Combination therapy with interleukin-6 receptor superantagonist Sant7 and dexamethasone induces antitumor effects in a novel SCID-hu In vivo model of human multiple myeloma.

Interleukin-6 (IL-6) protects multiple myeloma cells against apoptosis induced by glucocorticoids. Here, we investigated whether inhibition of the IL-6 signaling pathway by the IL-6 receptor superantagonist Sant7 enhances the in vivo antitumor effects of dexamethasone on the IL-6-dependent multiple myeloma cell line INA-6. For this purpose, we used a novel murine model of human multiple myeloma in which IL-6-dependent INA-6 multiple myeloma cells were directly injected into human bone marrow implants in severe combined immunodeficient (SCID) mice (SCID-hu). The effect of in vivo drug treatments on multiple myeloma cell growth was monitored by serial determinations of serum levels of soluble IL-6 receptor (shuIL-6R), which is released by INA-6 cells and served as a marker of tumor growth. In SCID-hu mice engrafted with INA-6 cells, treatment with either Sant7 or dexamethasone alone did not induce significant reduction in serum shuIL-6R levels. In contrast, the combination of Sant7 with dexamethasone resulted in a synergistic reduction in serum shuIL-6R levels after 6 consecutive days of treatment. Gene expression profiling of INA-6 cells showed down-regulation of proliferation/maintenance and cell cycle control genes, as well as up-regulation of apoptotic genes in multiple myeloma cells triggered by Sant7 and dexamethasone combination. In vitro colony assays showed inhibition of myeloid and erythroid colonies from normal human CD34(+) progenitors in response to dexamethasone, whereas Sant7 neither inhibited colony growth nor potentiated the inhibitory effect of dexamethasone. Taken together, these results indicate that inhibition of IL-6 signaling by Sant7 significantly potentiates the therapeutic action of dexamethasone against multiple myeloma cells, providing the preclinical rationale for clinical trials of Sant7 in combination with dexamethasone to improve patient outcome in multiple myeloma.     

Recurrent Metastatic Chordoma to the Liver: A Case Report and Review of the Literature

Chordoma is a rare malignant neoplasm derived from notochordal tissue that primarily affects the axial skeleton. Almost 40% of patients have non-cranial chordoma metastases. The most common metastatic sites are the lungs, bones, lymph nodes, and subcutaneous tissue. We present a 52-year female with a history of sacral chordoma presenting with abdominal fullness, early satiety, and a palpable abdominal mass. Abdominal magnetic resonance imaging (MRI) revealed an isolated, highly vascularized, and multilobed liver mass in the left lateral segment. The mass was surgically removed using a clean surgical margin. A histological examination and immunohistochemical staining were consistent with a metastatic chordoma. Two years later, follow-up imaging studies showed a 6.5 × 4.0 × 2.0 cm right liver lesion with multiple lungs, chest wall, pleural, and diaphragmatic lesions. Microscopic- and immunohistochemical staining revealed a recurrent metastatic chordoma. Herein, we present a unique case of metastatic recurrent chordoma in the liver with the involvement of other sites. To the best of our knowledge, no other case of recurrent liver metastasis has been reported.     

Substituting Resistance Spot Welding with Flexible Laser Spot Welding to Join Ultra-Thin Foil of Inconel 718 to Thick 410 Steel

This paper investigated various aspects of replacing existing micro-resistance spot welding (micro-RSW) with micro-laser spot welding for joining Inconel 718 thin foils to thick 410 steel stack-up to allow faster, non-contact joining together with flexibility in spot positioning and removal of tip dressing required for RSW electrodes. The joint quality was evaluated based on the mechanical strength, microstructural characteristics and joint strength at elevated temperature as these joints are often used for high-temperature applications. Experimental investigations were performed using micro-RSW and micro-laser spot welding to obtain the 90° peel and lap shear specimens, each comprising four spots. The obtained strength from laser joints was significantly higher than that of micro-RSW joints due to larger weld nugget formation and interface width. The process map for obtaining good quality welds was also identified, and about a 17% reduction in joint strength was obtained when welded specimens were subjected to elevated temperature (i.e., 500 °C) in comparison with room temperature. This reduction was compensated for using the flexibility of laser welding to add two extra spots. The overall performance of the micro-laser spot welds was found to be better than the micro-RSW considering joint strength, flexibility in placing the spots and time to produce the welds.     

Single-Incision Laparoscopic Cholecystectomy Versus Conventional Laparoscopic Cholecystectomy: Meta-analysis and Systematic Review of Randomized Controlled Trials

Background

The objective of this study was to analyze systematically the randomized, controlled trials that compared single-incision laparoscopic cholecystectomy (SILC) and conventional laparoscopic cholecystectomy (CLC).

Methods

The meta-analysis was conducted according to the Quality of Reporting of Meta-analysis (QUORUM) standards. The included studies were analyzed systematically using the statistical software package RevMan. The summated outcomes were expressed as the risk ratios (RR) for dichotomous variables and standardized mean differences (SMD) for continuous variables.

Results

Eleven randomized trials encompassing 858 patients were retrieved from the electronic databases. In the random effects model, postoperative pain, postoperative complications, length of hospital stay, cosmesis score, conversion rate, and time to return to normal activities were statistically comparable between the two cholecystectomy techniques. SILC was associated with a longer operating time [SMD 0.71; 95?% confidence interval (CI) 0.38, 1.05; z?=?4.18; p?<?0.0001) and an increased requirement for additional port insertion (RR 6.54; 95?% CI 2.19, 19.57; z?=?3.36; p?<?0008). However, there was significant heterogeneity among the trials.

