Comparison of serial amnioinfusion strategies for isolated early-onset fetal renal anhydramnios.

Introduction The optimal protocol for serial amnioinfusions to maintain amniotic fluid in pregnancies with early onset-fetal renal anhydramnios before 22 weeks is not known. We compared the performance of two different approaches. Methods A secondary analysis was conducted of serial amnioinfusions performed by a single center during the external pilot and feasibility phases of the Renal Agenesis Fetal Therapy (RAFT) trial. During the external pilot, higher amnioinfusion volumes were given less frequently; in the feasibility study, smaller volume amnioinfusions were administered more frequently. Procedural details, complications, and obstetric outcomes were compared between the two groups using Pearson's chi-squared or Fisher's Exact tests for categorical variables and Student's t-tests or Wilcoxon Rank-Sum tests for continuous variables. The adjusted association between procedural details and chorioamniotic separation was obtained through a multivariate repeated measure logistic regression model. Results Eleven participants underwent 159 amnioinfusions (external pilot: three patients, 21 amnioinfusions; feasibility: eight patients, 138 amnioinfusions). External pilot participants had fewer amnioinfusions (7 vs. 19.5 in the feasibility group, p = 0.04), larger amnioinfusion volume (750 vs. 500 mL, p < 0.01), and longer interval between amnioinfusions (6 [4-7] vs. 4 [3-5] days, p < 0.01). In the external pilot, chorioamniotic separation was more common (28.6% vs. 5.8%, p < 0.01), preterm prelabor rupture of membranes (PPROM) occurred sooner after amnioinfusion initiation (28 ± 21.5 vs. 75.6 ± 24.1 days, p = 0.03), and duration of maintained amniotic fluid between first and last amnioinfusion was shorter (38 ± 17.3 vs. 71 ± 19 days, p=0.03), compared to the feasibility group. While delivery gestational age was similar (35.1 ± 1.7 vs. 33.8 ± 1.5 weeks, p=0.21), feasibility participants maintained amniotic fluid longer. Conclusion Small volume serial amnioinfusions performed more frequently maintain normal amniotic fluid volume longer because of delayed occurrence of PPROM.

FDA Approval Summary: Durvalumab and Pembrolizumab, Immune Checkpoint inhibitors for the Treatment of Biliary Tract Cancer.

On September 2, 2022, the Food and Drug Administration (FDA) approved durvalumab in combination with cisplatin and gemcitabine, for the treatment of patients with unresectable or metastatic biliary tract cancers (BTC). On October 31, 2023, the FDA approved pembrolizumab in combination with cisplatin and gemcitabine for the same indication. Approvals were based on two randomized, multiregional, placebo-controlled trials, which randomly allocated patients to receive durvalumab (TOPAZ-1) or pembrolizumab (KEYNOTE-966) in combination with chemotherapy or placebo in combination with chemotherapy. Overall survival (OS) was the primary endpoint in both studies. In both studies, a statistically significant and clinically meaningful improvement in OS was demonstrated. In the TOPAZ-1 trial the median OS of patients receiving durvalumab was 12.8 months (95% confidence interval [CI] 11.1, 14.0) and 11.5 months (95% CI 10.1, 12.5) in patients receiving placebo (HR 0.80 [95% CI 0.66, 0.97]). In the KEYNOTE-966 trial, the median OS of patients receiving pembrolizumab was 12.7 months (95% CI 11.5, 13.6) and 10.9 months (95% CI 9.9, 11.6) in patients receiving placebo (HR 0.83 [95% CI 0.72, 0.95]). The addition of checkpoint inhibitors to standard of care chemotherapy for this indication did not reveal any new adverse event signals and the safety profile was generally consistent with the known clinical experience with durvalumab, pembrolizumab, and the backbone chemotherapy regimen. The approvals of durvalumab and pembrolizumab in combination with standard of care cisplatin and gemcitabine for the treatment of unresectable or metastatic BTC add two new therapeutic option for these patients.

