PmrAB, the two-component system of Acinetobacter baumannii, controls the phosphoethanolamine modification of lipooligosaccharide in response to metal ions.

Acinetobacter baumannii is highly resistant to antimicrobial agents, and XDR strains have become widespread. A. baumannii has developed resistance to colistin, which is considered the last resort against XDR Gram-negative bacteria, mainly caused by lipooligosaccharide (LOS) phosphoethanolamine (pEtN) and/or galactosamine (GalN) modifications induced by mutations that activate the two-component system (TCS) pmrAB. Although PmrAB of A. baumannii has been recognized as a drug resistance factor, its function as TCS, including its regulatory genes and response factors, has not been fully elucidated. In this study, to clarify the function of PmrAB as TCS, we elucidated the regulatory genes (regulon) of PmrAB via transcriptome analysis using pmrAB-activated mutant strains. We discovered that PmrAB responds to low pH, Fe2+, Zn2+, and Al3+. A. baumannii selectively recognizes Fe2+ rather than Fe3+, and a novel region ExxxE, in addition to the ExxE motif sequence, is involved in the environmental response. Furthermore, PmrAB participates in the phosphoethanolamine modification of LOS on the bacterial surface in response to metal ions such as Al3+, contributing to the attenuation of Al3+ toxicity and development of resistance to colistin and polymyxin B in A. baumannii. This study demonstrates that PmrAB in A. baumannii not only regulates genes that play an important role in drug resistance but is also involved in responses to environmental stimuli such as metal ions and pH, and this stimulation induces LOS modification. This study reveals the importance of PmrAB in the environmental adaptation and antibacterial resistance emergence mechanisms of A. baumannii. IMPORTANCE: Antimicrobial resistance (AMR) is a pressing global issue in human health. Acinetobacter baumannii is notably high on the World Health Organization's list of bacteria for which new antimicrobial agents are urgently needed. Colistin is one of the last-resort drugs used against extensively drug-resistant (XDR) Gram-negative bacteria. However, A. baumannii has become increasingly resistant to colistin, primarily by modifying its lipooligosaccharide (LOS) via activating mutations in the two-component system (TCS) PmrAB. This study comprehensively elucidates the detailed mechanism of drug resistance of PmrAB in A. baumannii as well as its biological functions. Understanding the molecular biology of these molecules, which serve as drug resistance factors and are involved in environmental recognition mechanisms in bacteria, is crucial for developing fundamental solutions to the AMR problem.

Validation and comparison of prognostic scoring systems in patients with head and neck squamous cell carcinoma treated with nivolumab.

OBJECTIVE: Several scoring systems have been developed to predict prognosis in patients with refractory cancer. We aimed to validate eight scoring systems and determine the best method for predicting the prognosis of head and neck squamous cell carcinoma treated with nivolumab. METHODS: This multicentre retrospective study involved 154 patients with recurrent and/or metastatic head and neck squamous cell carcinoma treated with nivolumab between 2017 and 2020. Oncological outcomes were assessed according to the scoring systems, including MD Anderson Cancer Center + neutrophil-to-lymphocyte ratio and Hammersmith scores. Objective response, overall survival and progression-free survival were evaluated using logistic regression and Cox proportional hazards analyses. Receiver operating curve analysis was used to calculate the area under the curve and estimate the efficacy of each score. RESULTS: No significant associations were found between the responses and any score. Seven of the eight scoring systems were associated with disease control (odds ratio, 0.26-0.70). Amongst the eight scoring systems, MD Anderson Cancer Center + neutrophil-to-lymphocyte ratio showed the highest area under the curve for predicting response and disease control. Seven scoring systems were prognostic factors for progression-free survival (hazard ratio, 1.22-1.95). All eight scoring systems were prognostic factors for overall survival (hazard ratio, 1.62-3.83). According to the time-dependent receiver operating characteristics analysis for overall survival, the Hammersmith scoring system had the best predictive ability at 3 months, and the MD Anderson Cancer Center + neutrophil-to-lymphocyte ratio scoring system had the highest area under the curve between 6 and 24 months. CONCLUSIONS: MD Anderson Cancer Center + neutrophil-to-lymphocyte ratio and Hammersmith scoring systems were better predictors of prognosis in patients with head and neck squamous cell carcinoma treated with nivolumab.

Sema6D forward signaling impairs T cell activation and proliferation in head and neck cancer.