Conclusions

SILC does not offer any advantage over CLC for treating benign gallbladder disorders. CLC may be used assiduously for this purpose.     

Impact of Sarcopenia on Outcomes Following Intra-arterial Therapy of Hepatic Malignancies

Background

Assessment of patient performance status is often subjective. Sarcopenia—measurement of muscle wasting—may be a more objective means to assess performance status and therefore mortality risk following intra-arterial therapy (IAT).

Methods

Total psoas area (TPA) was measured on cross-sectional imaging in 216 patients undergoing IAT of hepatic malignancies between 2002 and 2012. Sarcopenia was defined as TPA in the lowest sex-specific quartile. Impact of sarcopenia was assessed relative to other clinicopathological factors.

Results

Indications for IAT included hepatocellular carcinoma (51 %), intrahepatic cholangiocarcinoma (13 %), colorectal liver metastasis (7 %), or other metastatic disease (30 %). Median TPA among men (568 mm²/m²) was greater than women (413 mm²/m²). IAT involved conventional chemoembolization (54 %), drug-eluting beads (40 %), or yttrium-90 (6 %). Median tumor size was 5.8 cm; most patients had multiple lesions (74 %). Ninety-day mortality was 9.3 %; 3-year survival was 39 %. Factors associated with risk of death were tumor size (HR?=?1.84) and Child's score (HR?=?2.15) (all P?<?0.05). On multivariate analysis, sarcopenia remained independently associated with increased risk of death (lowest vs. highest TPA quartile, HR?=?1.84; P?=?0.04). Sarcopenic patients had a 3-year survival of 28 vs. 44 % for non-sarcopenic patients.

Conclusions

Sarcopenia was an independent predictor of mortality following IAT with sarcopenic patients having a twofold increased risk of death. Sarcopenia is an objective measure of frailty that can help clinical decision-making regarding IAT for hepatic malignancies.     

Acute and Chronic Respiratory Symptoms among Primary Care Patients Who Smoke Crack Cocaine

Among inner-city populations in Canada, the use of crack cocaine by inhalation is prevalent. Crack smoking is associated with acute respiratory symptoms and complications, but less is known about chronic respiratory problems related to crack smoking. There is also a gap in the literature addressing the management of respiratory disease in primary health care among people who smoke crack. The purpose of our study was to assess the prevalence of acute and chronic respiratory symptoms among patients who smoke crack and access primary care. We conducted a pilot study among 20 patients who currently smoke crack (used within the past 30 days) and who access the “drop-in clinic” at an inner-city primary health care center. Participants completed a 20- to 30-min interviewer-administered survey and provided consent for a chart review. We collected information on respiratory-related symptoms, diagnoses, tests, medications, and specialist visits. Data were analyzed using frequency tabulations in SPSS (version 19.0). In the survey, 95 % (19/20) of the participants reported having at least one respiratory symptom in the past week. Thirteen (13/19, 68.4 %) reported these symptoms as bothersome. Chart review indicated that 12/20 (60 %) had a diagnosis of either asthma or chronic obstructive pulmonary disease (COPD), and four participants (4/20, 20 %) had a diagnosis of both asthma and COPD. Majority of the participants had been prescribed an inhaled medication (survey 16/20, 80 %; chart 12/20, 60 %). We found that 100 % (20/20) of the participants currently smoked tobacco, and 16/20 (80 %) had smoked both tobacco and marijuana prior to smoking crack. Our study suggests that respiratory symptoms and diagnoses of asthma and COPD are prevalent among a group of patients attending an inner-city clinic in Toronto and who also smoke crack. The high prevalence of smoking tobacco and marijuana among our participants is a major confounder for attributing respiratory symptoms to crack smoking alone. This novel pilot study can inform future research evaluating the primary health care management of respiratory disease among crack smokers, with the aim of improving health and health care delivery.     

Combination of proteasome inhibitors bortezomib and NPI-0052 trigger in vivo synergistic cytotoxicity in multiple myeloma

Our recent study demonstrated that a novel proteasome inhibitor NPI-0052 triggers apoptosis in multiple myeloma (MM) cells, and importantly, that is distinct from bortezomib (Velcade) in its chemical structure, effects on proteasome activities, and mechanisms of action. Here, we demonstrate that combining NPI-0052 and bortezomb induces synergistic anti-MM activity both in vitro using MM cell lines or patient CD138(+) MM cells and in vivo in a human plasmacytoma xenograft mouse model. NPI-0052 plus bortezomib-induced synergistic apoptosis is associated with: (1) activation of caspase-8, caspase-9, caspase-3, and PARP; (2) induction of endoplasmic reticulum (ER) stress response and JNK; (3) inhibition of migration of MM cells and angiogenesis; (4) suppression of chymotrypsin-like (CT-L), caspase-like (C-L), and trypsin-like (T-L) proteolytic activities; and (5) blockade of NF-kappaB signaling. Studies in a xenograft model show that low dose combination of NPI-0052 and bortezomib is well tolerated and triggers synergistic inhibition of tumor growth and CT-L, C-L, and T-L proteasome activities in tumor cells. Immununostaining of MM tumors from NPI-0052 plus bortezomib-treated mice showed growth inhibition, apoptosis, and a decrease in associated angiogenesis. Taken together, our study provides the preclinical rationale for clinical protocols evaluating bortezomib together with NPI-0052 to improve patient outcome in MM.