FDA Approval Summary: Fruquintinib for the Treatment of Refractory Metastatic Colorectal Cancer.

On November 8, 2023, the FDA approved fruquintinib, an inhibitor of vascular endothelial growth factor receptors (VEGFR)-1, -2, and -3, for the treatment of patients with metastatic colorectal cancer (mCRC) who have been previously treated with fluoropyrimidine­, oxaliplatin­, and irinotecan­based chemotherapy, an anti­VEGF therapy, and, if RAS wild­type and medically appropriate, an anti EGFR therapy. Approval was based on Study FRESCO-2, a globally-conducted, double-blind, placebo-controlled randomized trial. The primary endpoint was overall survival (OS). The key secondary endpoint was progression-free survival (PFS). A total of 691 patients were randomized (461 and 230 into the fruquintinib and placebo arms, respectively). Fruquintinib provided a statistically significant improvement in OS with a hazard ratio (HR) of 0.66 (95% CI: 0.55, 0.80; p<0.001). The median OS was 7.4 months (95% CI: 6.7, 8.2) in the fruquintinib arm and 4.8 months (95% CI: 4.0, 5.8) for the placebo arm. Adverse events observed were generally consistent with the known safety profile associated with inhibition of the VEGFR. The results of FRESCO-2 were supported by the FRESCO study, a double-blind, single country, placebo-controlled, randomized trial in patients with refractory mCRC who have been previously treated with fluoropyrimidine­, oxaliplatin­, and irinotecan­based chemotherapy. In FRESCO, the OS HR was 0.65 (95% CI: 0.51, 0.83; p<0.001). FDA concluded that the totality of the evidence from FRESCO-2 and FRESCO supported an indication for patients with mCRC with prior treatment with fluoropyrimidine, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and if RAS wild­type and medically appropriate, an anti-EGFR therapy.

Frailty as an Effect Modifier in Randomized Controlled Trials: A Systematic Review.

BACKGROUND: The effect of clinical interventions may vary by patients' frailty status. Understanding treatment effect heterogeneity by frailty could lead to frailty-guided treatment strategies and reduce overtreatment and undertreatment. This systematic review aimed to examine the effect modification by frailty in randomized controlled trials (RCTs) that evaluate pharmacological, non-pharmacological, and multicomponent interventions. METHODS: We searched PubMed, Web of Science, EMBASE, and ClinicalTrial.gov, from their inception to 8 December 2023. Two reviewers independently extracted trial data and examined the study quality with senior authors. RESULTS: Sixty-one RCTs that evaluated the interaction between frailty and treatment effects in older adults were included. Frailty was evaluated using different tools such as the deficit accumulation frailty index, frailty phenotype, and other methods. The effect of several pharmacological interventions (e.g., edoxaban, sacubitril/valsartan, prasugrel, and chemotherapy) varied according to the degree of frailty, whereas other treatments (e.g., antihypertensives, vaccinations, osteoporosis medications, and androgen medications) demonstrated consistent benefits across different frailty levels. Some non-pharmacological interventions had greater benefits in patients with higher (e.g., chair yoga, functional walking, physical rehabilitation, and higher dose exercise program) or lower (e.g., intensive lifestyle intervention, psychosocial intervention) levels of frailty, while others (e.g., resistance-type exercise training, moderate-intensive physical activity, walking and nutrition or walking) produced similar intervention effects. Specific combined interventions (e.g., hospital-based disease management programs) demonstrated inconsistent effects across different frailty levels. DISCUSSION: The efficacy of clinical interventions often varied by frailty levels, suggesting that frailty is an important factor to consider in recommending clinical interventions in older adults. REGISTRATION: PROSPERO registration number CRD42021283051.

Genetic and Functional Analyses of Cutibacterium Acnes Isolates Reveal the Association of a Linear Plasmid with Skin Inflammation.

