Efficacy, safety, and correlative biomarkers of bintrafusp alfa in recurrent or metastatic nasopharyngeal cancer patients: a phase II clinical trial.

Background: The strategy of dual blockade of TGF-ß and PD-L1 pathways has not been previously tested in platinum-refractory recurrent or metastatic nasopharyngeal cancer (R/M NPC) patients. This study aimed to evaluate the safety and efficacy of bintrafusp alfa in refractory R/M NPC patients. Methods: In this single-arm, single-centre phase II clinical trial, 38 histologically confirmed R/M NPC patients were enrolled and administered with bintrafusp alfa every 2 weeks. Primary endpoint was objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). Secondary endpoints included progression-free survival (PFS), overall survival (OS), duration of response (DOR), and safety. Findings: Thirty-eight patients were accrued (33 men; median age, 54 years). ORR was 23.7% (complete response, n = 2; partial response, n = 7). The median DOR was 19.2 months, median PFS was 2.3 months, median OS was 17.0 months, and 1-year OS rate was 63.2%. Unfortunately, 25 patients (65.7%) progressed within 8 weeks of treatment, 15 patients (39.5%) and 8 patients (21.1%) developed hyper-progressive disease (HPD) per RECIST v1.1 and tumor growth rate (TGR) ratio respectively. Sixteen patients (42.4%) experienced ≥ grade 3 treatment-related adverse events (TRAEs), most commonly anemia (n = 9, 23.7%) and secondary malignancies (n = 4, 10.5%). TRAEs led to permanent treatment discontinuation in 7 patients. Patients with strong suppression of plasma TGFß1 level at week 8 were unexpectedly associated with worse ORR (9.1% vs 44.4%, P = 0.046) and development of HPD. There was no correlation between PD-L1 expression and ORR. Interpretation: Bintrafusp alfa demonstrated modest activity in R/M NPC but high rates of HPD and treatment discontinuation secondary to TRAEs are concerning. Funding: The project was supported by Alice Ho Miu Ling Nethersole Charity Foundation Professorship Endowed Fund and Merck KGaA.

Endoscopic Posterior Ankle Decompression and Release After Total Ankle Arthroplasty.

Accurate positioning of the total ankle arthroplasty implant components with the absence of any hindfoot deformity does not preclude the development of bony impingement. In cases of ankle stiffness after total ankle arthroplasty, the usual limitation is in dorsiflexion. If triceps surae contracture is excluded or persistent restriction remains in ankle dorsiflexion after gastrocnemius recession or tendo-Achilles lengthening, posterior ankle capsulectomy, debridement of posterior ankle gutter, and release of the deep posterior deltoid ligament and the posterior talofibular ligament are indicated. In this Technical Note, the technical details of endoscopic posterior ankle decompression and release after total ankle arthroplasty are described.

Supraligamentous Approach of Lateral Release in Endoscopic Lateral Soft Tissue Procedure.

Many surgical methods are available for hallux valgus, but consensus regarding the best management has yet to be established. Minimally invasive techniques are gaining popularity with the potential advantages of better cosmetic outcome, less postoperative pain, and decreasing recovery time because surgical exposure and deep soft tissue dissection are less extensive and possibly gentler. Recently, techniques of the endoscopic distal soft tissue procedure have been reported, in which an endoscopic approach of the classic distal soft tissue procedure is described. The intermetatarsal ligament, adductor hallucis insertion, and the lateral capsuloligamentous complex of the first metatarsophalangeal joint is released during the endoscopic lateral release. However, the intermetatarsal ligament does not contribute to development of the hallux valgus deformity, and release of the ligament is not necessary for correction of the deformity. Instead, preservation of the intermetatarsal ligament may protect the interdigital nerve and reduce the risk of nerve injury during endoscopic lateral release. In this technical note, the technical details of supraligamentous approach of lateral release in endoscopic lateral soft tissue procedure (or EDSTP) is described. This approach can help to reduce the risk of injury to the interdigital nerve during endoscopic lateral release.

COVID-19 vaccine acceptance and hesitancy among ethnic minorities in Hong Kong.

