A Phase I Dose Escalation Study of the Safety,Tolerability, and Pharmacokinetics of Ipilimumab in Chinese Patients with Select Advanced Solid Tumors

Lessons Learned

• The overall safety profiles of ipilimumab 3 mg/kg and 10 mg/kg administered every 3 weeks, were consistent between Chinese patients with solid tumors in the current study and patients from previous U.S. ipilimumab monotherapy studies. No new safety signals were identified.
• The mean systemic exposures to ipilimumab (assessed by first dose area under the curve during the dosing interval and maximum serum concentration) were numerically lower in the Chinese patient population than in U.S. patients for both 3 mg/kg and 10 mg/kg doses; however, the range of serum concentrations in the Chinese and U.S. populations overlapped (3 mg/kg and 10 mg/kg), suggesting that ipilimumab pharmacokinetics was ethnically insensitive in this study.

BackgroundThis phase I, open‐label study assessed ipilimumab safety, tolerability, pharmacokinetics (PK), immunogenicity, and antitumor activity in Chinese patients with unresectable, metastatic, recurrent malignant melanoma (MM) or nasopharyngeal carcinoma (NPC).MethodsOf 39 patients enrolled, 25 received ipilimumab (11 patients received 3 mg/kg, and 14 patients received 10 mg/kg). Reasons for not receiving treatment were withdrawal of consent (3 patients), no longer meeting the criteria (10 patients), and one recorded as “other.” During the induction phase, patients received ipilimumab (3 mg/kg, i.v.), on day 1 of a 3‐week cycle, to a maximum of four doses or progressive disease (PD). During the maintenance phase at week 24, patients received ipilimumab (3 mg/kg, i.v.) on day 1 of a 12‐week cycle, to a maximum of 3 years or PD. Considering the co‐primary safety and PK endpoints, the successive dosing required nine patients with two or fewer dose‐limiting toxicities during the 42‐day observation period to proceed with a new cohort of nine patients at 10 mg/kg.ResultsIpilimumab safety and PK profiles were similar in Chinese and predominantly White populations. Ipilimumab was well tolerated. Most adverse events (AEs) were grades 1–2 and experienced by 11 patients treated with 3 mg/kg and 14 patients treated with 10 mg/kg. There were no new safety concerns. Incidence of anti‐ipilimumab antibodies was low (1 of 10 in the 3 mg/kg patients and 2 of 13 in the 10 mg/kg patients) and without safety implications. In the 3 mg/kg group, 8 of 11 patients had PD. In the 10 mg/kg group (all NPC, 0 MM patients), 11 of 14 patients had PD. Three patients had stable disease (one at 3 mg/kg and two at 10 mg/kg).ConclusionIpilimumab was well tolerated in Chinese patients, showing similar safety and PK to previous studies in predominantly White populations.     

Acute total hip arthroplasty for older patients with acetabular fractures: A meta-analysis

ObjectiveMultiple treatment options for acetabular fractures in geriatric patients exist. However, no large-scale studies have reported the outcomes of acute total hip arthroplasty (THA) in this patient population. We systematically evaluated all available evidence to characterize clinical outcomes, complications, and revisions of acute THA for acetabular fractures in geriatric patients.MethodsMeta-analysis of 21 studies of 430 acetabular fractures with mean follow-up of 44 months (range, 17−97 months). Two independent researchers searched and evaluated the databases of Ovid, Embase, and United States National Library of Medicine using a Boolean search string up to December 2019. Population demographics and complications, including presence of heterotopic ossification (HO), dislocation, infection, revision rate, neurological deficits, and venous thromboembolic event (VTE), were recorded and analyzed.ResultsWeighted mean Harris Hip Score was 83.3 points, and 20% of the patients had reported complications. The most common complication was HO, with a rate of 19.5%. Brooker grade III and IV HO rates were lower at 6.8%. Hip dislocation occurred at a rate of 6.1%, 4.1% of patients developed VTE, deep infection occurred in 3.8%, and neurological complications occurred in 1.9%. Although the revision rate was described in most studies, we were unable to perform a survival analysis because the time to each revision was described in only a few studies. The revision rate was 4.3%.ConclusionsAcute THA is a viable option for treatment of acetabular fracture and can result in acceptable clinical outcomes and survivorship rates in older patients but with an associated complication rate of approximately 20%. Considering the limited treatment options, THA might be a viable alternative for appropriately selected patients.     