Cutibacterium acnes is a commensal bacterium on the skin that is generally well-tolerated, but different strain types have been hypothesized to contribute to the disease acne vulgaris. To understand how some strain types might contribute to skin inflammation, we generated a repository of C. acnes isolates from skin swabs of healthy subjects and subjects with acne and assessed their strain-level identity and capacity to stimulate cytokine release. Phylotype II K-type strains were more frequent on healthy and nonlesional skin of subjects with acne than those isolated from lesions. Phylotype IA-1 C-type strains were increased on lesional skin compared with those on healthy skin. The capacity to induce cytokines from cultured monocyte-derived dendritic cells was opposite to this action on sebocytes and keratinocytes and did not correlate with the strain types associated with the disease. Whole-genome sequencing revealed a linear plasmid in high-inflammatory isolates within similar strain types that had different proinflammatory responses. Single-cell RNA sequencing of mouse skin after intradermal injection showed that strains containing this plasmid induced a higher inflammatory response in dermal fibroblasts. These findings revealed that C. acnes strain type is insufficient to predict inflammation and that carriage of a plasmid could contribute to disease.

FDA Approval Summary: Tremelimumab in Combination with Durvalumab for the Treatment of Patients with Unresectable Hepatocellular Carcinoma.

On October 21, 2022, the FDA approved tremelimumab (Imjudo) in combination with durvalumab for adult patients with unresectable hepatocellular carcinoma. The approval was based on the results from the HIMALAYA study, in which patients with unresectable hepatocellular carcinoma who were naïve to previous systemic treatment were randomly assigned to receive one of three study arms: tremelimumab in combination with durvalumab (n = 393), durvalumab (n = 389), or sorafenib (n = 389). The primary objective of improvement in overall survival (OS) for tremelimumab in combination with durvalumab compared with sorafenib met statistical significance with a stratified HR of 0.78 [95% confidence interval (CI), 0.66-0.92; P = 0.0035]. The median OS was 16.4 months (95% CI, 14.2-19.6) with tremelimumab in combination with durvalumab and 13.8 months (95% CI, 12.3-16.1) with sorafenib. Adverse reactions occurring in ≥20% of patients receiving tremelimumab in combination with durvalumab were rash, fatigue, diarrhea, pruritus, musculoskeletal pain, and abdominal pain. The recommended tremelimumab dose for patients weighing 30 kg or more is 300 mg, i.v., as a single dose in combination with durvalumab 1,500 mg at cycle 1/day 1, followed by durvalumab 1,500 mg, i.v., every 4 weeks. For those weighing less than 30 kg, the recommended tremelimumab dose is 4 mg/kg, i.v., as a single dose in combination with durvalumab 20 mg/kg, i.v., followed by durvalumab 20 mg/kg, i.v., every 4 weeks.

Case report: prolonged durable clinical benefit and low toxicity from combination endocrine therapy in a patient with recurrent endometrial carcinoma.

Background: Endometrial carcinoma is the most common gynecologic cancer, with increasing incidence and mortality. Combination endocrine therapy comprised of tamoxifen and progestational agents has demonstrated promising results in treating recurrent disease. This case report describes the prolonged clinical benefit of treatment with tamoxifen and megestrol acetate in a woman with recurrent, metastatic endometrial endometrioid carcinoma positive for estrogen (ER) and progesterone receptors (PR). Case: A 71-year-old gravida 1 para 1 woman presented with postmenopausal bleeding and vaginal discharge. Pelvic ultrasound and magnetic resonance imaging confirmed a 4.7 cm endometrial mass. The patient underwent a total laparoscopic hysterectomy, bilateral salpingo-oophorectomy, pelvic and para-aortic lymphadenectomy, and cystoscopy; pathology revealed a FIGO stage IA grade 1 ER/PR-positive endometroid endometrial adenocarcinoma. She continued under active surveillance for approximately 42 months until she experienced bone metastases in her pelvis, for which she received radiation therapy. Five months later, pulmonary metastases were detected, and she received six cycles of carboplatin and paclitaxel. She then started megestrol acetate and tamoxifen and has remained clinically stable with minimal side effects and reasonable quality of life for approximately 57 months. Conclusion: Our case suggests that combination endocrine therapy has the potential to provide substantial long-term clinical benefit in women with recurrent endometrial cancer and bone metastases, despite multiple prior treatments, allowing patients to experience stable disease and quality of life. In patients with recurrent endometrioid, ER/PR-positive disease, endocrine therapy alone or in combination with other targeted therapies are regimens that may be considered due to their low overall toxicity.

