The Effectiveness of Adjuvant PD-1 Inhibitors in Patients With Surgically Resected Stage III/IV Acral Melanoma.

Our aim was to assess the efficacy of adjuvant programmed cell death protein-1 (PD-1) inhibitors and compare the other adjuvant treatments in patients with surgically resected stage III or IV acral melanoma. This study is a multicenter, retrospective analysis. We included 114 patients with stage III or IV acral malignant melanoma who underwent surgery within the past 10 years. We analyzed the effect of adjuvant programmed cell death protein-1 inhibitors on disease-free survival (DFS). The mean follow-up was 40 months, during which 69 (59.5%) patients experienced recurrence. Among the participants, 64 (56.1%) received systemic adjuvant therapy. Specifically, 48.4% received anti-PD-1 therapy, 29.7% received interferon, 14.1% received tezozolomide, and 7.8% received B-Raf proto-oncogene/mitogen-activated protein kinase inhibitors. Patients who received adjuvant therapy had a median DFS of 24 (10.9-37.2) months, whereas those who did not receive adjuvant therapy had a median DFS of 15 (9.8-20.2) months. Multivariate analysis for DFS revealed that the receipt of adjuvant therapy and lymph node metastasis stage were independent significant parameters ( P = 0.021, P = 0.018, respectively). No statistically significant difference was observed for DFS between programmed cell death protein-1 inhibitor treatment and other adjuvant treatments. Regarding overall survival (OS), patients who received adjuvant treatment had a median OS of 71 (30.4-111.7) months, whereas those who did not receive adjuvant treatment had a median OS of 38 (16.7-59.3; P = 0.023) months. In addition, there were no significant differences in OS observed between various adjuvant treatment agents ( P = 0.122). In our study, we have shown that adjuvant therapy had a positive effect on both DFS and OS in patients with stages III-IV acral melanoma who underwent curative intent surgery. Notably, we found no significant differences between anti-PD-1 therapy and other adjuvant therapies.

The comparison of functional status and health-related parameters in ovarian cancer survivors with healthy controls.

PURPOSE: The primary purpose of this study was to evaluate functional status and health-related parameters in ovarian cancer (OC) survivors and to compare these parameters with healthy controls. The secondary purpose of this study was to compare these parameters in early and advanced OC survivors. METHODS: Thirty-two OC survivors (n = 15 early stage; n = 17 advanced stage) with no evidence/suspicion of cancer recurrence after completing adjuvant local and systemic treatments for at least 12 months and 32 healthy controls were recruited for functional- and health-related assessments. Participants were assessed using the following methods of measuring the following: 6-min walk test (6MWT) for functional exercise capacity, 30-s chair stand test (30 s-CST) for functional fitness and muscle endurance, a handheld dynamometer for peripheral muscle strength, and a handheld dynamometer for lower extremity strength, Medical Micro RPM for respiratory muscle strength, International Physical Activity Questionnaire-Short Form (IPAQ-SF) for physical activity level, and Eastern Cooperative Oncology Group Performance Scale (ECOG-PS) for performance status, Checklist Individual Strength (CIS) for fatigue, Treatment/Gynecological Oncology-Neurotoxicity (FACT/GOG-NTX) for neuropathy, the Hospital Anxiety and Depression Scale (HADS) for anxiety and depression level, and the World Health Organization-Five Well-Being Index (WHO-5) for generic quality of life. RESULTS: All OC survivors underwent surgery and chemotherapy, and only 9.4% received radiotherapy in addition to chemotherapy. The median recurrence-free period post-completion of adjuvant treatments was 24.00 (12.00-75.00) months. OC survivors had lower 6MWT (m) (p < 0.001, r = 1.50), peripheral muscle strength (p = 0.005, r = 0.72), knee extension (p < 0.001, r = 1.54), and respiratory muscle strength (maximal inspiratory pressure) (p < 0.001, r = 1.90) (maximal expiratory pressure) (p < 0.001, r = 1.68) compared to healthy controls. HADS-A (p = 0.005, r = 0.75) and CIS scores (p = 0.025, r = 0.59) were also higher in the OC survivors. Early-stage OC survivors had better 6MWT (m) than advanced-stage OC survivors (p = 0.005, r = 1.83). Peripheral muscle strength was lower in advanced-stage OC survivors (p = 0.013, r = 0.92). FACT/GOG-NTX scores were higher in early-stage OC survivors (p < 0.001, r = 1.42). No significant differences were observed between early- and advanced-stage OC survivors in other measures (p < 0.05). CONCLUSION: The findings suggest functional status, and health-related parameters are negatively affected in OC survivors. Additionally, higher levels of fatigue, neuropathy anxiety, and depression were reported in advanced OC survivors.

