Rare among the rarities--recurrent insulinoma

A patient with recurrent insulinoma without co-existing multiple endocrine neoplasia syndrome is described. In a 32-year-old man with recurrent episodes of symptomatic hypoglycemia, the supervised fast showed high insulin (24.5 IU/ml) and C-peptide level (3.06 ng/ml) with low blood sugar (27 mg/dl). A 1 x 1.5 cm nodule from the lower part of pancreatic body was removed on exploratory laparotomy. Histopathology confirmed the diagnosis of islet cell tumor. After 11 years, he started experiencing symptomatic hypoglycemic episodes with inappropriately elevated serum insulin and C-peptide levels (2.2 ng/ml). On pancreatic angiography, a 16 x 11 mm size tumor blush was noted. Due to fibrosis from previous surgery, distal pancreatectomy along with splenectomy was done. Histopathology confirmed the diagnosis of insulinoma. On both occasions, workup for multiple endocrine neoplasia turned out to be negative. He was given small amounts of intermediate acting insulin in early postoperative period, which was discontinued shortly thereafter.     

Labor management in a patient with von Willebrand disease

von Willebrand disease (VWD) is an inherited bleeding disorder involving a deficiency or abnormal function of a blood clotting protein called von Willebrand factor (VWF). Deficiency of VWF, therefore, shows primarily in organs with small blood vessels such as the skin, the gastrointestinal tract and the uterus. This case report describes management of a patient presenting with type II von Willebrand disease in labor. She had history of life-threatening hemorrhage from an operation for deviated nasal septum and had a risk of severe postpartum hemorrhage (PPH) within 48 hors of delivery, which was avoided by appropriate planning and timely management.     

Prolonged trastuzumab therapy in a patient with recurrent breast cancer and anthracycline-induced cardiac failure

Current practice precludes patients with pre-existing cardiac dysfunction from trastuzumab therapy. A 57-year-old patient with HER2 positive metastatic breast cancer and anthracycline-induced cardiac failure was safely treated with trastuzumab. At 46 months, left ventricular ejection fraction (LVEF) did fall to 38.3%, but 8 months later has recovered to 47%. She remains disease free and asymptomatic from cardiac dysfunction more than 6 years following breast cancer recurrence. We review the evidence for the use of trastuzumab in patients with controlled cardiac dysfunction, and suggest this group of patients should be considered for treatment with trastuzumab if no other or only less efficacious therapeutic options are available.     

Implants of type I collagen gel containing MG-63 osteoblast-like cells can act as stable scaffolds stimulating the bone healing process at the sites of the surgically-produced segmental diaphyseal defects in male rabbits

BACKGROUND: Three-dimensional (3-D) type I collagen gel culture systems allow long-term growth of osteoblast-like cells, in vitro. Whether the implantation of 3-D collagen systems can stimulate new bone formation was assessed in male rabbits. MATERIALS AND METHODS: A 10-mm segmental diaphyseal defect was surgically produced at the left and right limbs of 50 adult male rabbits. The 3-D systems containing MG-63 osteoblast-like cells were implanted at the right-limb defects of all 50 animals. Twenty-five left-limb defects were implanted with 3-D collagen gels containing no MG-63 cells, while the rest were left empty. The bone repair process was serially assessed by radiography for up to 8 weeks and by histological analysis for up to the week 32 post-surgery. RESULTS: Ninety-four per cent (94%) of the right-limb defects, presented radiographic evidence of complete bone-end bridging within 8 weeks. None of the 50 left-limb defects presented radiographic post-implantation evidence of bone-end bridging. The radiographic evidence of the bone-end bridging was corroborated with histological evidence of new bone formation, while the medullar canals were filled with bone marrow elements. CONCLUSION: Implants of the 3-D collagen gels containing osteoblast-like cells can be used as stable scaffolds allowing the migration/proliferation of the bone regenerating cells in male rabbits.     