Immune checkpoint inhibitors (ICIs) are indicated for a diverse range of cancer types, and characterizing the tumor immune microenvironment is critical for optimizing therapeutic strategies, including ICIs. T cell infiltration and activation status in the tumor microenvironment greatly affects the efficacy of ICIs. Here, we show that semaphorin 6D (Sema6D) forward signaling, which is reportedly involved in coordinating the orientation of cell development and migration as a guidance factor, impaired the infiltration and activation of tumor-specific CD8+ T cells in murine oral tumors. Sema6D expressed by nonhematopoietic cells was responsible for this phenotype. Plexin-A4, a receptor for Sema6D, inhibited T cell infiltration and partially suppressed CD8+ T cell activation and proliferation induced by Sema6D stimulation. Moreover, mouse oral tumors, which are resistant to PD-1-blocking treatment in wild-type mice, showed a response to the treatment in Sema6d-KO mice. Finally, analyses of public data sets of human head and neck squamous cell carcinoma, pan-cancer cohorts, and a retrospective cohort study showed that SEMA6D was mainly expressed by nonhematopoietic cells such as cancer cells, and SEMA6D expression was significantly negatively correlated with CD8A, PDCD1, IFNG, and GZMB expression. Thus, targeting Sema6D forward signaling is a promising option for increasing ICI efficacy.

Prognostic significance of nutritional indices in patients with head and neck squamous cell carcinoma treated with immune checkpoint inhibitors.

BACKGROUND: Although patients with head and neck squamous cell cancer (HNSCC) often show malnutrition, its effects on immune checkpoint inhibitor (ICI) treatment outcomes in these patients are unclear. OBJECTIVES: To investigate the prognostic influence of nutritional indices in patients with HNSCC treated with ICIs and determine the optimal indices. METHODS: This retrospective study included 106 patients with HNSCC treated with ICIs between 2017 and 2022. The prognostic influences of body mass index (BMI), geriatric nutritional risk index (GNRI), and prognostic nutritional index (PNI) on overall survival (OS) and progression-free survival (PFS) were analysed using the Kaplan-Meier method and Cox-regression models. RESULTS: The 1-year PFS rates in the groups with high and low BMI, GNRI, and PNI were, respectively, 24.2% and 28.4% (p = .731), 29.7% and 14.4% (p = .024), and 30.3% and 13.9% (p = .015). PNI was an independent prognostic factor for both PFS (hazard ratio (HR) = 1.89; 95% confidence interval (CI), 1.08-3.29) and OS (HR = 3.26; 95% CI, 1.66-6.40). CONCLUSIONS: PNI can predict ICI outcomes and should be assessed when ICI treatment is considered.

A multilocus sequence typing method of Staphylococcus aureus DNAs in a sample from human skin.

The skin and mucous membranes are the primary sites of Staphylococcus aureus colonization, particularly those of health care personnel and patients in long-term care centers. We found that S. aureus colonized with a higher abundance ratio on skins which had recovered from pressure injury (PI) than on normal skins in our earlier research on the skin microbiota of bedridden patients. Multilocus sequence typing (MLST) is a useful tool for typing S. aureus isolated from clinical specimens. However, the MLST approach cannot be used in microbiota DNA owing to the contamination from other bacteria species. In this study, we developed a multiplex-nested PCR method to determine S. aureus MLST in samples collected from human skins. The seven pairs of forward and reverse primers were designed in the upstream and downstream regions, which were conserved specifically in S. aureus. The first amplifications of the seven pairs were conducted in a multiplex assay. The samples were diluted and applied to conventional PCR for MLST. We confirmed that the method amplified the seven allele sequences of S. aureus specifically in the presence of untargeted DNAs from human and other skin commensal bacteria. Using this assay, we succeeded in typing sequence types (STs) of S. aureus in the DNA samples derived from the skins healed from PI. Peaks obtained by Sanger sequencing showed that each sample contained one ST, which were mainly categorized into clonal complex 1 (CC1) or CC5. We propose that this culture-free approach may be used in detecting S. aureus in clinical specimens without isolation.

Tumor-derived semaphorin 4A improves PD-1-blocking antibody efficacy by enhancing CD8+ T cell cytotoxicity and proliferation.

Immune checkpoint inhibitors (ICIs) have caused revolutionary changes in cancer treatment, but low response rates remain a challenge. Semaphorin 4A (Sema4A) modulates the immune system through multiple mechanisms in mice, although the role of human Sema4A in the tumor microenvironment remains unclear. This study demonstrates that histologically Sema4A-positive non-small cell lung cancer (NSCLC) responded significantly better to anti-programmed cell death 1 (PD-1) antibody than Sema4A-negative NSCLC. Intriguingly, SEMA4A expression in human NSCLC was mainly derived from tumor cells and was associated with T cell activation. Sema4A promoted cytotoxicity and proliferation of tumor-specific CD8+ T cells without terminal exhaustion by enhancing mammalian target of rapamycin complex 1 and polyamine synthesis, which led to improved efficacy of PD-1 inhibitors in murine models. Improved T cell activation by recombinant Sema4A was also confirmed using isolated tumor-infiltrating T cells from patients with cancer. Thus, Sema4A might be a promising therapeutic target and biomarker for predicting and promoting ICI efficacy.

