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The optimal surgical excision margins are uncertain for patients with thick (>2 mm) localised cutaneous melanomas. In our previous report of this multicentre, randomised controlled trial, with a median follow-up of 6·7 years, we showed that a narrow excision margin (2 cm vs 4 cm) did not affect melanoma-specific nor overall survival. Here, we present extended follow-up of this cohort. In this open-label, multicentre randomised controlled trial, we recruited patients from 53 hospitals in Sweden, Denmark, Estonia, and Norway. We enrolled clinically staged patients aged 75 years or younger diagnosed with localised cutaneous melanoma thicker than 2 mm, and with primary site on the trunk or upper or lower extremities. Patients were randomly allocated (1:1) to treatment either with a 2-cm or a 4-cm excision margin. A physician enrolled the patients after histological confirmation of a cutaneous melanoma thicker than 2 mm. Some patients were enrolled by a physician acting as responsible for clinical care and as a trial investigator (follow-up, data collection, and manuscript writing). In other cases physicians not involved in running the trial enrolled patients. Randomisation was done by telephone call to a randomisation office, by sealed envelope, or by computer generated lists using permuted blocks. Patients were stratified according to geographical region. No part of the trial was masked. The primary outcome in this extended follow-up study was overall survival and the co-primary outcome was melanoma-specific survival. All analyses were done on an intention-to-treat basis. The study is registered with ClinicalTrials.gov, number NCT03638492. Between Jan 22, 1992, and May 19, 2004, 936 clinically staged patients were recruited and randomly assigned to a 4-cm excision margin (n=465) or a 2-cm excision margin (n=471). At a median overall follow-up of 19·6 years (235 months, IQR 200–260), 621 deaths were reported—304 (49%) in the 2-cm group and 317 (51%) in the 4-cm group (unadjusted HR 0·98, 95% CI 0·83–1·14; p=0·75). 397 deaths were attributed to cutaneous melanoma—192 (48%) in the 2-cm excision margin group and 205 (52%) in the 4-cm excision margin group (unadjusted HR 0·95, 95% CI 0·78–1·16, p=0·61). A 2-cm excision margin was safe for patients with thick (>2 mm) localised cutaneous melanoma at a follow-up of median 19·6 years. These findings support the use of 2-cm excision margins in current clinical practice. The Swedish Cancer Society, Stockholm Cancer Society, the Swedish Society for Medical Research, Radiumhemmet Research funds, Stockholm County Council, Wallström funds.

Background This update of a randomized, prospective study presents the effect of external beam radiation therapy (EBRT) on long-term overall survival, local control, and limb function following limb-sparing surgery (LSS) for the treatment extremity soft tissue sarcoma (STS). Methods Following LSS, patients with extremity STS were randomized to receive EBRT or surgery alone. All patients with high-grade STS received adjuvant chemotherapy. Long-term follow-up was obtained through telephone interviews using a questionnaire based on validated methods. Overall survival (OS) was determined by Kaplan–Meier method. Results A total of 141 patients with extremity STS were randomized to receive adjuvant EBRT ( n  = 70) or LSS alone ( n  = 71). Median follow-up was 17.9 years. The 10- and 20-year survival was 77 % (95 % CI 66–85 %) and 64 % (95 % CI 52–75 %) for patients receiving LSS alone and 82 % (95 % CI 72–90 %) and 71 % (95 % CI 59–81 %) for patients receiving EBRT ( p  = 0.22). Of the 54 patients who completed telephone interviews, the incidence of local recurrence during the follow-up period was 4 % (1 of 24) in the LSS alone cohort compared with 0 % (0 of 30) in those who received EBRT ( p  = 0.44). Patients treated with EBRT tended to have more wound complications (17 vs. 12.5 %, p  = 0.72), clinically significant edema (25 vs. 12 %, p  = 0.31), and functional limb deficits (15 vs. 12 %, p  = 0.84). Conclusions Adjuvant EBRT following surgery for STS of the extremity provides excellent local control with acceptable treatment-related morbidity and no statistically significant improvement in overall survival.

