Delivery of ASCs in poloxamer addresses multiple facets of the complexity of nerve/muscle unit regeneration, representing a promising avenue for further study. Muscle Nerve 58: 251-260, 2018.

Diabetes is a systemic disease in which the body cannot regulate the amount of sugar, namely glucose, in the blood. High glucose toxicity has been implicated in the dysfunction of diabetic wound healing, following insufficient production (Type 1) or inadequate usage (Type 2) of insulin. Chronic non-healing diabetic wounds are one of the major complications of both types of diabetes, which are serious concerns for public health and can impact the life quality of patients significantly. In general, diabetic wounds are characterized by deficient chemokine production, an unusual inflammatory response, lack of angiogenesis and epithelialization, and dysfunction of fibroblasts. Increasing scientific evidence from available experimental studies on animal and cell models strongly associates impaired wound healing in diabetes with dysregulated fibroblast differentiation to myofibroblasts, interrupted myofibroblast activity, and inadequate extracellular matrix production. Myofibroblasts play an important role in tissue repair by producing and organizing extracellular matrix and subsequently promoting wound contraction. Based on these studies, hyperglycaemic conditions can interfere with cytokine signalling pathways (such as growth factor-β pathway) affecting fibroblast differentiation, alter fibroblast apoptosis, dysregulate dermal lipolysis, and enhance hypoxia damage, thus leading to damaged microenvironment for myofibroblast formation, inappropriate extracellular matrix modulation, and weakened wound contraction. In this review, we will focus on the current available studies on the impact of diabetes on fibroblast differentiation and myofibroblast function, as well as potential treatments related to the affected pathways.

This study aimed to evaluate whether the BETA‐2 score is a reliable early predictor of graft decline and loss of insulin independence after islet allotransplantation. Islet transplant procedures were stratified into 3 groups according to clinical outcome: long‐term insulin independence without islet graft decline (group 1, N = 9), initial insulin independence with subsequent islet graft decline and loss of insulin independence (group 2, N = 13), and no insulin independence (group 3, N = 13). BETA‐2 was calculated on day 75 and multiple times afterwards for up to 145 months posttransplantation. A BETA‐2 score cut‐off of 17.4 on day 75 posttransplantation was discerned between group 1 and groups 2 and 3 (area under the receiver operating characteristic 0.769, P = .005) with a sensitivity and negative predictive value of 100%. Additionally, BETA‐2 ≥ 17.4 at any timepoint during follow‐up reflected islet function required for long‐term insulin independence. While BETA‐2 did not decline below 17.4 for each of the 9 cases from group 1, the score decreased below 17.4 for all transplants from group 2 with subsequent loss of insulin independence. The reduction of BETA‐2 below 17.4 predicted 9 (1.5‐21) months in advance subsequent islet graft decline and loss of insulin independence (P = .03). This finding has important implications for posttransplant monitoring and patient care.

Background: This study investigates the psychometric properties of patient-reported outcome instruments for assessing outcomes in postsurgical traumatic digit amputation patients. The authors hypothesize that the Michigan Hand Outcomes Questionnaire (MHQ) and Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire are the most valid and reliable instruments. Methods: The authors studied traumatic digit amputation patients as part of the Finger Replantation and Amputation Challenges in Assessing Impairment, Satisfaction, and Effectiveness (FRANCHISE) study initiated by The Plastic Surgery Foundation. The MHQ, DASH questionnaire, Patient-Reported Outcomes Measurement Information System (PROMIS), and 36-Item Short-Form Health Survey were used to assess patients at least 1 year postoperatively. Internal consistency was measured by Cronbach’s alpha and criterion validity with Pearson correlation coefficient (r). Construct validity was tested with four predefined hypotheses. Discriminant validity was analyzed by receiver operating characteristic curves. Results: One hundred sixty-eight replantation and 74 revision amputation patients met the inclusion criteria. All instruments demonstrated fair to good internal consistency in both cohorts (0.7 < α < 0.9). The MHQ and DASH questionnaire scores correlated strongly (r > 0.60) in both cohorts. The 36-Item Short-Form Health Survey had moderate to weak correlation with the remaining instruments, and its mental component had poor discriminant validity (area under the curve, 0.64 to 0.67). The MHQ, DASH questionnaire, and PROMIS demonstrated good construct validity confirming 75 to 100 percent of predefined hypotheses, whereas the 36-Item Short-Form Health Survey confirmed only 25 percent. Conclusions: The authors recommend using the Michigan Hand Outcomes Questionnaire or the Disabilities of the Arm, Shoulder and Hand questionnaire when assessing patient-reported outcomes in digit amputation patients based on good internal consistency and validity. The Patient-Reported Outcomes Measurement Information System has fair validity and reliability but should be an adjunct instrument. The 36-Item Short-Form Health Survey should not be used as a primary assessment tool, but as an adjunct to assess overall quality of life.

Background Tumor initiation and subsequent progression are usually long-term processes, spread over time and conditioned by diverse aspects. Many cancers develop on the basis of chronic inflammation; however, despite dozens of years of research, little is known about the factors triggering neoplastic transformation under these conditions. Molecular characterization of both pathogenetic states, i.e., similarities and differences between chronic inflammation and cancer, is also poorly defined. The secretory activity of tumor cells may change the immunophenotype of immune cells and modify the extracellular microenvironment, which allows the bypass of host defense mechanisms and seems to have diagnostic and prognostic value. The phenomenon of immunosuppression is also present during chronic inflammation, and the development of cancer, due to its duration, predisposes patients to the promotion of chronic inflammation. The aim of our work was to discuss the above issues based on the latest scientific insights. A theoretical mechanism of cancer immunosuppression is also proposed. Conclusions Development of solid tumors may occur both during acute and chronic phases of inflammation. Differences in the regulation of immune responses between precancerous states and the cancers resulting from them emphasize the importance of immunosuppressive factors in oncogenesis. Cancer cells may, through their secretory activity and extracellular transport mechanisms, enhance deterioration of the immune system which, in turn, may have prognostic implications.

