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Zanzalintinib is a multitargeted tyrosine-kinase inhibitor that, when combined with atezolizumab, showed promising antitumour activity and manageable toxicity in a phase 1 study. We aimed to compare the efficacy and safety of zanzalintinib–atezolizumab versus regorafenib in patients with previously treated metastatic colorectal cancer. STELLAR-303 is a global, randomised, open-label, phase 3 trial done at 121 centres (including hospitals, academic medical centres, and specialised cancer research facilities) in 16 countries. Patients aged 18 years and older with confirmed metastatic adenocarcinoma of the colon or rectum, who had previously received standard-of-care therapy, and did not have microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) tumours were randomly assigned (1:1) in blocks of four to oral zanzalintinib (100 mg daily) plus intravenous atezolizumab (1200 mg every 3 weeks) or oral regorafenib (160 mg daily on days 1–21 of each 28-day cycle) using an interactive response technology system, stratified by geographical region, RAS status, and presence of liver metastases. Dual primary endpoints were overall survival in the intention-to-treat (ITT) population and in the subset of patients without liver metastases. Safety was assessed in all patients who received at least one dose of study drug. This report is based on a planned overall survival analysis (data cutoff April 30, 2025); the trial is active but not recruiting, and continues to the final overall survival analysis in the subset of patients without liver metastases. This trial is registered with ClinicalTrials.gov (NCT05425940). 1325 patients were screened for eligibility; between Sept 7, 2022, and July 15, 2024, 901 patients were randomly assigned to zanzalintinib–atezolizumab (n=451) or regorafenib (n=450). 528 (59%) patients were male and 373 (41%) were female; 485 (54%) were White, 338 (38%) were Asian, 18 (2%) were Black, 24 (3%) were other races, and 36 (4%) had race not reported. At a median follow-up of 18·0 months (IQR 14·6–21·5), zanzalintinib–atezolizumab showed a significant overall survival benefit versus regorafenib in the ITT population (stratified hazard ratio [HR] 0·80 [95% CI 0·69–0·93]; p=0·0045) with a median overall survival of 10·9 months (95% CI 9·9–12·1) versus 9·4 months (8·5–10·2). At the interim analysis of overall survival in the subset of patients without liver metastases, the stratified HR for zanzalintinib–atezolizumab versus regorafenib was 0·79 (95% CI 0·61–1·03); p=0·087 (median overall survival 15·9 months [95% CI 13·5–17·6] vs 12·7 months [10·9–15·5]). Grade 3 or worse treatment-related adverse events occurred in 268 (60%) of 446 patients receiving zanzalintinib–atezolizumab and 161 (37%) of 434 patients receiving regorafenib. There were five (1%) treatment-related deaths in the zanzalintinib–atezolizumab group and one (<1%) in the regorafenib group. STELLAR-303 is the first phase 3 trial to show a significant improvement in overall survival with an immunotherapy-based regimen, zanzalintinib–atezolizumab, in patients with relapsed or refractory metastatic colorectal cancer that is not MSI-H or dMMR. This combination represents a chemotherapy-free treatment option with a novel mechanism of action for heavily pretreated patients in need of improved therapies. Exelixis.