An Old Enemy: Still Nephrotoxic.

Tubulointerstitial nephritis (TIN) presents histopathologically as tubulitis and oedema/inflammation and fibrosis, affecting the renal tubules and interstitium with relative sparing of the glomeruli and vasculature. It can be acute or chronic or acute on chronic and has a wide range of etiologies. In this article, we report a case of a 44-year male who presented with acute TIN, associated with the use of diclofenac at therapeutic doses, that resolved with treatment but later progressed to chronic TIN after the patient resumed diclofenac therapy. The case is discussed in the context of literature regarding the nephrotoxic effects of nonsteroidal anti-inflammatory drugs (NSAIDs). Key Words: Nonsteroidal anti-inflammatory drugs, Acute kidney injury, Tubulointerstitial nephritis.

Replacement of a Stenotic Quadricuspid Aortic Valve With a Sutureless Prosthesis.

Quadricuspid aortic valve is a rare occurrence, usually presenting with insufficiency rather than stenosis. We report an aortic valve replacement in a septuagenarian with a stenotic quadricuspid aortic valve, achieving a good result with a Perceval (Sorin Biomedica Cardio Srl, Sallugia, Italy) sutureless bioprosthesis. We emphasize the particular technique of implantation and possible pitfalls. Sutureless bioprosthetic valves present a feasible option for aortic valve replacement in patients with uncommon valve morphologies, aiming to reduce operative time.

Profiling inflammation and tissue injury markers in perfusate and bronchoalveolar lavage fluid during human ex vivo lung perfusion.

Objectives: Availability of donor lungs suitable for transplant falls short of current demand and contributes to waiting list mortality. Ex vivo lung perfusion (EVLP) offers the opportunity to objectively assess and recondition organs unsuitable for immediate transplant. Identifying robust biomarkers that can stratify donor lungs during EVLP to use or non-use or for specific interventions could further improve its clinical impact. Methods: In this pilot study, 16 consecutive donor lungs unsuitable for immediate transplant were assessed by EVLP. Key inflammatory mediators and tissue injury markers were measured in serial perfusate samples collected hourly and in bronchoalveolar lavage fluid (BALF) collected before and after EVLP. Levels were compared between donor lungs that met criteria for transplant and those that did not. Results: Seven of the 16 donor lungs (44%) improved during EVLP and were transplanted with uniformly good outcomes. Tissue and vascular injury markers lactate dehydrogenase, HMGB-1 and Syndecan-1 were significantly lower in perfusate from transplanted lungs. A model combining IL-1ß and IL-8 concentrations in perfusate could predict final EVLP outcome after 2 h assessment. In addition, perfusate IL-1ß concentrations showed an inverse correlation to recipient oxygenation 24 h post-transplant. Conclusions: This study confirms the feasibility of using inflammation and tissue injury markers in perfusate and BALF to identify donor lungs most likely to improve for successful transplant during clinical EVLP. These results support examining this issue in a larger study.

Development of de novo aortic valve incompetence in patients with the continuous-flow HeartWare ventricular assist device.