Institutionalizing Community-engaged Translational Science in an Academic Institution: A Community Stakeholder-Driven Process.

BACKGROUND: Although studies have described the power imbalance in academic-community partnerships, little has been published describing how community-based participatory research-informed practitioners can change academic institutions to promote more effective community-engaged research. OBJECTIVES: This paper describes a university-funded community-based participatory project in which academic researchers and their community partners worked together to articulate, develop and advocate for institutionalizing best practices for equitable partnerships throughout the university. METHODS: Findings derive from a collaborative ethnographic process evaluation. RESULTS: The study describes the integral steps proposed to promote equitable community-university research collaboration, the process by which these principles and best practice recommendations were developed, and the institutional change outcomes of this process. CONCLUSIONS: When universities make even small investments toward promoting and nurturing community-engaged research, the quality of the science can be enhanced to advance health equity and community-university relationships can improve, particularly if based on trust, mutual respect, and openness to accomplish a shared vision.

Duodenal Adenocarcinoma in a patient with Lynch Syndrome. A Case Report and Facts Related to Small Intestine Cancer.

Diagnosing small bowel cancer has been challenging due to its unusual presentation and inaccessibility on endoscopy. A 41-year-old male with a history of irritable bowel syndrome underwent esophagogastroduodenoscopy (EGD) for worsening fatigue and lightheadedness despite iron supplements therapy for low hemoglobin. Initial upper endoscopy showed esophagitis and non-bleeding duodenal bulb ulcer with exudate. Endoscopic ultrasound (EUS) with fine-needle aspiration was done due to persistent concern of malignancy and demonstrated moderately differentiated adenocarcinoma in the second portion of the duodenum. Endoscopic ultrasound with fine-needle aspiration may be a superior approach to diagnosing duodenal carcinoma than EGD alone. Small bowel cancer can be a part of the tumor spectrum of Lynch syndrome. Duodenal adenocarcinomas present at a late stage and portend a poor prognosis. We present a case of duodenal adenocarcinoma in an otherwise healthy individual emphasizing the importance of malignancy in the differential and genetic counseling in individuals with the family risk factor.

"At the End I Have a Say": Engaging the Chinese Community in Advance Care Planning.

CONTEXT: Despite the association of advance care planning (ACP) with improved patient and caregiver outcomes, Chinese American elders have low rates of ACP. OBJECTIVES: Assess ACP facilitators/barriers in the San Francisco (SF) Chinese community and codesign, implement, and test community-based ACP-promoting pilot events. METHODS: A Chinese Community Committee (N = 19 community-based organization leaders, health system representatives, community members) conducted focus groups in Cantonese and English with Chinese older adults (age ≥55), caregivers, and community leaders. The Committee designed and implemented pilot events in-person and online. We analyzed focus group data using thematic analysis; assessed pre-to-post-event readiness to engage in ACP (validated survey; 14 scale, 4 = most ready); and assessed event acceptability. RESULTS: A total of 34 people participated in six focus groups. Themes described Chinese community-specific importance of ACP (e.g., reduces family burden), barriers (e.g., younger generations lack tools to discuss ACP with elders and vice versa), and facilitators (e.g., intergenerational events, culturally/linguistically appropriate materials). Based on focus groups findings, the Committee developed a novel ACP tool and designed intergenerational events. A total of 195 participants attended 10 events; 95% were Chinese, 90% spoke Chinese languages, 80% were women. ACP readiness increased significantly (1.66 [SD 0.84] vs. 2.03 [SD 0.85]; P < 0.001); 94% of participants were comfortable attending and 96% would recommend events. CONCLUSION: Community-developed intergenerational events that highlight the value of ACP and address barriers are acceptable and increase ACP engagement in the Chinese community.