Design and synthesis of N4,N9-disubstituted spermines for non-viral siRNA delivery--structure-activity relationship studies of siFection efficiency versus toxicity

PURPOSE: To study the effect of sequentially changing the chain length, oxidation level, and charge distribution in N4,N9-diacyl and N4,N9-dialkyl spermines on siRNA formulation, and then to compare their lipoplex transfection efficiency in cell lines. METHODS: Eight N4,N9-diacyl polyamines: N4,N9-[didecanoyl, dilauroyl, dimyristoyl, dimyristoleoyl, dipalmitoyl, distearoyl, dioleoyl and diretinoyl]-1,12-diamino-4,9-diazadodecane were synthesized. Their abilities to bind to siRNA and form nanoparticles were studied using a RiboGreen intercalation assay and particle sizing. Two diamides were also reduced to afford tetraamines N4,N9-distearyl- and N4,N9-dioleyl-1,12-diamino-4,9-diazadodecane. Delivery of fluorescein-labelled Label IT RNAi Delivery Control was studied in FEK4 primary skin cells and in an immortalized cancer cell line (HtTA), and compared with TransIT-TKO. RESULTS: The design, synthesis, and structure-activity relationship studies of a series of N4,N9-disubstituted spermines as efficient vectors for non-viral siRNA delivery to primary skin and cancer cell lines is reported. These non-liposomal cationic lipids are promising siRNA carriers based on the naturally occurring polyamine spermine showing that C-18 is a better chain length as shorter chains are more toxic. CONCLUSIONS: N4,N9-Distearoyl spermine and N4,N9-dioleoyl spermine are efficient siRNA formulation and delivery vectors, even in the presence of serum, comparable to TransIT-TKO. However, four positive charges distributed as in spermine was significantly more toxic.     

Prostate cancer stem/progenitor cells: identification, characterization, and implications

Several solid tumors have now been shown to contain stem cell-like cells called cancer stem cells (CSC). These cells, although generally rare, appear to be highly tumorigenic and may be the cells that drive tumor formation, maintain tumor homeostasis, and mediate tumor metastasis. In this Perspective, we first provide our insight on how a CSC should be defined. We then summarize our current knowledge of stem/progenitor cells in the normal human prostate (NHP), an organ highly susceptible to hyperproliferative diseases such as benign prostate hyperplasia (BPH) and prostate cancer (PCa). We further review the evidence that cultured PCa cells, xenograft prostate tumors, and patient tumors may contain stem/progenitor cells. Along with our discussion, we present several methodologies that can be potentially used to identify putative tumor-reinitiating CSC. Finally, we present a hypothetical model for the hierarchical organization of human PCa cells and discuss the implications of this model in helping understand prostate carcinogenesis and design novel diagnostic, prognostic, and therapeutic approaches.     

Tezepelumab Pharmacokinetics,Safety, and Tolerability After Administration via Vial-and-syringe,Accessorized Prefilled Syringe,or Autoinjector: A Randomized Trial in Healthy Volunteers

PurposeTezepelumab is an anti–thymic stromal lymphopoietin monoclonal antibody therapeutic in development for patients with severe, uncontrolled asthma. In ongoing Phase III studies, tezepelumab is administered via subcutaneous (SC) injections using a vial-and-syringe (V–S). This study compared the pharmacokinetic (PK) parameters, safety, and tolerability of tezepelumab administered subcutaneously via V–S versus via an accessorized prefilled syringe (APFS) or autoinjector (AI).MethodsThis single-center, randomized, open-label, parallel-group study was conducted in healthy volunteers aged 18–65 years. Participants, stratified according to weight (50 to <70 kg, 70 to <80 kg, or 80–90 kg), were randomized evenly to 9 groups representing injections to the abdomen, thigh, or upper arm via V–S, APFS, or AI. Tezepelumab PK parameters over 113 days were evaluated after a single 210-mg SC dose. The primary end points were comparison of C_max and AUC_0–∞ between device groups. Further PK parameters, immunogenicity, safety (including injection site reactions [ISRs] and injection site pain [visual analog scale]) were also assessed.FindingsA total of 315 adults were randomized to treatment. Geometric mean ratios for comparisons between device groups of C_max, AUC_0–∞, and AUC_0–last were close to 1, with 90% CIs all within the range of 0.8–1.25, meeting bioequivalence criteria. PK variables were also similar between devices across injection sites and weight categories. Across devices, thigh injection resulted in slightly higher exposure than upper arm injection, and abdomen injection resulted in exposure similar to or slightly lower than thigh injection; however, these differences were not clinically meaningful. Treatment-emergent anti-tezepelumab antibodies were present in 3 (2.9%), 1 (1.0%), and 0 participants in the V–S, APFS, and AI groups, respectively. Treatment-related adverse events were reported in 15.0% of participants overall (V–S, 10.7%; APFS, 18.1%; AI, 16.0%), including ISRs in 1 (1.0%), 3 (2.9%), and 3 (2.8%) participants in the V–S, APFS, and AI groups. Median visual analog scale pain score (0–100 mm scale) was 2 mm immediately after injection and was 0 mm at 30 min for all groups.ImplicationsTezepelumab PK parameters after a single 210-mg SC dose were comparable when administered via V–S, APFS, or AI. In all groups, immunogenicity rate and injection site pain were low, and ISRs were uncommon. These findings support administration of tezepelumab via APFS or AI, in addition to V–S, providing patients and physicians with greater choice and the potential convenience of at-home use. ClinicalTrials.gov identifier: NCT03989544.     