A total of 94 patients with colorectal cancer (CRC) were included in this study. Lymphocytic infiltration of CD45+ cells in the normal colon was more pronounced than that in the paired tumor stroma (p = 0.0008). The mean immunoscore of CD45+TILs was decreased in CRC compared with the controls (p = 0.0010). The percentage of CD3+ cells was higher in stage II than in stage IV (p = 0.0218) and showed a negative correlation with the TNM classification (r = -0.2867, p = 0.0109). The number of stromal CD4+TILs was higher in stage I than in stage III (p = 0.0116) and IV (p = 0.0104), and there was a negative correlation between this number and the stage (r = -0.3708, p = 0.0008). There was a positive correlation between the Ki-67 and CD45+ (r = 0.2468, p = 0.0294), CD3+ (r = 0.3822, p = 0.0006), and CD4+ cells (r = 0.5465, p < 0.0001). The levels of cancer-associated fibroblast (CAF) markers such as α-SMA, thrombin and fibronectin were significantly higher in CRC than in normal colonic mucosa. The immunohistochemical expression of α-SMA was negatively correlated with TILs, while fibronectin showed positive coexpression. A higher number of cells expressing IL-2Rα, PD-L1, CD33 and CD14 were found in colorectal adenocarcinomas than in controls. The number of CD14+ cells was also dependent on the TNM stage (p = 0.0444) and tumor budding (p = 0.0324). These findings suggest a suppressive impact of CRC on the adaptive immune response and emphasize the importance of CAFs in regulating tumor immunity.

Total pancreatectomy with islet autotransplantation (TPIAT) is an effective treatment option for non-diabetic patients with intractable chronic pancreatitis. The outcome and potential benefits for pre-diabetic and diabetic patients are less well established. Thirty-four patients underwent TPIAT were retrospectively divided into 3 groups according to pre-operative glycemic control: diabetes mellitus (DM) (n=5, 15%), pre-DM (n=11, 32%) and non-DM (n=18, 54%). Pre-operative fasting c-peptide was detectable and similar in all 3 groups. Islet yield in the DM group was comparable to pre-DM and non-DM groups (median islet equivalents [IEQ] was 191,800, 111,800, and 232,000IEQ, respectively). Patients received islet mass of over the target level of 2000IEQ/kg in pre-DM and DM at lower but clinically meaningful rates compared to the non-DM group: 45% (5/11) and 60% (3/5) for a combined 50% (8/16) rate, respectively, compared to 83% (15/18) for the non-DM group. At 1 year, fasting c-peptide and HbA1c did not differ between DM and pre-DM groups but c-peptide was significantly higher in non-DM. Islet transplantation failed (negative c-peptide) only in 1 patient. Pre-operatively, all patients experienced pancreatic pain with daily opioid dependence in 60% to 70%. Pancreatic-type pain gradually subsided completely in all groups with no differences in other painful somatic symptoms. Diabetic patients with measurable pre-operative c-peptide can achieve similar benefit from TPIAT, with comparable outcomes to pre-diabetic and non-diabetic patients including pain relief and the metabolic benefit of transplanted islets. Not surprisingly, endocrine outcomes for diabetic and pre-diabetics patients are substantially worse than in those with normal pre-operative glucose control.

Severe peripheral nerve injuries have devastating consequences on the quality of life in affected patients, and they represent a significant unmet medical need. Destruction of nerve fibers results in denervation of targeted muscles, which, subsequently, undergo progressive atrophy and loss of function. Timely restoration of neural innervation to muscle fibers is crucial to the preservation of muscle homeostasis and function. The goal of this study was to evaluate the impact of addition of adipose stem cells (ASCs) to polycaprolactone (PCL) nerve conduit guides on peripheral nerve repair and functional muscle recovery in the setting of a critical size nerve defect. To this end, peripheral nerve injury was created by surgically ablating 6 mm of the common peroneal nerve in a rat model. A PCL nerve guide, filled with ASCs and/or poloxamer hydrogel, was sutured to the nerve ends. Negative and positive controls included nerve ablation only (no repair), and reversed polarity autograft nerve implant, respectively. Tibialis anterior (TA) muscle function was assessed at 4, 8, and 12 weeks postinjury, and nerve and muscle tissue was retrieved at the 12-week terminal time point. Inclusion of ASCs in the PCL nerve guide elicited statistically significant time-dependent increases in functional recovery (contraction) after denervation; *25% higher than observed in acellular (poloxamer-filled) implants and indistinguishable from autograft implants, respectively, at 12 weeks postinjury (p < 0.05, n = 7-8 in each group). Analysis of single muscle fiber cross-sectional area (CSA) revealed that ASC-based treatment of nerve injury provided a better recapitulation of the overall distribution of muscle fiber CSAs observed in the contralateral TA muscle of uninjured limbs. In addition, the presence of ASCs was associated with improved features of re-innervation distal to the defect, with respect to neurofilament and S100 (Schwann cell marker) expression. In conclusion, these initial studies indicate significant benefits of inclusion of ASCs to the rate and magnitude of both peripheral nerve regeneration and functional recovery of muscle contraction, to levels equivalent to autograft implantation. These findings have important implications to improved nerve repair, and they provide input for future work directed to restoration of nerve and muscle function after polytraumatic injury.