TROPHY-U-01, a phase II open-label study of sacituzumab govitecan in patients with metastatic urothelial carcinoma progressing after platinum-based chemotherapy and checkpoint inhibitors: updated safety and efficacy outcomes.

BACKGROUND: Sacituzumab govitecan (SG) is a Trop-2-directed antibody-drug conjugate containing cytotoxic SN-38, the active metabolite of irinotecan. SG received accelerated US Food and Drug Administration approval for locally advanced (LA) or metastatic urothelial carcinoma (mUC) previously treated with platinum-based chemotherapy and a checkpoint inhibitor, based on cohort 1 of the TROPHY-U-01 study. Mutations in the uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) gene are associated with increased adverse events (AEs) with irinotecan-based therapies. Whether UGT1A1 status could impact SG toxicity and efficacy remains unclear. PATIENTS AND METHODS: TROPHY-U-01 (NCT03547973) is a multicohort, open-label, phase II registrational study. Cohort 1 includes patients with LA or mUC who progressed after platinum- and checkpoint inhibitor-based therapies. SG was administered at 10 mg/kg intravenously on days 1 and 8 of 21-day cycles. The primary endpoint was objective response rate (ORR) per central review; secondary endpoints included progression-free survival, overall survival, and safety. Post hoc safety analyses were exploratory with descriptive statistics. Updated analyses include longer follow-up. RESULTS: Cohort 1 included 113 patients. At a median follow-up of 10.5 months, ORR was 28% (95% CI 20.2% to 37.6%). Median progression-free survival and overall survival were 5.4 months (95% CI 3.5-6.9 months) and 10.9 months (95% CI 8.9-13.8 months), respectively. Occurrence of grade ≥3 treatment-related AEs and treatment-related discontinuation were consistent with prior reports. UGT1A1 status was wildtype (∗1|∗1) in 40%, heterozygous (∗1|∗28) in 42%, homozygous (∗28|∗28) in 12%, and missing in 6% of patients. In patients with ∗1|∗1, ∗1|∗28, and ∗28|∗28 genotypes, any grade treatment-related AEs occurred in 93%, 94%, and 100% of patients, respectively, and were managed similarly regardless of UGT1A1 status. CONCLUSIONS: With longer follow-up, the ORR remains high in patients with heavily pretreated LA or mUC. Safety data were consistent with the known SG toxicity profile. AE incidence varied across UGT1A1 subgroups; however, discontinuation rates remained relatively low for all groups.

Fragmentomic analysis of circulating tumor DNA-targeted cancer panels.

BACKGROUND: The isolation of cell-free DNA (cfDNA) from the bloodstream can be used to detect and analyze somatic alterations in circulating tumor DNA (ctDNA), and multiple cfDNA-targeted sequencing panels are now commercially available for Food and Drug Administration (FDA)-approved biomarker indications to guide treatment. More recently, cfDNA fragmentation patterns have emerged as a tool to infer epigenomic and transcriptomic information. However, most of these analyses used whole-genome sequencing, which is insufficient to identify FDA-approved biomarker indications in a cost-effective manner. PATIENTS AND METHODS: We used machine learning models of fragmentation patterns at the first coding exon in standard targeted cancer gene cfDNA sequencing panels to distinguish between cancer and non-cancer patients, as well as the specific tumor type and subtype. We assessed this approach in two independent cohorts: a published cohort from GRAIL (breast, lung, and prostate cancers, non-cancer, n = 198) and an institutional cohort from the University of Wisconsin (UW; breast, lung, prostate, bladder cancers, n = 320). Each cohort was split 70%/30% into training and validation sets. RESULTS: In the UW cohort, training cross-validated accuracy was 82.1%, and accuracy in the independent validation cohort was 86.6% despite a median ctDNA fraction of only 0.06. In the GRAIL cohort, to assess how this approach performs in very low ctDNA fractions, training and independent validation were split based on ctDNA fraction. Training cross-validated accuracy was 80.6%, and accuracy in the independent validation cohort was 76.3%. In the validation cohort where the ctDNA fractions were all <0.05 and as low as 0.0003, the cancer versus non-cancer area under the curve was 0.99. CONCLUSIONS: To our knowledge, this is the first study to demonstrate that sequencing from targeted cfDNA panels can be utilized to analyze fragmentation patterns to classify cancer types, dramatically expanding the potential capabilities of existing clinically used panels at minimal additional cost.

Nutrient Status in Patients with Frequent Episodic Tension-Type Headache: A Case-Control Study.