FDA Approval Summary: Tucatinib with Trastuzumab for Advanced Unresectable or Metastatic, Chemotherapy Refractory, HER2-Positive RAS Wild-Type Colorectal Cancer.

On January 19, 2023, the FDA granted accelerated approval to tucatinib in combination with trastuzumab for the treatment of patients with unresectable or metastatic RAS wild-type, HER2-positive colorectal cancer who have received prior treatment with fluoropyrimidine, oxaliplatin, and irinotecan. Approval was based on the pooled analysis of patients receiving tucatinib in combination with trastuzumab in MOUNTAINEER (NCT03043313), an open-label, multicenter trial. The primary endpoint was overall response rate (ORR) by RECIST 1.1 as per blinded central review committee (BIRC) assessment. The main secondary endpoint was duration of response (DOR) per BIRC assessment. Eighty-four eligible patients received the combination tucatinib and trastuzumab. With a median follow-up of 16 months, the ORR was 38% [95% confidence interval (CI): 28-49] and median DOR was 12.4 months (95% CI: 8.5-20.5); 81% of responders had a response lasting more than 6 months. The most common adverse reactions observed in at least 20% of patients receiving tucatinib in combination with trastuzumab were diarrhea, fatigue, rash, nausea, abdominal pain, infusion-related reactions, and fever. FDA concluded that the magnitude of ORR and durable responses observed in patients treated with tucatinib in combination with trastuzumab in the MOUNTAINEER trial are clinically meaningful, particularly in the context of a disease with estimated survival of 6-7 months with available therapy. This is the first approval for the subset of patients with HER2-positive colorectal cancer. This article summarizes the FDA's thought process and review of the data supporting this accelerated approval.

FDA Approval Summary: Futibatinib for Unresectable Advanced or Metastatic, Chemotherapy Refractory Intrahepatic Cholangiocarcinoma with FGFR2 Fusions or Other Rearrangements.

On September 30, 2022, the FDA granted accelerated approval to futibatinib for the treatment of adult patients with previously treated, unresectable, locally advanced or metastatic intrahepatic cholangiocarcinoma (iCCA) with FGFR2 fusions or other rearrangements. Approval was based on Study TAS-120-101, a multicenter open-label, single-arm trial. Patients received futibatinib 20-mg orally once daily. The major efficacy outcome measures were overall response rate (ORR) and duration of response (DoR) as determined by an independent review committee (IRC) according to RECIST v1.1. ORR was 42% (95% confidence interval, 32%-52%). Median DoR was 9.7 months. Adverse reactions occurring in ≥30% patients were nail toxicity, musculoskeletal pain, constipation, diarrhea, fatigue, dry mouth, alopecia, stomatitis, and abdominal pain. The most common laboratory abnormalities (≥50%) were increased phosphate, increased creatinine, decreased hemoglobin, and increased glucose. Ocular toxicity (including dry eye, keratitis, and retinal epithelial detachment) and hyperphosphatemia are important risks of futibatinib, which are listed under Warnings and Precautions. This article summarizes the FDA's thought process and data supporting the approval of futibatinib.

The development and validation of a patient-reported outcome measure to assess financial hardship among older cancer survivors in China: hardship and recovery with distress survey.