BACKGROUND: In this study we investigated the development of aortic incompetence (AI) and change in aortic root and left ventricular dimensions after implantation of the continuous-flow HeartWare ventricular assist device (HVAD) in our adult patient cohort. METHODS: A retrospective analysis of serial echocardiograms was performed on patients implanted with an HVAD between July 2009 and July 2013. Data from echocardiograms performed before and at 1 and 2 years (±3 months) were analyzed. Patients with native aortic valves (AoVs) with no previous intervention and HVAD in situ for ≥6 months were included. RESULTS: A total of 73 HVADs in 71 patients with a mean duration of support of 624 ± 359 days were included in our study. One patient developed moderate AI at 1 year (1.9%). Mild or greater AI was more likely in those with a closed or intermittently opening AoV at 1 year (p = 0.005). Aortic annulus dimensions increased significantly at 1 and 2 years, regardless of extent of AI. At 2 years, in those with mild or worse AI, the sinuses of Valsalva were also larger (p = 0.002). Left ventricular end-diastolic dimension (LVEDD) was significantly reduced in those with no or trace AI at 1 and 2 years (p = 0.012 and p = 0.008, respectively), but remained unchanged in those with AI at both time-points. CONCLUSIONS: The development of more than mild AI is rare in HVAD patients at our center. When encountered, it is more common with a closed AoV. Dilation of the aortic annulus, and root dilation in those with mild or more AI, is seen with HVAD support over time.

Four-year outcomes with third-generation centrifugal left ventricular assist devices in an era of restricted transplantation.

OBJECTIVES: Third-generation ventricular assist devices (VADs) are associated with improved outcomes, though in recent clinical trials bridge-to-transplant (BTT) rates are ∼30% at 6 months, so that transplantation can be used as a 'bail out' for serious complications. In the UK, there was a significant reduction in heart transplantation rates over the last decade, so that transplantation from VADs is much less frequent. The objective of this study was to determine outcomes and their predictors in this situation of low BTT rates, and as patients were exposed to long-term support, the incidence and outcomes of VAD thrombosis. METHODS: We analysed outcomes for 102 consecutive patients between 2009 and 2013 (mean age 47 ± 13; VentrAssist n = 6 and HeartWare n = 96). The median duration of support was 462 ± 426 days. RESULTS: Survival rates on the device were 75 and 66% at 1 and 2 years, respectively. Older age and more acute INTERMACS groups were significantly related to reduced survival within the first 90 days (P = 0.030 and 0.010, respectively). Poor preoperative right ventricular (RV) function had a negative effect on survival after 1 year (P = 0.009), though not earlier. VAD thrombosis (n = 24 HeartWare and n = 1 VentrAssist) occurred at 0.18 events per patient-year for HeartWare and 0.07 for VentrAssist devices at a median time of onset at 404 ± 281 days. There was no significant effect of VAD thrombosis on survival. Only 14 of 102 patients were transplanted at a median of 334 ± 347 days, and only 3 were transplanted within the first 6 months. CONCLUSIONS: Third-generation left ventricular assist device implants with a low rate of transplantation have similar survival to destination therapy, and are susceptible to long-term complications of VAD thrombosis and right heart failure.

Vascular anastomotic complications in lung transplantation: a single institution's experience.

