODS: Medical records were reviewed and data collected on NC over a 6-year period (2006-2012) from the departmental archives. Disease free survival (DFS) was analyzed by Kaplan-Meier method. RESULTS: A total of 18 patients met the study criteria. Fourteen patients had intra-ventricular neurocytoma (IVNC), right lateral ventricle being the most common site of origin. Gross total resection and near total resection were achieved in eight cases each whereas tumor decompression and biopsy could be done in two cases. On post-operative histopathological examination, eight patients were found to have atypical NC while 10 patients had typical NC. All patients underwent adjuvant radiation. The median dose of post-operative radiation was 56 Gy. All patients were alive at their final follow-up. One patient had both clinical and radiological evidence of local relapse. In the evaluable patients (n = 18), after a median follow-up of 35 months the DFS rate at 2 years and 3 years are 100% and 83% respectively. CONCLUSION: Use of adjuvant radiation to a total dose of 56 Gy enhances the local control and achieves superior survival in patients of NC. Use of 3D conformal planning techniques may help us to achieve better therapeutic ratio in patients with NC.

Clinical outcome of patients with primary gliosarcoma treated with concomitant and adjuvant temozolomide: A single institutional analysis of 27 cases.

CONTEXT AND AIM: The prognosis of primary gliosarcoma (PGS) remains dismal with current treatment modalities. We analyzed the outcome of PGS patients treated with concurrent and adjuvant temozolomide (TMZ). SETTINGS AND DESIGN: Retrospective single institutional analysis. MATERIALS AND METHODS: We retrospectively evaluated 27 patients of PGS treated with radiotherapy (RT) and TMZ during 2007-2012. STATISTICAL ANALYSIS USED: Overall survival (OS) was estimated by the use of Kaplan Meier method and toxicities were evaluate using common terminology criteria for adverse events version 2.0 (National Cancer Institute, USA). RESULTS: Median age at presentation and Karnofsky performance status was 45 years and 90 respectively and male: female ratio was 20:7. Patients received adjuvant RT to a total dose of 60 Gy at 2 Gy/fraction. All patients except 5 received adjuvant TMZ to a median number of 6 cycles. Grade 2 and 3 hematological toxicity was seen in 8% and 4% of patients respectively during concurrent RT. During adjuvant chemotherapy, 13.6% had Grade 3 thrombocytopenia and 9.5% had Grade 3 neutropenia. Median OS was 16.7 months (1 year and 2 year actuarial OS was 70.8% and 32.6% respectively). Adjuvant TMZ was associated with a better survival (median survival 21.21 vs. 11.93 months; P = 0.0046) on univariate analysis and also on multivariate analysis (hazard ratio 1.82, 95% confidence interval: 1.503-25.58; P = 0.012). CONCLUSIONS: The results of our study, largest series of patients with PGS treated with concurrent and adjuvant TMZ shows an impressive survival with acceptable toxicity. We suggest TMZ be included in the "standard of care" for this tumor.

Rate of CRL4(CRBN) substrate Ikaros and Aiolos degradation underlies differential activity of lenalidomide and pomalidomide in multiple myeloma cells by regulation of c-Myc and IRF4.

Recent discoveries suggest that the critical events leading to the anti-proliferative activity of the IMiD immunomodulatory agents lenalidomide and pomalidomide in multiple myeloma (MM) cells are initiated by Cereblon-dependent ubiquitination and proteasomal degradation of substrate proteins Ikaros (IKZF1) and Aiolos (IKZF3). By performing kinetic analyses, we found that the downregulation or proteasomal degradation of Ikaros and Aiolos led to specific and sequential downregulation of c-Myc followed by IRF4 and subsequent growth inhibition and apoptosis. Notably, to ensure growth inhibition and cell death, sustained downregulation of Ikaros and Aiolos, c-Myc or IRF4 expression was required. In addition, we found that the half-maximal rate, rather than the final extent of Ikaros and Aiolos degradation, correlated to the relative efficacy of growth inhibition by lenalidomide or pomalidomide. Finally, we observed that all four transcription factors were elevated in primary MM samples compared with normal plasma cells. Taken together, our results suggest a functional link between Ikaros and Aiolos, and the pathological dysregulation of c-Myc and IRF4, and provide a new mechanistic understanding of the relative efficacy of lenalidomide and pomalidomide based on the kinetics of substrate degradation and downregulation of their downstream targets.

Tumor invasion of the pulmonary veins: a unique source of systemic embolism detected by transesophageal echocardiography.

Two patients with a malignancy involving the lungs and spontaneous systemic embolization in whom transesophageal echocardiography detected masses consistent with tumor invading the pulmonary veins are reported. In the first patient, tumor embolization resulted in acute aortic obstruction. Transesophageal echocardiography revealed tumor present in the pulmonary veins that extended into the left atrium. This was confirmed by magnetic resonance imaging. The second patient had a stroke. Transesophageal echocardiography demonstrated a mass in the right pulmonary vein in this patient as well. In patients with pulmonary malignancy who have a systemic embolic event, tumor emboli from the pulmonary vein should be included in the differential diagnosis of possible causes of the event. Transesophageal echocardiography is a valuable tool for diagnosis of tumor involvement of the pulmonary veins in such patients.

Diagnostic value of carcinoembryonic antigen assay of pleural & peritoneal effusions in malignancy.

Carcinoembryonic antigen (CEA) assays were performed on effusion fluid and plasma samples of 55 patients; 38 with malignant and 17 with benign disease. Sensitivity of plasma CEA was 60.5 per cent while specificity was 76.5 per cent. Sensitivity of effusion fluid CEA was 52.63 per cent but specificity was 100 per cent. Sensitivity of the cytological examination of the fluid was 60.5 per cent and no false positive diagnosis was made. Detection rate of malignancy increased to 81.6 per cent (31 of 38) when cytology and effusion fluid CEA were used in adjunction for diagnosis, with 100 per cent specificity.

Surgical complications of gynecologic surgery.

Complications of gynecological surgery are considerable and when reviewed in detail are almost frightening. There is no substitute for experience and intimate knowledge of the intricate pelvic structures in health and disease.Anyone who is active in the field is sooner or later going to experience some difficulty whether it be due to his miscalculation or to innate conditions in the patient which are beyond his/her control.It is the responsibility of the pelvic surgeon to recognize the complication and apply proper corrective measures. The patient should not be given false hopes of sure success nor should she be deprived of whatever hope for success does exist.

Re-irradiation in head and neck cancers: an Indian tertiary cancer centre experience.

OBJECTIVE: To explore the treatment outcomes of patients treated with re-irradiation for recurrent or second primary head and neck cancer. METHOD: An analysis was performed of 79 head and neck cancer patients who underwent re-irradiation for second primaries or recurrent disease from January 1999 to December 2011. RESULTS: Median time from previous radiation to re-irradiation for second primary or recurrence was 53.6 months (range, 2.7-454.7 months). Median age at diagnosis of first primary was 54 years. Median re-irradiation dose was 45 Gy (range, 45-60 Gy). Acute grade 3 or worse toxicity was seen in 30 per cent of patients. Median progression-free survival for recurrent disease was 15.0 months (95 per cent confidence interval, 8.33-21.66). The following factors had a statistically significant, positive impact on progression-free survival: patient age of less than 50 years (median progression-free survival was 29.43, vs 13.9 months for those aged 50 years or older; p = 0.004) and disease-free interval of 2 years or more (median progression-free survival was 51.66, vs 13.9 months for those with less than 2 years disease-free interval). CONCLUSION: Re-irradiation of second primaries or recurrences of head and neck cancers with moderate radiation doses yields acceptable progression-free survival and morbidity rates.

Cereblon is a direct protein target for immunomodulatory and antiproliferative activities of lenalidomide and pomalidomide.

Thalidomide and the immunomodulatory drug, lenalidomide, are therapeutically active in hematological malignancies. The ubiquitously expressed E3 ligase protein cereblon (CRBN) has been identified as the primary teratogenic target of thalidomide. Our studies demonstrate that thalidomide, lenalidomide and another immunomodulatory drug, pomalidomide, bound endogenous CRBN and recombinant CRBN-DNA damage binding protein-1 (DDB1) complexes. CRBN mediated antiproliferative activities of lenalidomide and pomalidomide in myeloma cells, as well as lenalidomide- and pomalidomide-induced cytokine production in T cells. Lenalidomide and pomalidomide inhibited autoubiquitination of CRBN in HEK293T cells expressing thalidomide-binding competent wild-type CRBN, but not thalidomide-binding defective CRBN(YW/AA). Overexpression of CRBN wild-type protein, but not CRBN(YW/AA) mutant protein, in KMS12 myeloma cells, amplified pomalidomide-mediated reductions in c-myc and IRF4 expression and increases in p21(WAF-1) expression. Long-term selection for lenalidomide resistance in H929 myeloma cell lines was accompanied by a reduction in CRBN, while in DF15R myeloma cells resistant to both pomalidomide and lenalidomide, CRBN protein was undetectable. Our biophysical, biochemical and gene silencing studies show that CRBN is a proximate, therapeutically important molecular target of lenalidomide and pomalidomide.

Dexamethasone synergizes with lenalidomide to inhibit multiple myeloma tumor growth, but reduces lenalidomide-induced immunomodulation of T and NK cell function.

To determine the effect of dexamethasone on the antimyeloma effects of lenalidomide, we tested in vitro proliferation, tumor suppressor gene expression, caspase activity, cell cycling, and apoptosis levels in a series of multiple myeloma (MM) and plasma cell leukemia cell lines treated with lenalidomide and dexamethasone, alone or in combination. The effect of dexamethasone on the immunomodulatory activities of lenalidomide such as T cell and natural killer (NK) cell activation was measured via interleukin [IL]-2 production, and interferon-gamma and granzyme B production respectively. Lenalidomide inhibited proliferation in most cell lines tested, and this effect was enhanced by dexamethasone. This effect was observed in MM cells containing the high-risk cytogenetic abnormalities t(4;14), t(14;16), del17p, del13, and hypodiploidy. Mechanistically, lenalidomide plus dexamethasone synergistically induced expression of the tumor suppressor genes Egr1, Egr2, Egr3, p15, p21, and p27 in MM cell lines and MM patient cells. The combination activated caspases 3, 8, and 9; and induced cell cycle arrest and apoptosis. Lenalidomide alone increased T cell production of IL-2, and NK cell production of interferon-gamma and granzyme B. Notably, dexamethasone antagonized these immunostimulatory effects of lenalidomide in a dose-dependent manner. These data further elucidate the mechanism of action of lenalidomide and dexamethasone in MM, and suggest that use of low-dose dexamethasone with lenalidomide may retain the antiproliferative effect of lenalidomide while permitting greater immunomodulatory effects of this combination regimen.

Apremilast, a cAMP phosphodiesterase-4 inhibitor, demonstrates anti-inflammatory activity in vitro and in a model of psoriasis.

BACKGROUND AND PURPOSE: Apremilast is an orally administered phosphodiesterase-4 inhibitor, currently in phase 2 clinical studies of psoriasis and other chronic inflammatory diseases. The inhibitory effects of apremilast on pro-inflammatory responses of human primary peripheral blood mononuclear cells (PBMC), polymorphonuclear cells, natural killer (NK) cells and epidermal keratinocytes were explored in vitro, and in a preclinical model of psoriasis. EXPERIMENTAL APPROACH: Apremilast was tested in vitro against endotoxin- and superantigen-stimulated PBMC, bacterial peptide and zymosan-stimulated polymorphonuclear cells, immunonoglobulin and cytokine-stimulated NK cells, and ultraviolet B light-activated keratinocytes. Apremilast was orally administered to beige-severe combined immunodeficient mice, xenotransplanted with normal human skin and triggered with human psoriatic NK cells. Epidermal skin thickness, proliferation index and inflammation markers were analysed. KEY RESULTS: Apremilast inhibited PBMC production of the chemokines CXCL9 and CXCL10, cytokines interferon-gamma and tumour necrosis factor (TNF)-alpha, and interleukins (IL)-2, IL-12 and IL-23. Production of TNF-alpha by NK cells and keratinocytes was also inhibited. In vivo, apremilast significantly reduced epidermal thickness and proliferation, decreased the general histopathological appearance of psoriasiform features and reduced expression of TNF-alpha, human leukocyte antigen-DR and intercellular adhesion molecule-1 in the lesioned skin. CONCLUSIONS AND IMPLICATIONS: Apremilast displayed a broad pattern of anti-inflammatory activity in a variety of cell types and decreased the incidence and severity of a psoriasiform response in vivo. Inhibition of TNF-alpha, IL-12 and IL-23 production, as well as NK and keratinocyte responses by this phosphodiesterase-4 inhibitor suggests a novel approach to the treatment of psoriasis.