Starting the fight in the tumor: expert recommendations for the development of human intratumoral immunotherapy (HIT-IT).

A European Society for Medical Oncology (ESMO)-sponsored expert meeting was held in Paris on 8 March 2018 which comprised 11 experts from academia, 11 experts from the pharmaceutical industry and 2 clinicians who were representatives of ESMO. The focus of the meeting was exclusively on the intratumoral injection/delivery of immunostimulatory agents with the aim of harmonizing the standard terms and methodologies used in the reporting of human intratumoral immunotherapy (HIT-IT) clinical trials to ensure quality assurance and avoid a blurring of the data reported from different studies. The goal was to provide a reference document, endorsed by the panel members that could provide guidance to clinical investigators, pharmaceutical companies, ethics committees, independent review boards, patient advocates and the regulatory authorities and promote an increase in the number and quality of HIT-IT clinical trials in the future. Particular emphasis was placed not only on the development of precise definitions to facilitate a better understanding between investigators but also on the importance of systematic serial biopsies as a driver for translational research and the need for the recording and reporting of data, to facilitate a better understanding of the key processes involved.

Age-related endothelial dysfunction in human skeletal muscle feed arteries: the role of free radicals derived from mitochondria in the vasculature.

AIM: This study sought to determine the role of free radicals derived from mitochondria in the vasculature in the recognized age-related endothelial dysfunction of human skeletal muscle feed arteries (SMFAs). METHODS: A total of 44 SMFAs were studied with and without acute exposure to the mitochondria-targeted antioxidant MitoQ and nitric oxide synthase (NOS) blockade. The relative abundance of proteins from the electron transport chain, phosphorylated (p-) to endothelial (e) NOS ratio, manganese superoxide dismutase (MnSOD) and the mitochondria-derived superoxide (O2-) levels were assessed in SMFA. Endothelium-dependent and endothelium-independent SMFA vasodilation was assessed in response to flow-induced shear stress, acetylcholine (ACh) and sodium nitroprusside (SNP). RESULTS: MitoQ restored endothelium-dependent vasodilation in the old to that of the young when stimulated by both flow (young: 68 ± 5; old: 25 ± 7; old + MitoQ 65 ± 9%) and ACh (young: 97 ± 4; old: 59 ± 10; old + MitoQ: 98 ± 5%), but did not alter the initially uncompromised, endothelium-independent vasodilation (SNP). Compared to the young, MitoQ in the old diminished the initially elevated mitochondria-derived O2- levels and appeared to attenuate the breakdown of MnSOD. Furthermore, MitoQ increased the ratio of p-eNOS to NOS and the restoration of endothelium-dependent vasodilation in the old by MitoQ was ablated by NOS blockade. CONCLUSION: This study demonstrated that MitoQ reverses age-related vascular dysfunction by what appears to be an NO-dependent mechanism in human SMFAs. These findings suggest that mitochondria-targeted antioxidants may have utility in terms of counteracting the attenuated blood flow and vascular dysfunction associated with advancing age.

Surgical and endoscopic palliation for pancreatic cancer.

Patients with pancreatic cancer often present with locally advanced or metastatic disease and are deemed not to be candidates for a curative resection. Palliation in these patients focuses on relief of biliary obstruction, gastroduodenal obstruction and pain. Palliative treatment modalities include both surgical and nonsurgical approaches. Biliary obstruction is often initially treated with endoscopic biliary stenting. Two major types of biliary stents are used, plastic and metallic stents. Both of these provide similar initial relief of biliary obstruction, however, plastic stents have a greater propensity for occlusion and should primarily be used in patients with anticipated short survival duration. Metallic stents have a greater initial cost, but provide an overall cost-saving in patients with expected survival duration of over 6 months. Surgical palliation for biliary obstruction should be primarily considered in patients who fail endoscopic biliary decompression or who develop clinical evidence of gastroduodenal obstruction. In these patients, surgical palliation should consist of biliary decompression with a choledochojejunostomy when ever feasible, a gastroduodenal bypass and a chemical splanchnicectomy for pain relief. An initial prophylactic gastroenterostomy at the time of endoscopic biliary decompression is rarely indicated. The role of palliative pancreaticoduodenectomy remains controversial and to date there are no prospective randomized data to support its role in palliation of locally advanced pancreatic cancer. This review examines the available data from prospective trials for surgical and nonsurgical palliation of locally advanced and metastatic pancreatic cancer.

