Randomized, phase II selection study of ramucirumab and paclitaxel versus FOLFIRI in refractory small bowel adenocarcinoma: SWOG S1922

Background: Small bowel adenocarcinoma is a rare malignancy with limited evidence to support the choice of systemic chemotherapy beyond the frontline setting. Though second-line therapy has historically been extrapolated from colorectal cancers, recent molecular data has demonstrated small bowel adenocarcinoma to be genomically unique when compared to either colon or gastric cancer. Retrospective analyses of irinotecan- and taxane-based therapies and one prospective phase II clinical trial of nab-paclitaxel have demonstrated clinical activity in this cancer. Ramucirumab/paclitaxel represents an active combination in the management of gastric cancer. SWOG 1922 evaluates the use of FOLFIRI or ramucirumab/paclitaxel in the second- and later-line setting for small bowel adenocarcinoma. Methods: This is randomized, phase II, selection design clinical trial of FOLFIRI (5-fluorouracil, leucovorin and irinotecan) every two weeks or ramucirumab D1,15 and paclitaxel D1,8,15 every 4 weeks with the primary endpoint of progression-free survival (PFS). Secondary endpoints include response rate, overall survival, and safety. Archived paraffin tumor tissue collection and serial blood collections are included for correlative analyses. Key eligibility criteria include having mismatch repair proficient/microsatellite stable small bowel adenocarcinoma (ampullary location excluded); metastatic or locally advanced unresectable disease; prior fluoropyrimidine and/or oxaliplatin therapy; no prior treatment with irinotecan, ramucirumab, or taxanes; no recent bleeding, blood clots, or bowel perforation/fistula; and Zubrod performance status of 0/1. Measurable disease is not required. The null hypothesis is median PFS of 2.5 months. If a median PFS of at least 3.5 months is observed in one or both arms, the goal is to choose the better regimen with respect to this endpoint. The design provides a 90% probability of selecting the more active arm, assuming a hazard ratio of 1.4, if both arms meet this threshold. This trial is open and, as of September 1, 2021, 21 of 94 planned patients have been enrolled

Cetuximab as Second-Line Therapy in Patients with Metastatic Esophageal Adenocarcinoma: A Phase II Southwest Oncology Group Study (S0415)

IntroductionEsophageal adenocarcinomas commonly express the epidermal growth factor receptor. This trial assessed the 6-month overall survival probability in metastatic esophageal cancer patients treated with cetuximab as second-line therapy.MethodsThis was a multicenter, open-label phase II study of single-agent cetuximab for metastatic esophageal adenocarcinoma patients who failed one prior chemotherapy regimen. Adequate organ function and Zubrod performance status of 0 to 2 were required. Patients received cetuximab 400 mg/m2 intravenously (IV) on week 1 and 250 mg/m2 IV weekly thereafter. The primary objective was to determine 6-month overall survival. Secondary end points included progression-free survival, response rate, and toxicity. Tumor tissue was collected for correlative studies.ResultsSixty-three patients were registered, with eight ineligible or never treated. Fifty-five eligible patients (49 men, 6 women; median age = 61.2 years [range, 30.7–88.5]) were enrolled. Twenty patients survived more than 6 months for a 6-month overall survival rate of 36% (95% confidence interval [CI]: 24–50%). The median overall survival was 4.0 months (95% CI: 3.2–5.9). Median progression-free survival was 1.8 months (95% CI: 1.7–1.9). One partial response and two unconfirmed partial responses were observed. Two patients experienced grade 4 fatigue. There was one treatment-related death due to pneumonitis. Germline polymorphisms of epidermal growth factor receptor, epidermal growth factor, interleukin (IL)-8, cyclooxygenase (COX)-2, vascular epidermal growth factor receptor (VEGF), CCND1, neuropilin 1 (NRP1), and K-ras mutational status were not associated with response or survival.ConclusionsThe 6-month overall survival rate of 36% observed on this study failed to meet the primary survival objective. Thus, cetuximab alone cannot be recommended in the second-line treatment of metastatic esophageal cancer

Establishing the First Geriatric Medicine Fellowship Program in Ghana

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/151282/1/jgs16014.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/151282/2/jgs16014_am.pd

A randomized phase 2 study of trastuzumab and pertuzumab (TP) compared to cetuximab and irinotecan (CETIRI) in advanced/metastatic colorectal cancer (mCRC) with HER2 amplification: SWOG S1613