Ethnic minorities account for 8% of the Hong Kong population, most are Filipino and Indonesian domestic helpers taking care of children and the elderly. To understand the COVID-19 vaccination rates and factors associated with vaccine acceptance of ethnic minorities, we performed a cross-sectional questionnaire study recruiting Hong Kong ethnic minorities aged ≥18 years between 1 July and 18 July 2021 in public areas. Demographics, knowledge about COVID-19, vaccination status, intention and reasons to receive the vaccine, and planning to be re-vaccinated were analyzed. Continuous and categorical variables were compared using unpaired t-test and Chi-square test, respectively. Potential confounders were adjusted using multiple logistic regression. 2,012 ethnic minorities participated, with a mean age of 39 years, of which 97.6% were female, 79.5% were Filipino, and 17.5% were Indonesian. 80.6% of participants were categorized as vaccine acceptance, and 69.2% were willing to be re-vaccinated. There were significantly more Filipinos than Indonesians in the vaccine acceptance group (p < .001). Subjects in the vaccine acceptance group were more likely to have higher education (p < .001), a higher COVID-19 knowledge score (p < .001), received information from the Government website (p = .003) and not from their friends or family members (p = .02), and were more confident in judging the accuracy of the information (p < .001). Logistic regression showed the mean knowledge score (ß = 3.07, p < .001) and receiving information from official Government websites (adjusted OR = 1.37, p = .03) were significant factors that positively influenced vaccine acceptance. The Hong Kong Government should improve COVID-19 vaccination acceptance among ethnic minorities through public education using official channels.

Nasopharyngeal carcinoma MHC region deep sequencing identifies HLA and novel non-HLA TRIM31 and TRIM39 loci.

Despite pronounced associations of major histocompatibility complex (MHC) regions with nasopharyngeal carcinoma (NPC), causal variants underlying NPC pathogenesis remain elusive. Our large-scale comprehensive MHC region deep sequencing study of 5689 Hong Kong Chinese identifies eight independent NPC-associated signals and provides mechanistic insight for disrupted transcription factor binding, altering target gene transcription. Two novel protective variants, rs2517664 (Trs2517664 = 4.6%, P = 6.38 × 10-21) and rs117495548 (Grs117495548 = 3.0%, P = 4.53 × 10-13), map near TRIM31 and TRIM39/TRIM39-RPP21; multiple independent protective signals map near HLA-B including a previously unreported variant, rs2523589 (P = 1.77 × 10-36). The rare HLA-B*07:05 allele (OR < 0.015, P = 5.83 × 10-21) is absent in NPC, but present in controls. The most prevalent haplotype lacks seven independent protective alleles (OR = 1.56) and the one with additional Asian-specific susceptibility rs9391681 allele (OR = 2.66) significantly increased NPC risk. Importantly, this study provides new evidence implicating two non-human leukocyte antigen (HLA) genes, E3 ubiquitin ligases, TRIM31 and TRIM39, impacting innate immune responses, with NPC risk reduction, independent of classical HLA class I/II alleles.

Two-year follow-up of a randomized phase III clinical trial of nivolumab vs. the investigator's choice of therapy in the Asian population for recurrent or metastatic squamous cell carcinoma of the head and neck (CheckMate 141).

BACKGROUND: The present study evaluated the 2-year survival of the Asian population in the CheckMate 141 trial. METHODS: The CheckMate 141 trial included patients with recurrent or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN). In the present study, 34 Asian patients (nivolumab group: 23 patients; investigator's choice of therapy [IC] group: 11 patients) were analyzed. RESULTS: The median overall survival (OS) was 12.1 and 6.2 months for the nivolumab and IC groups, respectively. The estimated 2-year OS rates were 22.7% and 0% for the nivolumab and IC groups, respectively. In the nivolumab group, the patients with any treatment-related adverse events (TRAEs), including skin-related disorders, showed better OS than the patients without any TRAEs. CONCLUSIONS: Nivolumab demonstrated prolonged OS benefits in the Asian population with platinum-refractory R/M SCCHN and a favorable safety profile. TRAEs, including skin-related disorders, may be favorable prognostic factors for nivolumab efficacy. CLINICAL TRIAL REGISTRATION: NCT02105636.

