Therapeutic Effects of Anti-PD1 Immunotherapy on Hepatocellular Carcinoma Under Administration of Tacrolimus.

BACKGROUND: Liver transplantation (LT) is the treatment of choice for patients with hepatocellular carcinoma (HCC). Recurrence of HCC after LT occurs in 10% to 20% of cases. Preclinical studies to evaluate immune checkpoint inhibitors in conjunction with immunosuppressant treatment in transplant recipients have been lacking. Here, we evaluated the efficacy, safety, and mechanism of programmed cell death-1 (PD1) blockade under tacrolimus treatment in transplant recipients. METHODS: We used a murine allogeneic skin transplantation model and murine syngeneic subcutaneous and orthotopic HCC models and measured the tumor volume and the change in tumor-infiltrating lymphocytes under PD1 blockade and tacrolimus treatment. RESULTS: Tacrolimus treatment prolonged allograft survival in the allogeneic transplantation model and enhanced tumor growth in both subcutaneous and orthotopic HCC models. PD1 blockade suppressed tumor growth and lung metastasis in correlation with the number of infiltrating CD8 + T cells. Under tacrolimus treatment, PD1 blockade still resulted in an antitumor effect accompanied by a significant increase in tumor-infiltrating CD8 + T cells, natural killer cells, dendritic cells, and natural killer T cells. Tacrolimus treatment rescued the acceleration of transplant rejection induced by PD1 blockade in the allogeneic transplantation model. CONCLUSIONS: Our data suggest that treatment with high-dose tacrolimus in conjunction with PD1 blockade has an antitumor effect and reduces transplant rejection in mouse models of allograft skin transplantation and HCC. Thus, these results suggest that a clinical trial of PD1 inhibitors for HCC in LT merits consideration.

ENERGI-F703 gel, as a new topical treatment for diabetic foot and leg ulcers: A multicenter, randomized, double-blind, phase II trial.

Background: Diabetic foot and leg ulcers are a major cause of disability among patients with diabetes mellitus. A topical gel called ENERGI-F703, applied twice daily and with adenine as its active pharmaceutical ingredient, accelerated wound healing in diabetic mice. The current study evaluated the safety and efficacy of ENERGI-F703 for patients with diabetic foot and leg ulcers. Methods: This randomized, double-blind, multicenter, phase II trial recruited patients from eight medical centers in Taiwan. Patients with intractable diabetic foot and leg ulcers (Wagner Grade 1-3 without active osteomyelitis) were randomly assigned (2:1) to receive topical ENERGI-F703 gel or vehicle gel twice daily for 12 weeks or until complete ulcer closure. The investigator, enrolled patients and site personnel were masked to treatment allocation. Intention to treat (ITT) population and safety population were patient to primary analyses and safety analyses, respectively. Primary outcome was complete ulcer closure rate at the end of treatment. This trial is registered with ClinicalTrials.gov, number NCT02672436. Findings: Starting from March 15th, 2017 to December 26th, 2019, 141 patients were enrolled as safety population and randomized into ENERGI-F703 gel (n = 95) group or vehicle gel (n = 46) group. In ITT population, ENERGI-F703 (n = 90) and vehicle group showed ulcer closure rates of 36.7% (95% CI = 26.75% - 47.49%) and 26.2% (95% CI = 13.86% - 42.04%) with difference of 9.74 % (95 % CI = -6.74% - 26.23%) and 25% quartiles of the time to complete ulcer closure of 69 days and 84 days, respectively. There were 25 (26.3%) patients in ENERGI-F703 group and 11 (23.9%) patients in vehicle group experiencing serious adverse events and five deaths occurred during the study period, none of them related to the treatment. Interpretation: Our study suggests that ENERGI-F703 gel is a safe and well-tolerated treatment for chronic diabetic foot and leg ulcers. Further studies are needed to corroborate our findings in light of limitations. Funding: Energenesis Biomedical Co., Ltd.

Digit Replantation under Wide-Awake Local Anesthesia.