Phase II Study of Panitumumab Monotherapy in Chemotherapy‐Naïve Frail or Elderly Patients with Unresectable RAS Wild‐Type Colorectal Cancer: OGSG 1602

Lessons Learned

• Panitumumab monotherapy showed favorable efficacy and feasibility in the treatment of frail or elderly patients with RAS wild‐type unresectable colorectal cancer.
• It is especially effective for left‐sided tumors; therefore, panitumumab as first‐line treatment could be an additional therapeutic option for frail elderly patients, particularly in those who are unsuitable for upfront oxaliplatin‐based or irinotecan‐based combination regimens.

BackgroundFirst‐line panitumumab monotherapy is expected to be well tolerated and improve survival in patients ineligible for intensive chemotherapy. However, its safety and efficacy in chemotherapy‐naïve frail or elderly patients with unresectable RAS wild‐type (WT) colorectal cancer (CRC) have not been studied. The aim of this phase II trial was to evaluate the efficacy and safety of panitumumab as first‐line treatment.MethodsWe conducted a multicenter phase II study on patients aged ≥76 years or ≥65 years considered unsuitable for intensive chemotherapy. Panitumumab 6 mg/kg of intravenous infusion was administered every 2 weeks. The primary endpoint was disease control rate (DCR). Secondary endpoints included progression‐free survival (PFS), overall survival (OS), response rate (RR), time to treatment failure (TTF), and incidence of grade 3 or 4 toxicities.ResultsThirty‐six patients (median age: 81 [range, 67–88] years) were enrolled between February 2017 and August 2018. Two patients were excluded from the analysis of efficacy: one from lack of image examination at baseline and the other from lack of a measurable lesion. Thirty‐three (91.6%) patients had a performance status (PS) of 0 or 1, whereas two (5.6%) patients and one (2.8%) patient had a PS of 2 and 3, respectively. Twenty‐eight patients (77.8%) had left‐sided CRC, whereas eight (22.2%) had right‐sided CRC. The RR was 50.0% (95% confidence interval [CI], 32.4–67.6), including three patients (8.8%) who had complete responses. A total of 26.5% had stable diseases, resulting in a DCR of 76.5% (90% CI, 61.5–87.7). The RR of patients with left‐ and right‐sided tumors was 65.4% (95% CI, 44.3–82.8) and 0.0% (95% CI, 0.0–36.9), respectively. Major grade 3 or 4 nonhematologic toxicities were rash (n = 6, 16.7%), hypomagnesemia (n = 4, 11.1%), fatigue (n = 3, 8.3%), paronychia (n = 2, 5.6%), and hyponatremia (n = 2, 5.6%). The only grade 3 hematologic toxicity was neutropenia (n = 1, 2.8%).ConclusionPanitumumab monotherapy showed favorable efficacy and feasibility in frail or elderly patients with RAS WT unresectable CRC. Survival analysis including OS, PFS, and TTF is currently in progress.     