Background: Financial hardship has been described as a patient's economic experiencefollowing cancer-related treatment. Standardized patient-reported outcome measures(PROM) to assess this distress has not been well-studied, especially among older cancer survivors. Objective: The aim of this study was to develop and validate PROM for assessing the financial hardship of older cancer survivors in China. Methods: Items were generated using qualitative interviews and literature review. Items were screened based on Delphi expert consultation and patients' opinions. Item response theory (IRT) and classical test theory (CTT) were used to help reduce items. Retained items formed a pilot instrument that was subjected to psychometric testing. A cut-off score for the new instrument for predicting poor quality of life was identified by receiver operating characteristic (ROC) analysis. Results: Qualitative interviews and literature review generated 135 items, which were reduced to 60 items because of redundancy. Following Delphi expert consultation and patients' evaluation, 24 items with high importance were extracted. Sixteen items were selected due to satisfactory statistical analysis based on CTT and IRT. Ten items were retained and comprised 2 domains after loadings in exploratory factor analysis (EFA). Internal consistency was satisfactory (α = 0.838). Test-retest reliability was good (intraclass correlation, 0.909). The ROC analysis suggested that the cut-off of 18.5 yielded an acceptable sensitivity and specificity. Conclusions: The PROM for Hardship and Recovery with Distress Survey (HARDS) consists of 10 items that specifically reflect the experiences of financial hardship among older Chinese cancer survivors, and it also showed good reliability and validity in clinical settings.

Exceptional responses to PARP inhibitors in patients with metastatic breast cancer in oncologic crisis.

PURPOSE: Cancers deficient in homologous recombination DNA repair, such as those with BRCA1 or BRCA2 (BRCA1/2) mutations rely on a pathway mediated by the enzyme poly(adenosine diphosphate-ribose) polymerase (PARP). PARP inhibitors (PARPi's) have demonstrated efficacy in treating patients with germline (g)BRCA1/2, somatic (s)BRCA1/2, and gPALB2 mutations in clinical trials. However, patients with a poor performance status (PS) and those with severe organ impairment are often excluded from clinical trials and cancer-directed treatment. METHODS: We report the cases of two patients with metastatic breast cancer who had poor PS, significant visceral disease, and gPALB2 and sBRCA mutations, who derived significant clinical benefit from treatment with PARP inhibition. RESULTS: Patient A had germline testing demonstrating a heterozygous PALB2 pathogenic mutation (c.3323delA) and a BRCA2 variant of unknown significance (c.9353T>C), and tumor sequencing revealed PALB2 (c.228_229del and c.3323del) and ESR1 (c.1610A>C) mutations. Patient B was negative for pathologic BRCA mutations upon germline testing, but tumor sequencing demonstrated somatic BRCA2 copy number loss and a PIK3CA mutation (c.1633G>A). Treatment with PARPi's in these two patients with an initial PS of 3-4 and significant visceral disease resulted in prolonged clinical benefit. CONCLUSION: Patients with a poor PS, such as those described here, may still have meaningful clinical responses to cancer treatments targeting oncogenic drivers. More studies evaluating PARPi's beyond gBRCA1/2 mutations and in sub-optimal PS would help identify patients who may benefit from these therapies.

Improving Dose-Optimization Processes Used in Oncology Drug Development to Minimize Toxicity and Maximize Benefit to Patients.

This review highlights strategies to integrate dose optimization into premarketing drug development and discusses the underlying statistical principles. Poor dose optimization can have negative consequences for patients, most commonly because of toxicity, including poor quality of life, reduced effectiveness because of inability of patients to stay on current therapy or receive subsequent therapy because of toxicities, and difficulty in developing combination regimens. We reviewed US Food and Drug Administration initial approvals (2019-2021) of small molecules and antibody-drug conjugates for oncologic indications to determine the proportion with a recommended dosage at the maximum tolerated dose or the maximal administered dose, to characterize the use of randomized evaluations of multiple dosages in dose selection, to describe the frequency of dose modifications at the recommended dosage, and to identify case examples that highlight key principles for premarket dose optimization during drug development. Herein, we highlight major principles for dose optimization and review examples of recent US Food and Drug Administration approvals that illustrate how investigation of dose- and exposure-response relationships and use of randomized dose trials can support dose optimization. Although there has been some progress, dose optimization through randomized dose evaluation in oncology trials is not routinely conducted. Dose optimization is essential to ensure that patients receive therapies which maximize efficacy while minimizing toxicity.