BACKGROUND: Digit replantation under wide-awake local anesthesia is a challenging method, and there are only a few works of literature on this procedure. This article describes the authors' clinical experience in finger replantation under wide-awake local anesthesia compared to general anesthesia. METHODS: Fifty-one patients who received single finger replantation after initial sharp amputation were included in the study, of whom 16 received wide-awake local anesthesia and 35 general anesthesia treatment. The indications for wide-awake local anesthesia were sharp amputation injury, estimated operation time less than 3 hours, and cooperative patients. The wide-awake local anesthesia was performed with 1% or 2% lidocaine infiltrated at the volar midpoint of the metacarpophalangeal joint of the affected digit without sedation medications. Demographic data included surgical outcome, waiting time, operation time, and hospital stay. RESULTS: A total of 51 consecutive patients were included in this study. There were significantly shorter waiting times and operation times in the wide-awake local anesthesia group. The other parameters showed no significant differences. The overall success rate was 76.47 percent, with a mean overall operation time of 207 minutes. CONCLUSIONS: In selected patients, finger replantation can be successfully performed under wide-awake local anesthesia, which has lower anesthesia risk and fewer medical expenses than general anesthesia. The method is feasible for single-digit replantation. Therefore, the finger replantation under wide-awake local anesthesia is a practicable alternative to general anesthesia. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

Prognostic significance of positive surgical margins for scalp angiosarcoma.

BACKGROUND: Scalp angiosarcomas (AS) are aggressive soft tissue sarcomas that present with outcomes different from other AS of the head and neck region. Due to the rarity of the disease, limited data on the clinical outcome of scalp AS are available. In particular, the prognostic significance of surgical margins remains controversial and the impact of margin status on survival has not been documented. METHODS: We retrospectively reviewed 41 scalp AS patients, including 30 patients with localized disease and 11 patients with initial distant metastasis, treated in our institution between 1997 and 2017. Survival was determined by Kaplan-Meier analysis. In the 30 patients without distant metastasis (localized disease), univariate and multivariate analysis using the Cox proportional hazards model were used to determine clinicopathologic characteristics associated with recurrence free survival (RFS), locoregional control (LRC), and overall survival (OS). RESULTS: Totally 41 patients diagnosed with scalp AS were identified, including 30 patients with localized disease and 11 patients with initial distant metastasis on diagnosis. Overall, the median follow-up period was 19.3 (range 0.3-128.5) months. The median survival time was 16.6 (range 0.3-144.3) months and the 5-year OS (95% Confidence Interval (CI)) rate was 22% (12%-42%). In the 30 patients with localized disease, univariate analysis showed that positive margins, either lateral-side or deep-side, were significant prognostic factors for RFS, LRC, and OS (p < 0.05). On multivariate analysis, positive margins emerged as adverse prognostic factors for RFS (Hazard Ratio (HR) 4.29, 95% CI, 1.71-10.75, p = 0.002), LRC (HR 6.35, 95% CI, 2.19-18.37, p = 0.001), and OS (HR 4.73, 95% CI, 1.71-13.07, p = 0.003). CONCLUSION: Scalp AS is associated with high local recurrence rates and poor survival outcomes. Positive surgical margins are adverse prognostic factors for survival.

Tracheal reconstruction with nail grafts: A novel approach.

BACKGROUND: The replacement of tracheal defects has been a challenge for investigators worldwide. We aimed to develop autologous nail grafts for the reconstruction of anterior tracheal defects. METHODS: Toenail grafts were implanted to improve the structural integrity of the trachea in patients with tracheal diseases. We clinically applied these grafts for the partial replacement of the cervical tracheal cartilage. Data on graft construction details, clinical outcomes, bronchoscopy, and 3-dimensional computed tomography examinations were collected. RESULTS: The nail grafts were implanted in 4 patients. The trachea was successfully reconstructed in all cases. Bronchoscopy was performed 3 times to document healing: immediately, 1 month, and 3 months after surgery. All grafts were well vascularized and incorporated into the tracheal wall and were covered with the respiratory mucosa. Three of the patients survived during the study period, but 1 patient died of progressive lung cancer. CONCLUSIONS: Toenail grafts potentially may be used as an alternative strategy for the closure of small defects during tracheal reconstruction.