BackgroundCOM701, a novel first-in-class immune checkpoint inhibitor (ICI) binds to poliovirus receptor related immunoglobulin domain containing (PVRIG) leading to enhanced activation of T and NK-cells. COM701 in combination with nivolumab has a favorable safety profile, is well tolerated and demonstrates antitumor activity.1 We hypothesized that the addition of BMS-986207 as a triplet thereby inhibiting the DNAM axis will have an acceptable safety/tolerability profile. We present preliminary results on safety/tolerability and pharmacokinetics (PK) parameters.MethodsUsing an accelerated titration and 3+3 study design we enrolled 14 patients (pts) with advanced solid tumors. Doses of COM701 were 0.3, 1, 3, 10 or 20 [mg/kg IV Q4 wks]; in combination with nivolumab and BMS-986207 (both 480 mg IV Q4 wks). Key objectives were to evaluate the safety and tolerability, to determine the recommended dose for expansion (RDFE) and to characterize preliminary pharmacokinetic parameters. Key inclusion criteria: Age ≥ 18 yrs, histologically confirmed locally advanced or metastatic solid malignancy and has exhausted all available standard treatments. Key exclusion criteria: history of immune-related toxicities on prior immunotherapy treatment leading to discontinuation.ResultsIn the safety population [N=14], 12 pts reported treatment emergent adverse events (TEAEs). The most frequent TEAES [≥3 pts] were fatigue 5 pts (36%), pyrexia 3 pts (21%), vomiting 3 pts (21%). No DLTs were reported in any of the dose levels. The most frequent tumor types enrolled: CRC (n=3), and prostate, melanoma and OVCA/primary peritoneal cancer (n=2 each). Median number of prior therapies was 10 (range 1–19). Four pts had received prior immunotherapy. Serious adverse events [≥2 pts] were 2 pts (14%) with G3 abdominal pain, 2 pts (14%) with vomiting (1pt with G1/2 vomiting, 1 pt with G3 vomiting) all assessed by the investigator as unrelated to study drug. Preliminary PK profiles of COM701 were generally dose proportional.ConclusionsCOM701 in combination with BMS-986207 and nivolumab demonstrates a favorable safety, tolerability and PK profiles. COM701 20 mg/kg has been selected as the RDFE in combination with BMS-986207 and nivolumab (both 480 mg) all administered IV Q4 wks. The expansion cohorts are enrolling pts with platinum resistant ovarian cancer and endometrial cancer. Data cutoff 28 Jun 2021.AcknowledgementsThis study is in collaboration with Bristol Myers Squibb.Trial RegistrationNCT04570839ReferencesVaena, DA, Fleming GF et al. COM701 with or without nivolumab: Results of an ongoing phase 1 study of safety, tolerability and preliminary antitumor activity in patients with advanced solid malignancies (NCT03667716). J Clin Oncol 2021;39: (suppl 15; abstr 2504).Ethics ApprovalThe study obtained ethics approval form all the participating sites. All study participants gave informed consent before taking part.- 0002: START2020.15- 0003: 20210109- 0005: IRB20-1549- 0006: 21-060- 0007: IRB-AAAT4904- 0012: 2020-0755- 0013: STMW2020.16- 0015: 20210109

It is thought that equal numbers of invasive and noninvasive recurrences develop after conservative treatment for ductal carcinoma in situ. We analyzed our data to see if this was true. A prospective database of 878 conservatively treated patients with ductal carcinoma in situ was analyzed. Among 551 excision patients, there were 88 recurrences. Thirty-five percent were invasive. Among 327 excision plus radiotherapy patients, there were 59 recurrences. Fifty-three percent were invasive. In an attempt to predict which patients develop invasive recurrences, prolonged time to recurrence was the only statistically significant factor. The median time to local recurrence for irradiated patients was more than twice as long when compared with nonirradiated patients, during which there is more time for local recurrence to progress to invasion. Irradiated patients had more breast scarring, making diagnosis by palpation and mammography harder. Irradiated patients develop invasive recurrences at a statistically higher rate than nonirradiated patients. Follow-up evaluation with magnetic resonance imaging should be considered.

\"ARE you going to use those yellow pieces of paper Papa just gave to you, Mamma? May I have one for my doll's dress?

The feathered inhabitants of the woods, who have lived in shy seclusion, are now sought out by bird clubs and by solitary ramblers. Opera-glass and patient watching reveal in part the secrets of the forest, but the birds still keep a woodland reserve Study them as we will, we are the seekers, and are seldom met halfway.

Silicosis due to artificial stone (AS) has emerged over the last decade as an increasing global issue. We report the first eight UK cases. All were men; median age was 34 years (range 27–56) and median stone dust exposure was 12.5 years (range 4–40) but in 4 cases was 4–8 years. One is deceased; two were referred for lung transplant assessment. All cases were dry cutting and polishing AS worktops with inadequate safety measures. Clinical features of silicosis can closely mimic sarcoidosis. UK cases are likely to increase, with urgent action needed to identify cases and enforce regulations.

Thanks to the interest of the grown-ups, we became last week pretty \"warm\" upon the question of the authorship and first publication of The Snow Bird. This week's correspondence completes the quest, and brings out the last and very interesting facts in the case. First comes a Passenger who was related to the author of the poem:

[PREEYA KALIDAS] says: I CONSIDER myself to be British Asian, yet my whole culture is Asian. However, my life is quite unconventional for an Asian girl. Although I've never faced any direct racism when I went for work, I think its telling that glossy magazines are afraid to put black or Asian models on their covers, apart from Naomi Campbell. Hopefully things will get easier for the new generation of Asian girls. There are lots of career opportunities out there for both Asian and non-Asian women - it's an exciting time for all of us.