OBJECTIVE: To investigate the relationship between frequent episodic tension-type headache (FE-TTH) and 25-hydroxyvitamin-D (25(OH)D), folate, vitamin B12, and magnesium. DESIGN-METHODS: A prospective case-control study involving adults with FETTH and age-sex matched healthy controls (HC) was performed. Individuals under the responsibility of the three provincial Health Centres of the prefecture of Trikala (Central Greece) were recruited during their regular check-up visits. The relationship between FETTH and serum levels of 25(OH)D, vitamin B12, folate, and magnesium was investigated (primary outcomes). Demographics, daily habits, somatometrics, psychometric and sleep quality measurements, laboratory indices, cardiovascular comorbidities and medications taken were also recorded and compared (secondary outcomes). Potential associations of the above-listed parameters with headache parameters (headache frequency, severity and analgesic consumption) were also examined (secondary outcomes). RESULTS: Between September and December 2020, 30 patients with FETTH and 30 HC were successfully recruited. Demographics, comorbidities, regular medications, smoking habits, alcohol and coffee consumption, body mass index measurements, markers of systemic inflammation, folate and vitamin B12 levels were similar between the two groups (P>0.05). Lower serum 25(OH)D was both univariately (P<0.001) and multivariately [OR= 0.72, 95%CI=(0.55, 0.94) per 1ng/ml increase] associated with FETTH, while serum magnesium was found lower in FETTH only according to the univariate approach (P=0.036). Higher levels of depression (P=0.050) and anxiety (P=0.020), as well as poor quality of sleep (P=0.008), were univariately associated with FETTH. Only the effect of anxiety remained significant following the multivariate logistic regression [OR=7.90, 95%CI=(1.00, 62.47)]. Headache parameters were not associated with any one of the assessed variables. DISCUSSION: Lower serum 25(OH)D was related to the presence of FETTH. This finding could imply a potential role for vitamin D in the pathophysiology of TTH.

The October 23, 2011, Van (Turkey) earthquake and its relationship with neighbouring structures.

The present work reports the analysis of a possible relationship due to stress transfer between the two earthquakes that hit the province of Van, Eastern Turkey, on October 23, 2011 (Mw = 7.2) and on November 9, 2011 (Mw = 5.6). The surface displacement field of the mainshock has been obtained through a combined data set made up of differential interferograms from COSMO-SkyMed and ENVISAT satellites, integrated with continuous GPS recordings from the Turkish TUSAGA-AKTIF network. This allowed us to retrieve the geometry and the slip distribution of the seismic source and to compute the Coulomb Failure Function (CFF) variation on the aftershock plane, in order to assess a possible causal relationship between the two events. Our results show that the November 9 earthquake could have been triggered by the October 23 shock, with transferred stress values largely exceeding 1 bar.

Alveolar soft-part sarcoma of the extremity: a case report.

Alveolar soft-part sarcoma (ASPS) is a rare form of soft tissue sarcoma and is most often seen in adolescents and young adults. Surgical excision of the primary tumor and pulmonary metastases has resulted in prolonged survival in some patients while the benefit of adjuvant chemotherapy and/or radiotherapy has been disputed. An 11- year-old boy with ASPS which presented with a markedly vascular tumor in the left thigh, and multiple bilateral pulmonary metastases 8 months after diagnosis is described. The patient has remained disease-free for over 5 years since the initial diagnosis.

Radiofrequency ablation of intra-articular osteoid osteoma of the hip.

Diagnosis and treatment of intra-articular osteoid osteoma is challenging. We present 16 patients with intra-articular osteoid osteomas of the hip treated with percutaneous radiofrequency ablation. Eight osteoid osteomas were located in the femoral head, six in the femoral neck, and two in the acetabulum. Three of the 16 patients had had an incorrect previous diagnosis. Percutaneous radiofrequency ablation was a clinical and technical success in all 16 patients. Within the first 24 h after the procedure, pain improved in all patients. Five patients had pain relief within the first 3 days after the procedure, nine patients within the first week and two patients within 2 weeks. Residual or recurrent symptoms were not reported by the last follow-up. At the 12-month follow-up, computed tomography and magnetic resonance imaging showed complete ossification and bone regeneration at the site of the lesion in three patients, partial ossification in six patients and no changes in seven patients. Computed tomography-guided percutaneous radiofrequency ablation is a simple, minimally invasive, safe and effective method for the treatment of most intra-articular osteoid osteomas.