The Wound Microbiology and the Outcomes of the Systemic Antibiotic Prophylaxis in a Mass Burn Casualty Incident.

This paper describes the wound microbiology and outcome of using systemic antibiotic prophylaxis (SAP) in mass burn casualties (MBC). The charts of 31 patients (mean age: 21 years, mean burn area: 42% of the total body surface area) injured in a dust explosion were reviewed for 1 month after the burn. Polymicrobial and rare pathogen wound infections (Acinetobacter junii, Aeromonas sobri, et al) were common in MBC due to sterility breech. Following the use of SAP for 2 to 14 days after admission, there was a reduction in wound infection rate from 45% at week 1 postburn to 10% at week 4. In addition, no blood stream infection occurred in the first week after the burns. Multidrug-resistant Acinetobacter baumannii, Klebsiella pneumoniae, and Candida albicans were the top three wound pathogens cultured. Multidrug-resistant microorganism infections were found in 39% of the patients, and the odds ratios for the these infections in burn patients with more than ≥40% total body surface area and in patients receiving two or more classes of antibiotics were 41.7 (95% confidence interval [CI] = 2.1-810.7, P = .01) and 9.9 (95% CI= 1.0-92.7, P = .04), respectively. Although SAP did not prevent wound or blood stream infections, no mortality occurred in our patients. A randomized controlled study is needed to investigate the impact of SAP on burn mortality in MBC.

Response of a local hospital to a burn disaster: Contributory factors leading to zero mortality outcomes.

OBJECTIVE: To investigate the outcomes of a local healthcare system in managing a burn mass casualty incident (BMCI). METHODS: Thirty-three victims admitted to the National Taiwan University Hospital within 96h of the explosion were included in the study. Data were recorded on: patient demographics, Baux score, laboratory data, management response, treatment strategies, and outcomes. Case notes from June 27, 2015 to November 2015 were reviewed with a focus on fluid resuscitation, ventilation support, nutrition, infection control, sepsis treatment, and wound closure plan. RESULTS: Female predominance (mean age: 21.7 years) and lower extremity circumferential flame burns were the characteristics of the burn injury. The mean Baux score was 70±18. The mean burn area was 42% of the total body surface area (TBSA). A total of 79% patients arrived at the hospital within 24h of sustaining injuries. Intensive care unit (ICU) admission criteria were modified to accommodate patients with 40% TBSA of burns, facilities were expanded from 4 ICU beds to 18 beds, and new staff was recruited. A total of 36% patients (n=12/33, 62±13 TBSA of burns) required fluid resuscitation. The mean volume of Lactate Ringer administered in the first 24h of burns was 3.34±2.18ml/kg/%TBSA, while the mean volume of fresh frozen plasma administered was 0.60±0.63ml/kg/h. Forty-two percent patients were intubated on the day of admission, and 71% of the intubated patients had inhalation injuries that were confirmed by diagnostic bronchoscopy. The mean intubation period was 17±9 days. The incidence of pulmonary edema was 58% (n=7/12), possibly due to sub-optimal monitoring. Of these, 57% (n=4/7) patients progressed to adult respiratory distress syndrome, but were successfully treated with early strict fluid restriction, systemic antibiotics, ventilation support, and bronchial lavage. A total of 94% patients received grafting. The mean grafted area was 4432.3±3891cm2. Tube feeding was provided to patients with burns >40% TBSA. All patients tolerated gastric tube feeding without conversion to duodenal switch. On admission, all patients received prophylactic antibiotics. Septic shock was noted in 12 patients, but no mortality occurred. The mean hospital stay was 1.5 days per percent burn. CONCLUSIONS: This article highlights the value of precise triage, traffic control, and effective resource allocation in treating a BMCI. Effective supporting systems for facility expansion, staff recruitment, medical supplies and clear-cut treatment strategies for severely burned patients are contributory factors leading to zero mortalities in our series, in addition to young age and minimal inhalation injuries. The need for reevaluation of the safety of cornstarch powder in festival activities is clear.

