Immune checkpoint inhibitors in advanced nasopharyngeal carcinoma: Beyond an era of chemoradiation?

Now is an exciting era of development in immunotherapy checkpoint inhibitors and their effect on the treatment of NPC. While the general prognosis of R/M disease is poor, immunotherapy offers some promise in a malignancy associated with EBV and characterized by a peritumoural immune infiltrate. Our study aims to review past and on-going clinical trials of monoclonal antibody therapies against the checkpoint inhibitors (e.g. PD1 and CTLA-4), in R/M NPC. All randomized and nonrandomized controlled trials involving immune checkpoint inhibitor interventions for treatment of NPC were included in the study. We utilized a validated “risk of bias” tool to assess study quality. Four separate Phase I–II trials report the potential of PD1 inhibitor treatment for patients with NPC. Within the observed groups, camrelizumab combined with chemotherapy achieved an objective response in 91% of patients as first-line treatment for metastatic NPC (PFS 68% at 1-year) but this was associated with a high rate of grade >3 adverse events (87%; CTCAE version 4.03). The remaining three studies focused on recurrent NPC disease in patients who had received at least one line of prior chemotherapy. Within this group, camrelizumab monotherapy achieved an objective response in 34% of patients (PFS 27% at 1-year; range across all three studies 20.5–34%). No NPC trial has yet reported on specific outcomes for non-PD1 checkpoint inhibitors but 11 on-going studies include alternative targets (e.g. PD-L1/CTLA-4) as combination or monotherapy treatments. In considering checkpoint immunotherapies for NPC, initial results show promise for anti-PD1 interventions. Further phase I–III trials are in progress to clarify clinical outcomes, fully determine safety profiles, and optimize drug combinations and administration schedules.     

Therapeutic cooperation between auranofin,a thioredoxin reductase inhibitor and anti-PD-L1 antibody for treatment of triple-negative breast cancer

Triple-negative breast cancer (TNBCs) is a very aggressive and lethal form of breast cancer with no effective targeted therapy. Neoadjuvant chemotherapies and radiotherapy remains a mainstay of treatment with only 25–30% of TNBC patients responding. Thus, there is an unmet clinical need to develop novel therapeutic strategies for TNBCs. TNBC cells have increased intracellular oxidative stress and suppressed glutathione, a major antioxidant system, but still, are protected against higher oxidative stress. We screened a panel of antioxidant genes using the TCGA and METABRIC databases and found that expression of the thioredoxin pathway genes is significantly upregulated in TNBC patients compared to non-TNBC patients and is correlated with adverse survival outcomes. Treatment with auranofin (AF), an FDA-approved thioredoxin reductase inhibitor caused specific cell death and impaired the growth of TNBC cells grown as spheroids. Furthermore, AF treatment exerted a significant in vivo antitumor activity in multiple TNBC models including the syngeneic 4T1.2 model, MDA-MB-231 xenograft and patient-derived tumor xenograft by inhibiting thioredoxin redox activity. We, for the first time, showed that AF increased CD8^+Ve T-cell tumor infiltration in vivo and upregulated immune checkpoint PD-L1 expression in an ERK1/2-MYC-dependent manner. Moreover, combination of AF with anti-PD-L1 antibody synergistically impaired the growth of 4T1.2 primary tumors. Our data provide a novel therapeutic strategy using AF in combination with anti-PD-L1 antibody that warrants further clinical investigation for TNBC patients.     

A new clinical test in gastroduodenal perforation.

Forty-nine cases of gastroduodenal perforation were subjected to new air insufflation test. The clinical and radiological criteria of air insufflation test were applied to every patient of this study. Forty-seven cases (95.9%) were positive to the new test whereas 2 negative cases turned out to be old sealing perforation. The new test is highly useful in preoperative detection of site of perforation in perforative peritonitis.     

Rheological characterisation of dextran-concanavalin A mixtures as a basis for a self-regulated drug delivery device.

The rheological characterisation of glucose sensitive mixtures containing dextran and concanavalin A (con A) with and without glucose, was undertaken using oscillatory rheometry at 20 and 37 degrees C so that comparative data could be gathered in the linear viscoelastic (LVE) range. Measurements for a series of mixtures showed that complex viscosity is a function not only of the con A concentration but of the content and molecular weight of the dextran used. The extent of liquefaction on addition of glucose also depended on these factors. The tan delta profiles confirmed the change from semi-solid towards fluid behaviour. This occurs when glucose effects dismantling of the three-dimensional structure of the dextran-con A system by competitive binding to the glucose receptors in the protein. For the mixtures studied, the changes occurred between contents of 0 and 1% (w/w) glucose at 20 and 37 degrees C and form a useful basis for the formulation of a self-regulating delivery device for the control of hyper-and hypoglycaemia in diabetes.     

Assessment of alcohol and other drug use behaviors in health professions students.

Alcohol and other drug (AOD) use behaviors of health professions students (HPS) were assessed by surveying both university-based HPS and other nursing programs in a Midwestern state in 1999. Response was 2,646 (56.4%) of surveyed students. Family history of alcohol-related and drug-related problems were reported by 39.8% and 13.9%, respectively, with 42.6% of respondents reporting one or both. Among nursing respondents, 48.1%, 19.2% and 51.1%, respectively, reported family problems with alcohol, drugs, or one or both. Past-year alcohol use was comparable to undergraduate college students (UCS) nationally (83%); heavy drinking, tobacco and recreational drug use by HPS were lower. Past year drug use was highest among medical students. Marijuana was the predominant illicit drug; medical students and males most often reported use. Health professions educational systems should proactively address student AOD prevention, education and assistance needs.     

Interstitial cystitis treated with intravesical doxorubicin

Three patients with interstitial cystitis diagnosed on the basis of clinical symptoms, classic endoscopic findings, and a typical histologic picture were treated with intravesical doxorubicin. All 3 patients showed remarkable improvement, as manifested by complete clearance of irritative bladder symptoms and healing of ulceration. Doxorubicin therefore may be the breakthrough drug for interstitial cystitis.     

Angiosarcoma of the pleura.

Angiosarcoma is a rare, highly malignant tumor arising from endothelial cells of small blood vessels. They usually occur in the skin, deep soft tissues, breast and liver. Pleural angiosarcomas are extremely rare and are restricted to case reports in medical literature. It is very difficult to distinguish them from malignant mesotheliomas on clinical, radiological and even histopathological features. Immunohistochemistry is valuable in making the diagnosis, showing negative reactivity for mesothelial markers and positivity for vascular markers. Prognosis is generally dismal except in occasional cases where the disease is localized and amenable for surgical resection. We report a 55-year-old man who presented to us with chest pain, cough and hemoptysis and was diagnosed to have a pleural angiosarcoma.