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.     

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.     

Physiological analysis to quantify training load in badminton.

OBJECTIVE: To estimate the training load of specific on court training regimens based on the magnitude of variation of heart rate-lactate response during specific training and to determine the magnitude of variation of biochemical parameters (urea, uric acid, and creatine phosphokinase (CPK)) 12 hours after the specific training programme so as to assess training stress. METHODS: The study was conducted on six national male badminton players. Maximum oxygen consumption (VO2), ventilation (VE), heart rate, and respiratory quotient were measured by a protocol of graded treadmill exercise. Twelve training sessions and 35 singles matches were analysed. Heart rate and blood lactate were monitored during technical training routines and match play. Fasting blood samples collected on two occasions--that is, during off season and 12 hours after specific training--were analysed for serum urea, uric acid, and CPK. RESULTS: Analysis of the on court training regimens showed lactate values of 8-10.5 mmol/l in different phases. The percentage of maximum heart rate ranged from 82% to 100%. Urea, uric acid, and CPK activity showed significant changes from (mean (SD)) 4.93 (0.75) mmol/l to 5.49 (0.84) mmol/l, 0.23 (0.04) to 0.33 (0.06) mmol/l, and 312 (211.8) to 363 (216.4) IU/l respectively. CONCLUSION: Maximum lactate reported in the literature ranges from 3-6 mmol/l. Comparatively high lactate values and high percentage of maximum heart rate found in on court training show a considerable stress on muscular and cardiovascular system. The training load needs appropriate monitoring to avoid over-training. Workouts that are too intensive may interfere with coordination, a factor that is important in sports requiring highly technical skill such as badminton.     

Intraabdominal pressures during natural activities in patients treated with continuous ambulatory peritoneal dialysis

Intraabdominal pressures were measured during natural activities in 6 men, age 24-62 years, treated with continuous ambulatory peritoneal dialysis. The pressures were measured with a pressure transducer secured at the level of the umbilicus in the supine, sitting, and upright positions with 0-3 liters intraperitoneal fluid during talking, coughing, straining, changing position, walking, jogging, exercycling, jumping and weight lifting. Coughing and straining generated the highest intraabdominal pressures in every position. The pressures with weight lifting were proportional to the magnitude of the weight lifted up to 50 lbs, but were lower than those during coughing and straining. The pressures were generally higher with greater intraabdominal fluid volumes, especially with jumping and coughing. Exercycling was associated with lower intraabdominal pressure than was jogging, and the pressures were only minimally influenced by intraperitoneal fluid volumes. The results of this study can be used as a guide in establishing preventive measures in patients with intraperitoneal fluid to decrease complication rates related to raised intraabdominal pressures such as dialysate leaks, hernias and hemorrhoids.