Curcumin accelerates cutaneous wound healing via multiple biological actions: The involvement of TNF-α, MMP-9, α-SMA, and collagen.

Curcumin, a constituent of the turmeric plant, has antitumor, anti-inflammatory, and antioxidative effects, but its effects on wound healing are unclear. We created back wounds in 72 mice and treated them with or without topical curcumin (0.2 mg/mL) in Pluronic F127 gel (20%) daily for 3, 5, 7, 9, and 12 days. Healing in wounds was evaluated from gross appearance, microscopically by haematoxylin and eosin staining, by immunohistochemistry for tumour necrosis factor alpha and alpha smooth muscle actin, and by polymerase chain reaction amplification of mRNA expression levels. Treatment caused fast wound closure with well-formed granulation tissue dominated by collagen deposition and regenerating epithelium. Curcumin increased the levels of tumour necrosis factor alpha mRNA and protein in the early phase of healing, which then decreased significantly. However, these levels remained high in controls. Levels of collagen were significantly higher in curcumin-treated wounds. Immunohistochemical staining for alpha smooth muscle actin was increased in curcumin-treated mice on days 7 and 12. Curcumin treatment significantly suppressed matrix metallopeptidase-9 and stimulated alpha smooth muscle levels in tumour necrosis factor alpha-treated fibroblasts via nuclear factor kappa B signalling. Thus, topical curcumin accelerated wound healing in mice by regulating the levels of various cytokines.

Surgical treatment of distal digit amputation: success in distal digit replantation is not dependent on venous anastomosis.

BACKGROUND: Although digit amputation at or distal to the distal interphalangeal joint is a common injury, it remains a challenging problem to restore digital length and pulp because of the lack of healthy vessels and the absence of proper vascular size for reanastomosis. The purpose of the present study was to review the authors' clinical experience with distal digital replantation and to test the hypothesis that success in distal digit replantation is not dependent on venous anastomosis. METHODS: Twenty-eight patients with 31 complete distal digit amputations were included in the study. Data regarding patient demographic, replantation technique, and surgical outcome were analyzed. RESULTS: Sixteen digits were replanted with arterial and venous anastomoses (group A). Eleven digits were replanted with only arterial anastomosis (group B). Composite grafting was performed in four digits without vascular anastomosis (group C). The success rates in group A and group B were 81.3 and 81.8 percent, respectively. None of the composite grafts survived. Fisher's exact test was used for statistical analysis. Although group C has the lowest survival rate (p < 0.05), the differences between the survival rates in group A and group B (p > 0.05) were insignificant. CONCLUSIONS: The overall success rate of distal digit replantations in the authors' series was 81 percent, and there were no differences in the survival rates between replantations with and without venous anastomosis. Finally, the authors conclude that success in distal digit replantation is not dependent on venous anastomosis and suggest that replantation should be encouraged in complete distal digital amputation, even without venous anastomosis. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

The use of artificial dermis for reconstruction of full thickness scalp burn involving the calvaria.

The incidence of extensive full thickness scalp burn involving the calvaria is rare and can be very difficult to reconstruct, as the application of local or free tissue transfer is limited. Although wound closure can be achieved with bone debridement and immediate or delayed split-thickness autografting, the result may be problematic due to unstable skin graft surface. The use of artificial dermis that may provide stable thick coverage in the treatment scalp and skull burn has rarely been reported in literature. We encountered two patients who suffered from severe head burns involving the calvarium. Following debridement including the necrotic bone, the artificial dermis (Integra) was used for immediate wound coverage which was 15 cmx10 cm in one case and 5 cmx6 cm in another. Three weeks later, ultra-thin skin grafting was placed on the neodermis. Compared to split-thickness skin graft, this technique provides a thicker coverage for wound closure. Neither skin breakdown nor ulceration was noted in the 1-year follow-up. This paper reports the successful use of artificial dermis for reconstruction of severe scalp burn with calvarial bone involvement.