Background: HER2 (ERBB2) over-expression and amplification (HER2+) is seen in a small but distinct subset (2-3%) of mCRC and is enriched in RAS/BRAF wild type (WT) tumors. This subset is characterized by a limited response to anti-epidermal growth factor receptor monoclonal antibodybased (anti-EGFR) therapy and a promising response to dual-HER2 inhibition. Methods: In this multicenter, open label, randomized, phase 2 trial, we enrolled 54 patients with RAS/BRAF WT HER2+ mCRC who had had disease progression after 1 or 2 previous therapies. HER2 status was confirmed centrally with immunohistochemistry (IHC) and in-situ hybridization (ISH). HER2+ was defined as IHC 3+ or 2+ and ISH amplified (dual-probe HER2/CEP17 ratio \u3e 2.0). Patients were then randomly assigned in a 1:1 ratio to receive either TP (trastuzumab [loading 8 mg/kg then 6 mg/kg] + pertuzumab [loading 840 mg then 420 mg] every 3 weeks) or CETIRI (cetuximab 500 mg/m2 + irinotecan 180 mg/m2 every 2 weeks). Crossover was allowed for patients on CETIRI arm to TP (cTP) after progression. Restaging (per RECIST v1.1) was performed at 6 and 12 weeks and then every 8 weeks until progression. The primary endpoint was progression-free survival (PFS). Key secondary endpoints were overall response rate (ORR), overall survival (OS) and safety. Results: A total of 54 (out of planned 62 due to low accrual) patients were randomized to TP (26) and CETIRI (28) between 10/2017 and 12/2021. By 8/18/2022, 20 patients had crossed over to cTP arm. One CETIRI patient was not analyzable. The results for key endpoints by protocol defined stratification factors, prior irinotecan (Piri) (yes or no) and HER2/CEP17 ratio (HCR) (\u3e5 or ≤5), are summarized as of data cut-off of 9/6/2022. PFS did not vary significantly by treatment: medians 4.4 (95%CI: 1.9 - 7.6) months in TP group and 3.7 (95%CI: 1.6 - 6.7) months in CETIRI group (p = 0.35). Grade≥3 adverse events occurred in 23%, 46% and 40% of patients in TP, CETIRI and cTP groups. Conclusions: Dual-HER2 inhibition with TP appears to be a safe and effective treatment option for patients with RAS/BRAF WT HER2+ mCRC with a promising response rate of31%.Higher level of HER2 amplification may provide a greater degree of clinical benefit from TP compared to CETIRI. Future correlative efforts will explore biomarkers of response/resistance with this strategy

Tapinarof Cream 1% Once Daily for the Treatment of Plaque Psoriasis: Case Photography of Clinical Outcomes from Three Phase 3 Trials

Tapinarof cream 1% (VTAMA(®); Dermavant Sciences, Inc.) is a non-steroidal, topical, aryl hydrocarbon receptor agonist approved by the US Food and Drug Administration (FDA) to treat plaque psoriasis in adults and under investigation for the treatment of psoriasis in children down to 2 years of age, and for atopic dermatitis in adults and children down to 2 years of age. The PSOARING phase 3 clinical trial program evaluated tapinarof cream 1% once daily (QD) in adults with mild to severe plaque psoriasis for up to 52 weeks (NCT03956355, NCT03983980, NCT04053387). Here we present case photography documenting outcomes in the PSOARING trials. Cases illustrate various outcomes across different body areas, including responses meeting the formal FDA-mandated regulatory endpoint of a Physician Global Assessment (PGA) score of 0 (clear) or 1 (almost clear) and a decrease of at least 2 points from baseline at week 12, meaningful clinical improvement not meeting this formal endpoint, patient-reported outcomes, and pre-specified adverse events of special interest (AESIs). Tapinarof cream 1% QD demonstrated rapid and highly statistically significant efficacy, with improvements in disease activity and quality of life. In addition, a high rate (40.9%; n = 312/763) of complete disease clearance (PGA = 0) was achieved, and improvements exceeding National Psoriasis Foundation treatment goals were demonstrated. After first achieving complete disease clearance (PGA = 0), patients treated with tapinarof experienced an approximately 4-month remittive effect off therapy. Incidence and severity of folliculitis and contact dermatitis AESIs were generally mild or moderate, localized to the site of application, and associated with low discontinuation rates. Medical images are of importance in trials of dermatologic therapies to inform clinical decision-making and enhance patient assessment. Tapinarof cream 1% QD is efficacious and well tolerated in patients with mild to severe plaque psoriasis, with clinically relevant improvements seen early in the course of treatment. Clinicaltrials.gov numbers: NCT03956355, NCT03983980, NCT04053387

Can Monkeys Choose Optimally When Faced with Noisy Stimuli and Unequal Rewards?