Human skeletal muscle feed arteries: evidence of regulatory potential.

AIM: Recently, it has been recognized that human skeletal muscle feed arteries can be harvested during exploratory surgery for melanoma. This approach provides vessels for in vitro study from a wide spectrum of relatively healthy humans. Although, the regulatory role of skeletal muscle feed arteries in rodent models has been documented, whether such vessels in humans possess this functionality is unknown. METHODS: Therefore, skeletal muscle feed arteries (~950 µm OD) from 10 humans (48 ± 4, 27-64 years) were studied using pressure myography. Vessel function was assessed using potassium chloride (KCl), phenylephrine (PE), acetylcholine (ACh) and sodium nitroprusside (SNP) concentration-response curves (CRCs) to characterize non-receptor and receptor-mediated vasoconstriction as well as endothelium-dependent and independent vasodilation respectively. To understand the physiological relevance of the diameter changes as a result of pharmacological stimulation, the estimated conductance ratio (CR) was calculated. RESULTS: Vessel function protocols revealed significant vasoconstriction in response to PE and KCl (35 ± 6; 43 ± 9%vasoconstriction, respectively) and significant vasodilation with ACh and SNP (85 ± 7; 121 ± 17% vasodilation, respectively). Both PE and KCl significantly reduced the CR (0.26 ± 0.05 and 0.23 ± 0.07, respectively), whereas ACh and SNP increased the CR (2.56 ± 0.10 and 5.32 ± 1.3, respectively). CONCLUSION: These novel findings provide evidence that human skeletal muscle feed arteries are capable of generating significant diameter changes that would translate into significant changes in vascular conductance. Thus, human skeletal muscle feed arteries likely play a significant role in regulating vascular conductance and subsequently blood flow in vivo.

The value of specialization--is there an outcome difference in the management of fistulas complicating diverticulitis.

PURPOSE: The value of specialization has frequently been challenged by many health care institutions and providers. This review was conducted to determine whether there were any outcome differences in the management of fistulas complicating diverticulitis. METHODS: We conducted an historical cohort study using hospital charts of all cases of fistulas complicating diverticulitis that were operated on in four university-affiliated hospitals between 1975 and 1995. There were 122 patients, with 37 under the care of fully trained colorectal surgeons and 85 under the care of general surgeons. RESULTS: There were no significant differences in patient demographics, preoperative comorbidities, or the number of preoperative diagnostic investigations between the two groups. The colorectal surgeons performed more intraoperative ureteral stenting (Colorectal Surgery 55.5 percent vs. General Surgery 24.4 percent, P = 0.001). The general surgeons performed more initial diverting Hartmann's and colostomy procedures (Colorectal Surgery 5.4 percent vs. General Surgery 27 percent, P = 0.013). The patients in the General Surgery group had longer preoperative lengths of stay (median Colorectal Surgery 3 (range, 1-28) days vs. General Surgery 8 (range, 0-29) days; P < 0.001), longer postoperative lengths of stay (median Colorectal Surgery 11 (range, 5-40) days vs. General Surgery 14 (range, 2-80) days; P = 0.001), and longer total lengths of stay (median Colorectal Surgery 14 (range, 6-62) days vs. General Surgery 24 (range, 6-100) days; P < 0.001). The patients in the General Surgery group experienced a higher rate of wound infections (Colorectal Surgery 5.4 percent vs. General Surgery 12.9 percent), and a larger proportion of them experienced complications (Colorectal Surgery 27 percent vs. General Surgery 41.2 percent). CONCLUSIONS: We conclude that specialization in colon and rectal surgery contributed to an improved outcome, with a lower rate of diverting procedures, a shorter hospital stay, and a lower rate of complications.