内囊预警综合征的临床特征和预后

目的 分析内囊预警综合征（capsular warning syndrome，CWS）的临床特点、影像学特征及治疗预后，
以提高对此病的认识。
方法 回顾性分析战略支援部队特色医学中心神经内科2013年1月-2018年12月收住院治疗的CWS的
临床资料、影像学特征及治疗预后情况。
结果 共12例患者，男性8例（66.67%），中位年龄为60岁。高脂血症9例（75.0%），高血压8例
（66.67%），糖尿病4例（33.33%），肿瘤病史3例（25.0%）。纯运动性卒中4例（33.33%），运动伴有构
音障碍者4例（33.33%），运动及感觉性障碍3例（25.00%），纯感觉障碍1例（8.33%）。影像学示豆纹
动脉供血区新发脑梗死6例（50%）。所有患者给予口服双联抗血小板治疗，其中3例症状复发患者又
给予静脉溶栓和静脉抗血小板治疗。3个月随访，所有患者均未再出现症状发作，10例mRS评分为0
分，2例mRS评分分别为4分及3分。
结论 CWS主要表现为运动障碍，发作刻板，常见原因为动脉粥样硬化性。在本组病例中发现双重
抗血小板治疗有效，静脉溶栓效果不肯定。     

Diffusion-weighted MRI and PET/CT reproducibility in epithelial ovarian cancers during neoadjuvant chemotherapy

PurposeTo investigate the reproducibility of diffusion-weighted (DW) MRI and ¹⁸F-Fluorodeoxyglucose (¹⁸F-FDG)-Positron emission tomography/CT (PET/CT) in monitoring response to neoadjuvant chemotherapy in epithelial ovarian cancer.Materials and methodsTen women (median age, 67 years; range: 41.8–77.3 years) with stage IIIC-IV epithelial ovarian cancers were included in this prospective trial (NCT02792959) between 2014 and 2016. All underwent initial laparoscopic staging, four cycles of carboplatine-paclitaxel-based chemotherapy and interval debulking surgery. PET/CT and DW-MRI were performed at baseline (C0), after one cycle (C1) and before surgery (C4). Two nuclear physicians and two radiologists assessed five anatomic sites for the presence of ≥ 1 lesion. Target lesions in each site were defined and their apparent diffusion coefficient (ADC), maximal standardized uptake value (SUV-max), SUV-mean, SUL-peak, metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were monitored (i.e., 10 patients × 5 sites × 3 time-points). Their relative early and late changes were calculated. Intra/inter-observer reproducibilities of qualitative and quantitative analysis were estimated with Kappa and intra-class correlation coefficients (ICCs).ResultsFor both modalities, inter- and intra-observer agreement percentages were excellent for initial staging but declined later for DW-MRI, leading to lower Kappa values for inter- and intra-observer variability (0.949 and 1 at C0, vs. 0.633 and 0.643 at C4, respectively) while Kappa values remained > 0.8 for PET/CT. Inter- and intra-observer ICCs were > 0.75 for SUV-max, SUL-peak, SUV-mean and their change regardless the time-point. ADC showed lower ICCs (range: 0.013–0.811). ANOVA found significant influences of the evaluation time, the measurement used (ADC, SUV-max, SUV-mean, SUV-max, SUL-peak, MTV or TLG) and their interaction on ICC values (P = 0.0023, P< 0.0001 and P =0.0028, respectively).ConclusionWhile both modalities demonstrated high reproducibility at baseline, only SUV-max, SUL-peak, SUV-mean and their changes maintained high reproducibility during chemotherapy.     

Predicting osimertinib‐treatment outcomes through EGFR mutant‐fraction monitoring in the circulating tumor DNA of EGFR T790M‐positive patients with non‐small cell lung cancer (WJOG8815L)

The WJOG8815L phase II clinical study involves patients with non‐small cell lung cancer (NSCLC) that harbored the EGFR T790M mutation, which confers resistance to EGFR tyrosine kinase inhibitors (TKIs). The purpose of this study was to assess the predictive value of monitoring EGFR genomic alterations in circulating tumor DNA (ctDNA) from patients with NSCLC that undergo treatment with the third‐generation EGFR‐TKI osimertinib. Plasma samples of 52 patients harboring the EGFR T790M mutation were obtained pretreatment (Pre), on day 1 of treatment cycle 4 (C4) or cycle 9 (C9), and at diagnosis of disease progression or treatment discontinuation (PD/stop). CtDNA was screened for EGFR‐TKI‐sensitizing mutations, the EGFR T790M mutation, and other genomic alterations using the cobas EGFR Mutation Test v2 (cobas), droplet digital PCR (ddPCR), and targeted deep sequencing. Analysis of the sensitizing—and T790M—EGFR mutant fractions (MFs) was used to determine tumor mutational burden. Both MFs were found to decrease during treatment, whereas rebound of the sensitizing EGFR MF was observed at PD/stop, suggesting that osimertinib targeted both T790M mutation‐positive tumors and tumors with sensitizing EGFR mutations. Significant differences in the response rates and progression‐free survival were observed between the sensitizing EGFR MF‐high and sensitizing EGFR MF‐low groups (cutoff: median) at C4. In conclusion, ctDNA monitoring for sensitizing EGFR mutations at C4 is suitable for predicting the treatment outcomes in NSCLC patients receiving osimertinib (Clinical Trial Registration No.: UMIN000022076).