We review the leaky competing accumulator model for two-alternative forced-choice decisions with cued responses, and propose extensions to account for the influence of unequal rewards. Assuming that stimulus information is integrated until the cue to respond arrives and that firing rates of stimulus-selective neurons remain well within physiological bounds, the model reduces to an Ornstein-Uhlenbeck (OU) process that yields explicit expressions for the psychometric function that describes accuracy. From these we compute strategies that optimize the rewards expected over blocks of trials administered with mixed difficulty and reward contingencies. The psychometric function is characterized by two parameters: its midpoint slope, which quantifies a subject's ability to extract signal from noise, and its shift, which measures the bias applied to account for unequal rewards. We fit these to data from two monkeys performing the moving dots task with mixed coherences and reward schedules. We find that their behaviors averaged over multiple sessions are close to optimal, with shifts erring in the direction of smaller penalties. We propose two methods for biasing the OU process to produce such shifts

Aberrant development corrected in adult-onset Huntington's disease iPSC-derived neuronal cultures via WNT signaling modulation

Aberrant neuronal development and the persistence of mitotic cellular populations have been implicated in a multitude of neurological disorders, including Huntington's disease (HD). However, the mechanism underlying this potential pathology remains unclear. We used a modified protocol to differentiate induced pluripotent stem cells (iPSCs) from HD patients and unaffected controls into neuronal cultures enriched for medium spiny neurons, the cell type most affected in HD. We performed single-cell and bulk transcriptomic and epigenomic analyses and demonstrated that a persistent cyclin D1+ neural stem cell (NSC) population is observed selectively in adult-onset HD iPSCs during differentiation. Treatment with a WNT inhibitor abrogates this NSC population while preserving neurons. Taken together, our findings identify a mechanism that may promote aberrant neurodevelopment and adult neurogenesis in adult-onset HD striatal neurons with the potential for therapeutic compensation

Admission to hospital for bronchiolitis in England: Trends over five decades, geographical variation and association with perinatal characteristics and subsequent asthma

Background: Admission of infants to hospital with bronchiolitis consumes considerable healthcare resources each winter. We report an analysis of hospital admissions in England over five decades. Methods: Data were analysed from the Hospital In-Patient Enquiry (HIPE, 1968-1985), Hospital Episode Statistics (HES, 1989-2011), Oxford Record Linkage Study (ORLS, 1963-2011) and Paediatric Intensive Care Audit Network (PICANet, 2003-2012). Cases were identified using International Classification of Diseases (ICD) codes in discharge records. Bronchiolitis was given a separate code in ICD9 (used in England from 1979). Geographical variation was analysed using Local Authority area boundaries. Maternal and perinatal risk factors associated with bronchiolitis and subsequent admissions for asthma were analysed using record-linkage. Results: All-England HIPE and HES data recorded 468 138 episodes of admission for bronchiolitis in infants aged <1 year between 1979 and 2011. In 2011 the estimated annual hospital admission rate was 46.1 (95% CI 45.6 to 46.6) per 1000 infants aged <1 year. Between 2004 and 2011 the rates rose by an average of 1.8% per year in the all-England HES data, whereas admission rates to paediatric intensive care changed little (1.3 to 1.6 per 1000 infants aged <1 year). A fivefold geographical variation in hospital admission rates was observed. Young maternal age, low social class, low birth weight and maternal smoking were among factors associated with an increased risk of hospital admission with bronchiolitis. Conclusions: Hospital admissions for infants with bronchiolitis have increased substantially in recent years. However, cases requiring intensive care have changed little since 2004

Pharmacological interventions for chronic pain in children:an overview of systematic reviews

We know little about the safety or efficacy of pharmacological medicines for children and adolescents with chronic pain, despite their common use. Our aim was to conduct an overview review of systematic reviews of pharmacological interventions that purport to reduce pain in children with chronic noncancer pain (CNCP) or chronic cancer-related pain (CCRP). We searched the Cochrane Database of Systematic Reviews, Medline, EMBASE, and DARE for systematic reviews from inception to March 2018. We conducted reference and citation searches of included reviews. We included children (0-18 years of age) with CNCP or CCRP. We extracted the review characteristics and primary outcomes of ≥30% participant-reported pain relief and patient global impression of change. We sifted 704 abstracts and included 23 systematic reviews investigating children with CNCP or CCRP. Seven of those 23 reviews included 6 trials that involved children with CNCP. There were no randomised controlled trials in reviews relating to reducing pain in CCRP. We were unable to combine data in a meta-analysis. Overall, the quality of evidence was very low, and we have very little confidence in the effect estimates. The state of evidence of randomized controlled trials in this field is poor; we have no evidence from randomised controlled trials for pharmacological interventions in children with cancer-related pain, yet cannot deny individual children access to potential pain relief. Prospero ID: CRD42018086900.</p