Actinic keratosis is a common precursor to squamous-cell carcinoma. Several topical treatments are effective but require weeks of application. In four randomized trials, topical treatment with ingenol mebutate for 2 to 3 days was effective in clearing actinic keratoses. Actinic keratoses are premalignant lesions that are common in light-skinned populations worldwide. 1 In the United States, the most common form of lesion-directed therapy for actinic keratoses is cryosurgery, although other locally ablative therapies are used. 2 In addition to potential scarring, recurrence rates are high with some of these treatment approaches. 3 Other treatments for actinic keratosis are applied to an entire field of sun-damaged skin, and many studies have shown the emergence of clinically visible actinic keratoses after application. These treatments include imiquimod, fluorouracil, diclofenac, and photodynamic therapy. 1 Drawbacks to the self-applied topical field therapies currently available include a long duration . . .

Aims/hypothesisThe safety and efficacy of glucagon-like peptide-1 receptor agonists (GLP1RAs) and dipeptidyl peptidase-4 inhibitors (DPP4is) in major cardiovascular adverse events were previously examined in cardiovascular outcome trials. However, the effects of these drugs on adverse limb outcomes were poorly examined. This study aimed to determine the real-world outcomes of patients with diabetes mellitus receiving GLP1RAs as compared with those receiving DPP4is in terms of major adverse cardiovascular and limb events.MethodsA retrospective cohort study was conducted with data collected by the Taiwan National Health Insurance database between 1 May 2011 and 31 December 2017. Patients who were treated for type 2 diabetes with a GLP1RA or DDP4i during this period (n = 1,080,993), were identified. The primary outcome was a composite of major adverse limb events, defined as peripheral artery disease (PAD), critical limb ischaemia, percutaneous transluminal angioplasty or peripheral bypass for PAD, and amputation. The secondary cardiovascular outcome was the composite of cardiovascular death, non-fatal myocardial infarction and non-fatal ischaemic stroke. Propensity-score matching (PSM) at a 1:3 ratio between GLP1RA and DPP4i groups was done to minimise possible selection bias.ResultsA total of 948,342 individuals treated between 1 May 2011 and 31 December 2017, were identified, with 4460 in the GLP1RA group and 13,380 in the DPP4i group after PSM. The incidence of primary composite outcome events was significantly lower in those treated with GLP1RAs compared with those treated with DPP4is (2.59 vs 4.22 events per 1000 person-years; subdistribution HR [SHR] 0.63 [95% CI 0.41, 0.96]), primarily due to lower rates of amputation (1.29 events per 1000 person-years for GLP1RAs vs 2.4 events per 1000 person-years for DPP4is; SHR 0.55 [95% CI 0.30, 0.99]). Treatment with GLP1RAs was also associated with significantly lower risks of secondary composite outcome events (11.02 vs 17.95 events per 1000 person-years; HR 0.62 [95% CI 0.51, 0.76]). Moreover, the observed beneficial effects of GLP1RAs on reducing composite adverse limb outcomes were particularly noticeable in the non-cardiovascular patients and statin users (p for interaction <0.05).Conclusions/interpretationIn individuals with diabetes, the use of GLP1RAs was associated with significantly lower risks of major adverse limb events when compared with the use of DPP4is. The reduction in risk was driven largely by reduced rate of amputations. Moreover, treatment with GLP1RAs was also associated with lower risks of cardiovascular death, non-fatal stroke, non-fatal myocardial infarction and death from any cause. However, some unexplored confounding factors may exist in this observation study and future large-scale randomised controlled trials are needed.

This study tested the hypothesis that changes in indirect markers of muscle damage following maximal eccentric exercise would be smaller for the knee extensors (KE) and flexors (KF) compared with the elbow flexors (EF) and extensors (EE). A total of 17 sedentary men performed five sets of six maximal isokinetic (90° s −1 ) eccentric contractions of EF (range of motion, ROM: 90°–0°, 0 = full extension), EE (55°–145°), KF (90°–0°), and KE (30°–120°) using a different limb with a 4–5-week interval in a counterbalanced order. Changes in maximal isometric and concentric isokinetic strength, optimum angle, limb circumference, ROM, plasma creatine kinase activity and myoglobin concentration, muscle soreness, and echo-intensity of B-mode ultrasound images before and for 5 days following exercise were compared amongst the four exercises using two-way repeated-measures ANOVA. All variables changed significantly following EF, EE, and KF exercises, but KE exercise did not change the optimum angle, limb circumference, and echo-intensity. Compared with KF and KE, EF and EE showed significantly greater changes in all variables, without significant differences between EF and EE. Changes in all variables were significantly greater for KF than KE. For the same subjects, the magnitude of change in the dependent variables following exercise varied among the exercises. These results suggest that the two arm muscles are equally more susceptible to muscle damage than leg muscles, but KF is more susceptible to muscle damage than KE. The difference in the susceptibility to muscle damage seems to be associated with the use of muscles in daily activities.