Clearance Profile of Circulating Tumor Human Papillomavirus DNA During Radiotherapy Predicts Clinical Outcomes in Human Papillomavirus-Related Oropharyngeal Cancer.

PURPOSE: This study aimed to examine whether circulating tumor human papillomavirus type 16 (HPV16) DNA (ctHPV16DNA) can help identify patients with locally advanced HPV16-related oropharyngeal squamous cell carcinoma who may benefit from deintensified treatment. MATERIALS AND METHODS: We serially collected blood samples before, during, and after treatment from 22 patients who received 70 Gy radiotherapy alone and longitudinally quantified ctHPV16DNA using droplet digital polymerase chain reaction. We correlated the clearance profile of ctHPV16DNA with clinical outcomes. RESULTS: The percentage of patients with detectable ctHPV16DNA decreased after every 10 Gy of radiotherapy. By contrast, the percentage of patients who later developed treatment failure among patients with detectable ctHPV16DNA gradually increased as radiotherapy proceeded, reaching 100% after 60 Gy of radiotherapy. We defined patients with and without detectable ctHPV16DNA after receiving 40 Gy as having slow and rapid clearance profiles, respectively. All 12 patients with a rapid clearance profile remained disease-free after radiotherapy. Of the 10 patients with a slow clearance profile, three had persistent or progressive disease at response evaluation after radiotherapy and one developed distant metastasis during follow-up (ie, four patients experienced treatment failure). The median follow-up for surviving patients was 38.6 months, and the 3-year failure-free survival rates of patients with rapid and slow clearance profiles were 100% and 58%, respectively (P = .02). Neither baseline ctHPV16DNA levels nor metabolic tumor volume was an independent predictor of the pattern of the clearance profile. CONCLUSION: In patients with HPV16-related oropharyngeal squamous cell carcinoma receiving radiotherapy, a slow ctHPV16DNA clearance profile could prelude unfavorable outcomes. Monitoring ctHPV16DNA is essential for determining the clearance profile, which might help optimize treatment intensity individually.

Distant metastasis in head and neck squamous cell carcinoma variants: A population-based study.

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) with distant metastasis (DM) has poor prognosis. HNSCC has several histological variants with varying characteristics. We investigated the DM rates and prognoses of patients with DM among the HNSCC variants. METHODS: We obtained data from 54 722 cases using the Surveillance, Epidemiology, and End Results database. Odds ratios (ORs) for DM and hazard ratios (HRs) for overall survival (OS) were estimated using a logistic regression model and a Cox proportional hazard model, respectively. RESULTS: DM rate was the lowest in verrucous carcinoma and the highest in basaloid squamous cell carcinoma (BSCC) (0.2% and 9.4%, respectively). ORs for DM were 3.63 for adenosquamous carcinoma, 6.80 for BSCC, and 3.91 for spindle cell carcinoma (SpCC). SpCC was significantly associated with a poor OS (HR, 1.61). CONCLUSIONS: DM rates differed among the HNSCC variants. The prognosis of metastatic SpCC is worse than that of other metastatic HNSCCs.

Early-stage glottic cancer of rare squamous cell carcinoma variants: a population-based study.

BACKGROUND: Squamous cell carcinoma (SCC) is the most common histological type of laryngeal cancer. Several variants of SCC have been reported. However, how these variants differ from conventional SCC and how they should be treated remain to be elucidated. OBJECTIVE: To compare the prognosis of early-stage glottic cancer among SCC variants. METHODS: We obtained data from 12471 cases using the Surveillance, Epidemiology, and End Results database. Disease-specific survival (DSS) and overall survival (OS) rates were estimated using the Kaplan-Meier method. A Cox proportional hazard model was used to estimate hazard ratios (HRs) according to the variants. RESULTS: HRs for DSS and OS compared with well-differentiated SCC were 3.83 and 3.48 for adenosquamous, 1.42 and 1.42 for basaloid, 1.14 and 1.17 for papillary, 0.85 and 0.94 for spindle, and 0.81 and 1.00 for verrucous SCC. The difference in DSS among the treatment modalities was significant in conventional and papillary SCC (p < .001 and p = .032, respectively). CONCLUSIONS: The prognosis of SCC variants, except for adenosquamous SCC, is comparable to that of conventional SCC.

Radiation vs surgery for early-stage laryngeal verrucous carcinoma: A population-based propensity score matched-study.

BACKGROUND: Verrucous carcinoma (VC) is a rare variant of squamous cell carcinoma. