Malignant pleural mesothelioma (MPM) is a rare malignancy of the pleura that is frequently resistant to conventional therapies. Immunotherapy is a promising investigational approach for MPM that has shown some evidence of clinical benefit in select patients. However, tumor-induced immunosuppression is likely a major impediment to achieving optimal clinical responses to immunotherapeutic intervention. MPM contains a variable degree of infiltrating T-regulatory cells and M2 macrophages, which are believed to facilitate tumor evasion from the host immune system. Additional immunosuppressive factors identified in other human tumor types, such as tumor-associated programmed death ligand-1 expression, may be relevant for investigation in MPM. Conventional cytoreductive therapies, such as radiation, chemotherapy, and surgery, may play a critical role in successful immunotherapeutic strategies by ablating intratumoral and/or systemic immunosuppressive factors, thus creating a host environment more amenable to immunotherapy. This article reviews the immunotherapeutic approaches being evaluated in patients with MPM and discusses how immunotherapy might be rationally combined with conventional tumor cytoreductive therapies for this disease.

Since the cornea is an avascular tissue, the wound healing process is lengthy, with a need for sutures to stabilize the wound for a long time. Platelet-derived growth factor (PDGF) has been shown to accelerate wound healing in rat dermal models. Accelerated healing, if unaccompanied by side effects may reduce suture related complications such as astigmatism and infectious keratitis. This study evaluated the effect of PDGF on wound strength in corneal laceration and penetrating keratoplasty models using New Zealand white albino rabbits. Twenty-two rabbits were used in the corneal laceration model and sixteen rabbits in the penetrating keratoplasty model. The treated rabbits received 385 picomoles/drop of PDGF-BB dissolved in balanced salt solution six times on day 1 and three times a day for the remainder of the study. The control rabbits received balanced salt solution in the same dosing schedule. The pressure required to rupture the wound was measured using a pressure transducer. In the laceration model the PDGF treated group had mean (+/- standard deviation) average pressures on day 7 of 360 +/- 102 mm Hg for wound rupture compared to 210 +/- 102 mm Hg in the control group. (p = 0.005). The average pressures in the penetrating keratoplasty model on day 17 were 707 +/- 201 mm Hg for the controls and 1042 +/- 292 mm Hg for the PDGF treated group (p = 0.026). Histopathological evaluation of eyes not subjected to bursting showed increased fibroblasts at the wound junction with an increase in types III and type IV collagen production.(ABSTRACT TRUNCATED AT 250 WORDS)

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PurposeThis article reviews the mechanism of action of trastuzumab emtansine (T-DM1), existing clinical data relating to its use for human growth factor receptor 2 (HER2)-positive breast cancer, potential pathways of resistance, and ongoing studies evaluating this novel agent.BackgroundThe development of HER2-targeted therapies has dramatically improved clinical outcomes for patients with any stage of HER2-positive breast cancer. Although the positive effect of these treatments cannot be overstated, treatment resistance develops in the vast majority of those diagnosed with stage IV HER2-positive breast cancer. Moreover, HER2-directed therapies are most effective when combined with cytotoxic chemotherapy. The need for chemotherapy leads to significant adverse effects and a clear decrease in quality of life for those dealing with a chronic incurable disease. T-DM1 is a recently developed, novel antibody–drug conjugate in which highly potent maytanisinoid chemotherapy is stably linked to the HER2-targeted monoclonal antibody, trastuzumab.ResultsPreclinical and phase 1–3 clinical data support the significant antitumor activity of T-DM1. Importantly, several randomized studies also now demonstrate its clear superiority in terms of tolerability compared with standard chemotherapy-containing regimens. Its role in the treatment of trastuzumab-resistant metastatic breast cancer has now been established on the basis of the results of two phase 3 randomized studies, EMILIA (An Open-label Study of Trastuzumab Emtansine (T-DM1) vs Capecitabine + Lapatinib in Patients With HER2-positive Locally Advanced or Metastatic Breast Cancer) and TH3RESA (A Study of Trastuzumab Emtansine in Comparison With Treatment of Physician’s Choice in Patients With HER2-positive Breast Cancer Who Have Received at Least Two Prior Regimens of HER2-directed Therapy). The most common toxicities seen with T-DM1 are thrombocytopenia and an elevation in liver transaminases. Significant cardiac toxicity has not been demonstrated. Both in vitro cell line–based studies as well as exploratory analyses of archived tumor samples from the clinical trials are seeking to understand potential mechanisms of resistance to T-DM1. Ongoing studies are also evaluating the use of T-DM1 in the first-line metastatic, neoadjuvant, and adjuvant settings, as well as in combination with other targeted therapies.ConclusionT-DM1 represents the first successfully developed antibody drug conjugate for the treatment of HER2-positive advanced breast cancer.

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