Phase II single-arm study of nivolumab and ipilimumab (Nivo/Ipi) in previously treated classical Kaposi sarcoma (cKS).

BACKGROUND: Classical Kaposi sarcoma (cKS) is a rare human herpesvirus 8-associated sarcoma with limited treatment options. We evaluated the efficacy and safety of nivolumab in combination with ipilimumab in patients with previously treated progressive cKS. PATIENTS AND METHODS: cKS patients with progressive disease after one or more lines of systemic therapy and measurable disease by positron emission tomography/computed tomography and/or physical examination received nivolumab 240 mg every 2 weeks and ipilimumab 1 mg/kg every 6 weeks until progression or toxicity for a maximum of 24 months. The primary endpoint was overall response rate; secondary endpoints included 6-month progression-free survival (PFS) rate and safety. Immune correlates were explored using immunohistochemistry, DNA sequencing (596/648 genes) and RNA sequencing (whole transcriptome hybrid capture) of tumor specimens and matched blood. RESULTS: Eighteen male patients (median age 76.5 years) were enrolled between April 2018 and December 2020. At a median follow up of 24.4 months, overall response rate by RECIST v1.1 was 87%. Metabolic complete response as assessed by positron emission tomography/computed tomography was observed in 8 of 13 (62%) assessable patients. Some 6/13 achieved pathological complete response after treatment. In two patients, palliative limb amputation was prevented. Median PFS was not reached. The 6- month and 12-month PFS rate was 76.5% and 58.8%, respectively. Only four patients (22%) experienced grade 3-4 adverse events. The most frequent genomic alteration was biallelic copy number loss of the FOX1A gene. The majority of tumors carried a low tumor mutational burden, were microsatellite stable, mismatch repair proficient, did not express programmed death-ligand 1, and displayed only low lymphocytic infiltrates, rendering them immunologically 'cold'. CONCLUSIONS: This prospectively designed phase II study of nivolumab and ipilimumab demonstrates promising activity of this combination in progressive cKS representing a new treatment option in this population.

Long-term follow-up results of the multicenter phase II trial of regorafenib in patients with metastatic and/or unresectable GI stromal tumor after failure of standard tyrosine kinase inhibitor therapy.

BACKGROUND: This investigator-initiated trial provided the justification for the phase III GRID study resulting in worldwide regulatory approval of regorafenib as a third-line therapy for patients with metastatic gastrointestinal stromal tumors (GIST). We report the genotype analyses, long-term safety, and activity results from this initial trial of regorafenib in GIST. PATIENTS AND METHODS: The trial was conducted between February 2010 and January 2014, among adult patients with metastatic GIST, after failure of at least imatinib and sunitinib. Patients received regorafenib orally, 160 mg once daily, days 1-21 of a 28-day cycle. Clinical benefit rate (CBR), defined as complete or partial response (PR), or stable disease lasting ≥16 weeks per RECIST 1.1, progression-free survival (PFS), overall survival (OS), long-term safety data, and metabolic response by functional imaging were assessed. RESULTS: Thirty-three patients received at least one dose of regorafenib. The median follow-up was 41 months. CBR was documented in 25 of 33 patients [76%; 95% confidence interval (CI) 58% to 89%], including six PRs. The median PFS was 13.2 months (95% CI 9.2-18.3 months) including four patients who remained progression-free at study closure, each achieving clinical benefit for more than 3 years (range 36.8-43.5 months). The median OS was 25 months (95% CI 13.2-39.1 months). Patients whose tumors harbored a KIT exon 11 mutation demonstrated the longest median PFS (13.4 months), whereas patients with KIT/PDGFRA wild-type, non-SDH-deficient tumors experienced a median 1.6 months PFS (P < 0.0001). Long-term safety profile is consistent with previous reports; hand-foot skin reaction and hypertension were the most common reasons for dose reduction. Notably, regorafenib induced objective responses and durable benefit in SDH-deficient GIST. CONCLUSIONS: Long-term follow-up of patients with metastatic GIST treated with regorafenib suggests particular benefit among patients with primary KIT exon 11 mutations and those with SDH-deficient GIST. Dose modifications are frequently required to manage treatment-related toxicities. CLINICAL TRIAL NUMBER: NCT01068769.

Risk factors for sternal wound infection in children undergoing cardiac surgery: a case-control study.

SUMMARY: Complex and prolonged cardiovascular operations are increasingly performed on young infants and children. The aims of this study were to define the incidence, causative bacterial pathogens and risk factors for sternal wound infections (SWIs) in infants and children undergoing cardiac surgery. The study group included all children who underwent cardiac surgery by median sternotomy at a tertiary paediatric centre from 1999 to 2003 and who were diagnosed with a postoperative SWI. Charts were reviewed for pre-, intra- and postoperative variables. The findings were compared with control patients operated on immediately before and after the cases and analysed by a stepwise logistic regression model. Of the 1821 children who underwent cardiac surgery, 49 (2.69%) had SWI; full data were available for 47. Twenty-nine (61.7%) had superficial wound infection and 18 (38.3%) deep wound infection. The main bacterial pathogens were Staphylococcus aureus in 14 patients (39%) and Pseudomonas aeruginosa in 12 (33%). Three variables emerged as significant independent risk factors for SWI: young age (odds ratio: 0.63; 95% confidence interval: 0.47-0.85; P<0.001 for each additional year), cyanotic heart disease (4.93; 1.98-12.3; P<0.001), and central venous catheter (CVC) dwell time (1.15; 1.06-1.24; P<0.001 for each additional day). Gram-negative infections were significantly associated with preoperative oxygen treatment (P=0.007) and prolonged urinary catheter dwell time (P=0.004). This study confirms younger age as risk factor for SWI and adds cyanotic heart disease and duration of CVC as new independent risk factors. Specific risks for Gram-negative infections are identified and should help to introduce new preventive strategies to decrease the incidence and severity of SWI.