Implementation of an infant male circumcision programme,Pakistan

ObjectiveTo retrospectively review outcomes of a health provider-led infant circumcision programme in Pakistan.MethodsBased on World Health Organization guidelines, we trained surgical technicians and midwives to perform circumcisions using the Plastibell device at two Indus Health Network facilities. Programme tools include a training manual for health providers, information brochures for families, an enrolment form and standardized forms for documenting details of the procedure and outcomes. Infants aged 1–92 days were eligible for the study. Health workers contacted families on days 1 and 7 after the procedure to record any adverse events. We compared the characteristics of infants experiencing adverse events with infants facing no complications using multivariate logistic regression.FindingsBetween August 2016 and August 2018, 2822 circumcised male infants with mean age 22.8 days were eligible for the study. Of these, 2617 infants (92.7%) were followed up by telephone interviews of caretakers. Older infants were more likely to experience adverse events than infants circumcised between 1–30 days of age: 31–60 days: adjusted odds ratio, aOR: 2.03; 95% confidence interval, CI: 1.31–3.15; 61–92 days: aOR: 2.14; 95% CI: 1.13–4.05. Minor adverse events (100 infants; 3.8%) included failure of the bell to shed (90 infants) and minimal bleeding (10 infants). Major adverse events (eight infants; 0.3%) included bleeding that required intervention (four infants), infection (three infants) and skin tear (one infant).ConclusionStandardized training protocols and close monitoring enabled nonphysician health providers to perform safe circumcisions on infants aged three months or younger.     

Localization of Burkholderia cepacia Complex Bacteria in Cystic Fibrosis Lungs and Interactions with Pseudomonas aeruginosa in Hypoxic Mucus

The localization of Burkholderia cepacia complex (Bcc) bacteria in cystic fibrosis (CF) lungs, alone or during coinfection with Pseudomonas aeruginosa, is poorly understood. We performed immunohistochemistry for Bcc and P. aeruginosa bacteria on 21 coinfected or singly infected CF lungs obtained at transplantation or autopsy. Parallel in vitro experiments examined the growth of two Bcc species, Burkholderia cenocepacia and Burkholderia multivorans, in environments similar to those occupied by P. aeruginosa in the CF lung. Bcc bacteria were predominantly identified in the CF lung as single cells or small clusters within phagocytes and mucus but not as “biofilm-like structures.” In contrast, P. aeruginosa was identified in biofilm-like masses, but densities appeared to be reduced during coinfection with Bcc bacteria. Based on chemical analyses of CF and non-CF respiratory secretions, a test medium was defined to study Bcc growth and interactions with P. aeruginosa in an environment mimicking the CF lung. When test medium was supplemented with alternative electron acceptors under anaerobic conditions, B. cenocepacia and B. multivorans used fermentation rather than anaerobic respiration to gain energy, consistent with the identification of fermentation products by high-performance liquid chromatography (HPLC). Both Bcc species also expressed mucinases that produced carbon sources from mucins for growth. In the presence of P. aeruginosain vitro, both Bcc species grew anaerobically but not aerobically. We propose that Bcc bacteria (i) invade a P. aeruginosa-infected CF lung when the airway lumen is anaerobic, (ii) inhibit P. aeruginosa biofilm-like growth, and (iii) expand the host bacterial niche from mucus to also include macrophages.