Varicose veins of lower extremities (VVs) are a common multifactorial vascular disease. Genetic factors underlying VVs development remain largely unknown. Here we report the first large-scale study of VVs performed on a freely available genetic data of 408,455 European-ancestry individuals. We identified the 12 reliably associated loci that explain 13% of the SNP-based heritability, and prioritized the most likely causal genes CASZ1, PIEZO1, PPP3R1, EBF1, STIM2, HFE, GATA2, NFATC2, and SOX9. VVs-associated variants within these loci exhibited pleiotropic effects on several phenotypes including blood pressure/hypertension and blood cell traits. Gene set enrichment analysis revealed gene categories related to abnormal vasculogenesis. Genetic correlation analysis confirmed known epidemiological associations between VVs and deep venous thrombosis, weight, rough labor, and standing job, and found a genetic overlap with multiple traits that have not been previously suspected to share common genetic background with VVs. These traits included educational attainment, fluid intelligence and prospective memory scores, walking pace (negative correlation with VVs), smoking, height, number of operations, pain, and gonarthrosis (positive correlation with VVs). Finally, Mendelian randomization analysis provided evidence for causal effects of plasma levels of MICB and CD209 proteins, and anthropometric traits such as waist and hip circumference, height, weight, and both fat and fat-free mass. Our results provide novel insight into both VVs genetics and etiology. The revealed genes and proteins can be considered as good candidates for follow-up functional studies and might be of interest as potential drug targets.

Lower limb lymphedema (LLL) is a common postoperative complication following lymphadenectomy in cervical and endometrial cancers. Removal of the circumflex iliac nodes distal to the external iliac node (CINDEIN) is associated with LLL. Here, we sought to evaluate whether preserving the CINDEIN is helpful in reducing the incidence of LLL in women with cervical and endometrial cancers and to evaluate the safety of preserving CINDEIN. In this prospective randomized controlled trial, patients with clinical stage I A2 to II A cervical cancer and stage I to III endometrial carcinoma undergoing surgery were randomly assigned (1:1) to undergo pelvic lymphadenectomy with CINDEIN removal or preservation. The primary endpoint was the incidence of LLL at 24 months post-surgery. Eligible patients underwent sentinel lymph node (SLN) mapping with carbon nanoparticles (CNP). The study was registered with ClinicalTrials.gov, number ChiCTR2300071911. Between Jun 1, 2017, and Dec 31, 2018, 328 participants were randomly assigned to the two groups. Thirteen patients were excluded from the lymphedema analysis. A total of 158 patients in the CINDEIN preservation group and 157 in the CINDEIN removal group completed the follow-up examination. At baseline, no significant differences were observed between the two groups. The 3-year overall survival rate was 96.9% in the preservation group and 95.7% in the resection group. For cervical cancer and endometrial carcinoma, the incidence of LLL were significantly lower in the preservation group than in the removal group both at 24 months. No differences in the occurrence time of LLL were observed between the two groups. The LLL stages also showed no significant difference between the two groups. In the removal group, no CINDEIN metastases were identified in any patient. A total of 125 evaluable patients received the injection of CNP. None of the patients had CINDEIN detected as SLNs. CINDEIN removal is an important risk factor for LLL following lymphadenectomy in cervical and endometrial cancers. The metastasis rate of CINDEIN in cervical cancer and early endometrial cancer is relatively low, and preserving CINDEIN might be safe and helpful in reducing the occurrence of LLL.

Secondary lymphedema is a very common clinical issue with millions of patients suffering from pain, recurrent skin infections, and the constant need for a decongestive therapy. Well- established because of oncologic procedures, secondary lymphedema is also a well-known phenomenon after trauma. However, precise epidemiological data of posttraumatic lymphedema upon severe extremity injuries are rare. In the present study, we analyzed a patient cohort of 223 individuals who suffered closed fractures of the upper and lower extremity between 2016 and 2020. All of them simultaneously had a soft tissue injury, of 2nd and 3rd grade according to Tscherne classification. Typical symptoms of lymphedema were recorded in a retrospective cohort analysis through patient anamnesis and compared with documented clinical examination findings. Previous illnesses and trauma-specific characteristics were determined from patient files. Of all patients, 36% showed symptoms of secondary lymphedema and 8,5% reported recurrent skin infections, indicating severe lymphedema. Furthermore, comparing patients with and without lymphedema, additional trauma-associated parameters, such as total number of surgeries, degree of soft tissue damage, localization of the fracture in lower extremity, related to lymphedema progress could be identified. According to these data, posttraumatic secondary lymphedema has even in closed fractures, especially of the lower extremity, a highly underestimated clinical prevalence. Further prospective studies are required to validate these findings, identify high-risk groups, and guide early prophylactic and therapeutic interventions.