OBJECTIVES: Lung transplant recipients were reviewed to compare our early and current experience of vascular complications. Since 1995, we have had a policy of early identification and intervention. METHODS: We undertook a retrospective review of all adult lung transplants performed at our centre. Patients with pulmonary vascular complications before and after 1995 were identified and reviewed to determine changes in management and outcome. RESULTS: We identified a total of 13 patients with either pulmonary artery or venous obstruction out of a total of 720 adult lung transplants (1.8%). There were 9 females and 4 males with an age range of 25-64 years. Complications were more common in patients with fibrotic lung disease and involved 15 vascular anastomoses, most commonly the pulmonary arterial anastomosis. Prior to 1995, 5 cases were identified, all postoperatively. In this group, the mean time for identification of the complication was 9.4 (range 4-14) days. Only 1 patient survived to discharge. After 1995, vascular complications were identified intraoperatively in 4 cases and corrected immediately. Four cases were identified postoperatively (at <1-17 days) by a computed tomography pulmonary angiogram. Three were treated surgically within 24 h of diagnosis (using cardiopulmonary bypass with cold preservation). One patient was managed conservatively. Among patients identified after 1995, 5 survived to discharge. CONCLUSIONS: Though rare, pulmonary vascular complications after lung transplantation carry high mortality. In our opinion, early identification and intervention improves outcome. Intraoperative assessment by pressure gradient measurement and transoesophageal echocardiography is recommended. Despite this, mortality remains high and prevention is better than cure.

Informed consent in cardiac surgery: is it truly informed?

OBJECTIVE: To develop a validated questionnaire to measure how informed patients are when giving consent for elective coronary artery bypass grafting. METHODS: We developed a questionnaire covering the domains described in the consent guidelines published by the General Medical Council. The questionnaire was developed for use in face-to-face interviews as opposed to a self-administered questionnaire. Interviews were conducted after the patients had given consent for surgery. A total of 41 patients were interviewed. To validate the questionnaire we tested the interobserver reliability by using four different interviewers and the construct validity by comparing it with area deprivation index and with predicted intelligence quotient scores obtained from the National Adult Reading Test. RESULTS: The correlation of the ranking of the questions between the interviewers was satisfactory (Spearman's rank correlation coefficient, rs = 0.84-0.89). The total questionnaire scores correlated well with predicted intelligence quotient scores (rs = 0.48) but not with area deprivation index (rs = 0.01). Questions with the worst scores were those related to mortality, morbidity, alternative treatment options and their relative success rates and risks. CONCLUSIONS: We have developed a validated questionnaire which tests patient's level of knowledge with respect to surgical myocardial revascularisation. Our study identified areas of informed consent where the minimal level of knowledge is below the recommended level. The questionnaire could be used in audits and clinical trials in patients undergoing coronary artery bypass grafting. It could be used as a tool to measure the effectiveness of patient education programmes. With appropriate changes, this instrument could also be applied in other fields of medical intervention, which require patients to give informed consent.

A randomized, controlled trial of C0- Vs C2-guided therapeutic drug monitoring of cyclosporine in stable heart transplant patients.

BACKGROUND: Cyclosporine monitoring using 2-hour post-dose samples (C2) is thought to be more efficacious than using pre-dose levels (C0) in managing immunosuppression for transplant patients. We evaluated the effect of C2 monitoring on cyclosporine dose and clinical parameters in stable heart transplant patients. METHODS: 125 stable heart transplant patients were randomized to C0 or C2 monitoring of cyclosporine levels for a period of six months. All patients had both C0 and C2 samples taken, and clinicians were blinded to one of the samples depending on randomization. The primary endpoint was the relative change in cyclosporine (Neoral) dose during the study period and secondary endpoints were change in creatine clearance, mortality, infection, and acute rejection. RESULTS: There was a significant decrease in the cyclosporine dose for the C2 group as compared with the C0 group (-11 mg/day and -26 mg/day respectively, p = 0.0025). No proven rejection episodes occurred in either group and there was no significant difference in the incidence of infection (C0 6, C2 10; p = 0.14), the change in renal function (change in creatine clearance C(0) +0.54 ml/min; C2 -0.16 ml/min; p = 0.61), the number of blood tests or dose adjustments between groups over the study period. Analysis of the blinded samples revealed that the reduction of cyclosporine dose in the C2 group could not be accounted for by reduced immunosuppression . CONCLUSION: C2 monitoring allows a significant cyclosporine dose reduction without compromising patient outcome in stable heart transplant patients. Further studies are required to ascertain whether this dose reduction can be translated into clinical benefit.