Abbreviations

CIs

confidence intervals

ctDNA

circulating tumor DNA

ddPCR

droplet digital PCR

EGFR

epidermal growth factor receptor

MFs

mutant fractions

NGS

next‐generation sequencing

NSCLC

non‐small cell lung cancer

ORR

overall response rate

OS

overall survival

PD

progressive disease

PFS

progression‐free survival

PR

partial response

SD

stable disease

TKI

tyrosine kinase inhibitor

     

Significant reduction of postoperative pain and opioid analgesics requirement with an Enhanced Recovery After Thoracic Surgery protocol

ObjectiveTo evaluate differences in postoperative pain control and opioids requirement in thoracic surgical patients following implementation of an Enhanced Recovery after Thoracic Surgery protocol with a comprehensive postoperative pain management strategy.Material and MethodsA retrospective analysis of a prospectively maintained database of patients undergoing pulmonary resections by robotic thoracoscopy or thoracotomy from January 1, 2017, to January 31, 2019, was conducted. Multimodal pain management strategy (opioid-sparing analgesics, infiltration of liposomal bupivacaine to intercostal spaces and surgical sites, and elimination of thoracic epidural analgesia use in thoracotomy patients) was implemented as part of Enhanced Recovery after Thoracic Surgery on February 1, 2018. Outcome metrics including patient-reported pain levels, in-hospital and postdischarge opioids use, postoperative complications, and length of stay were compared before and after protocol implementation.ResultsIn total, 310 robotic thoracoscopy and 62 thoracotomy patients met the inclusion criteria. This pain management strategy was associated with significant reduction of postoperative pain in both groups with an overall reduction of postoperative opioids requirement. Median in-hospital opioids use (morphine milligram equivalent per day) was reduced from 30 to 18.36 (P = .009) for the robotic thoracoscopy group and slightly increased from 15.48 to 21.0 (P = .27) in the thoracotomy group. More importantly, median postdischarge opioids prescribed (total morphine milligram equivalent) was significantly reduced from 480.0 to 150.0 (P < .001) and 887.5 to 150.0 (P < .001) for the thoracoscopy and thoracotomy groups, respectively. Similar short-term perioperative outcomes were observed in both groups before and following protocol implementation.ConclusionsImplementation of Enhanced Recovery after Thoracic Surgery allows safe elimination of epidural use, better pain control, and less postoperative opioids use, especially a drastic reduction of postdischarge opioid need, without adversely affecting outcomes.     

Advancement of chimeric antigen receptor-natural killer cells targeting hepatocellular carcinoma

With the advance of genome engineering technology, chimeric antigen receptors (CARs)-based immunotherapy has become an emerging therapeutic strategy for tumors. Although initially designed for T cells in tumor immunotherapy, CARs have been exploited to modify the function of natural killer (NK) cells against a variety of tumors, including hepatocellular carcinoma (HCC). CAR-NK cells have the potential to sufficiently kill tumor antigen-expressing HCC cells, independent of major histocompatibility complex matching or prior priming. In this review, we summarize the recent advances in genetic engineering of CAR-NK cells against HCC and discuss the current challenges and prospects of CAR-NK cells as a revolutionary cellular immunotherapy against HCC.