Background: The outcome of patients with upper extremity deep vein thrombosis (UEDVT) has not been consistently compared with that in patients with lower extremity deep vein thrombosis (LEDVT). Methods: We used the Registro Informatizado de Enfermedad Trombo Embólica (RIETE) registry to compare the outcomes during the course of anticoagulant therapy in patients with UEDVT versus outcomes in patients with LEDVT. Results: As of August 2015, 37,366 patients with acute DVT had been enrolled in RIETE: 35094 (94%) had LEDVT, 1334 (3.6%) non-catheter related UEDVT (672 unprovoked and 662 provoked) and 938 (2.5%) had catheter-related UEDVT. During the course of anticoagulation, patients with unprovoked UEDVT had a higher rate of DVT recurrences (hazard ratio [HR]: 2.22; 95% CI: 1.37-3.43) and a similar rate of PE recurrences or major bleeding than those with unprovoked LEDVT. Patients with non-catheter-related provoked UEDVT had a similar outcome than those with provoked LEDVT. Among patients with UEDVT, those with non-catheter related unprovoked UEDVT had a lower rate of PE recurrences (HR: 0.06; 95% CI: 0-0.35) and major bleeding (HR: 0.20; 95% CI: 0.08-0.46) than those with catheter-related UEDVT or those with non-catheter related provoked UEDVT (HR: 0.10; 95% CI: 0.004-0.60; and 0.22; 95% CI: 0.08-0.52, respectively). On multivariable analysis, any difference had disappeared. Conclusion: During the course of anticoagulation, patients with UEDVT had a similar outcome than those with LEDVT. Among UEDVT patients, there were some differences according to the presence of catheter or additional risk factors for DVT. These differences disappeared after adjusting for potentially confounding variables.

Background Despite effective local therapy with surgery and radiotherapy (RT), ~50 % of patients with high-grade soft tissue sarcoma (STS) will relapse and die of disease. Since experimental data suggest a significant synergistic effect when antiangiogenic targeted therapies such as sorafenib are combined with RT, we chose to evaluate preoperative combined modality sorafenib and conformal RT in a phase I/II trial among patients with extremity STS amenable to treatment with curative intent. Methods For the phase I trial, eight patients with intermediate- or high-grade STS >5 cm in maximal dimension or low-grade STS >8 cm in maximal dimension received concomitant sorafenib (dose escalation cohort 1:200 twice daily, cohort 2:200/400 daily) and preoperative RT (50 Gy in 25 fractions). Sorafenib was continued during the entire period of RT as tolerated. Surgical resection was completed 4–6 weeks following completion of neoadjuvant sorafenib/RT. Three sorafenib dose levels were planned. Primary endpoints of the phase I trial were maximal tolerated dose and dose-limiting toxicity (DLT). Results Eight patients were enrolled in the phase I (five females, median age 44 years, two high-grade pleomorphic, two myxoid/round cell liposarcoma, four other). Median tumor size was 16 cm (range 8–29), and all tumors were located in the lower extremity. Two of five patients treated at dose level 2 developed DLT consisting of grade 3 rash not tolerating drug reintroduction. Other grade 3 side effects included anemia, perirectal abscess, and supraventricular tachycardia. Radiation toxicity (grade 1 or 2 dermatitis; N  = 8) and post-surgical complications (three grade 3 wound complications) were comparable to historical controls and other series of preoperative RT monotherapy. Complete pathologic reponse (≥95 % tumor necrosis) was observed in three patients (38 %). Conclusion Neoadjuvant sorafenib in combination with RT is tolerable and appears to demonstrate activity in locally advanced extremity STS. Further study to determine efficacy at dose level 1 is warranted. (ClinicalTrials.gov identifier NCT00805727).