Clinical utility of serial analysis of circulating tumour cells for detection of minimal residual disease of metastatic nasopharyngeal carcinoma.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is an important cancer in Hong Kong. We aim to utilise liquid biopsies for serial monitoring of disseminated NPC in patients to compare with PET-CT imaging in detection of minimal residual disease. METHOD: Prospective serial monitoring of liquid biopsies was performed for 21 metastatic patients. Circulating tumour cell (CTC) enrichment and characterisation was performed using a sized-based microfluidics CTC chip, enumerating by immunofluorescence staining, and using target-capture sequencing to determine blood mutation load. PET-CT scans were used to monitor NPC patients throughout their treatment according to EORTC guidelines. RESULTS: The longitudinal molecular analysis of CTCs by enumeration or NGS mutational profiling findings provide supplementary information to the plasma EBV assay for disease progression for good responders. Strikingly, post-treatment CTC findings detected positive findings in 75% (6/8) of metastatic NPC patients showing complete response by imaging, thereby demonstrating more sensitive CTC detection of minimal residual disease. Positive baseline, post-treatment CTC, and longitudinal change of CTCs significantly associated with poorer progression-free survival by the Kaplan-Meier analysis. CONCLUSIONS: We show the potential usefulness of application of serial analysis in metastatic NPC of liquid biopsy CTCs, as a novel more sensitive biomarker for minimal residual disease, when compared with imaging.

Mobility, prosthesis use and health-related quality of life of bilateral lower limb amputees from the 2008 Sichuan earthquake.

BACKGROUND:: The 2008 Sichuan Earthquake resulted in many amputees, yet due to the rare incidence, few studies have explored the rehabilitation outcomes and quality of life of bilateral lower limb amputees after major natural disasters. OBJECTIVES:: To evaluate rehabilitation outcomes of 17 young and adult bilateral lower limb amputees under the StandTall rehabilitation programme and to identify factors associated with successful functional recovery of bilateral amputees after large-scale disasters. STUDY DESIGN:: Cross-sectional study. METHODS:: Mobility (amputee mobility predictor), prosthesis use (Houghton Scale) and health-related quality of life (Trinity Amputation and Prosthesis Experience Scale, Short Form 12) were evaluated through questionnaires and performance-based assessments. Means of scores were compared using T-tests. RESULTS:: Subjects with bilateral through-knee or transtibial amputations had less activity restriction ( p < 0.01) and higher mobility ( p = 0.03). Subjects using prostheses more than 50% waking time had better general adjustment ( p = 0.02) and less functional restriction ( p = 0.01). Exercise and education were associated with higher mobility ( p = 0.06) and mental quality of life, respectively ( p = 0.09). CONCLUSIONS:: Amputation level and knee joint salvage, prosthesis use, exercise and education were associated with better rehabilitation outcomes including ambulation, adjustment and quality of life in bilateral lower limb amputees from the 2008 Sichuan Earthquake. CLINICAL RELEVANCE: The study examined a unique group of traumatic bilateral lower limb amputees who were young and healthy before having traumatic amputations from a single episode of natural disaster. The factors associated with better functional recovery after the earthquake were investigated and may support future development of post-disaster rehabilitation strategies for bilateral lower limb amputees.

Whole-exome sequencing identifies multiple loss-of-function mutations of NF-κB pathway regulators in nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) is an epithelial malignancy with a unique geographical distribution. The genomic abnormalities leading to NPC pathogenesis remain unclear. In total, 135 NPC tumors were examined to characterize the mutational landscape using whole-exome sequencing and targeted resequencing. An APOBEC cytidine deaminase mutagenesis signature was revealed in the somatic mutations. Noticeably, multiple loss-of-function mutations were identified in several NF-κB signaling negative regulators NFKBIA, CYLD, and TNFAIP3 Functional studies confirmed that inhibition of NFKBIA had a significant impact on NF-κB activity and NPC cell growth. The identified loss-of-function mutations in NFKBIA leading to protein truncation contributed to the altered NF-κB activity, which is critical for NPC tumorigenesis. In addition, somatic mutations were found in several cancer-relevant pathways, including cell cycle-phase transition, cell death, EBV infection, and viral carcinogenesis. These data provide an enhanced road map for understanding the molecular basis underlying NPC.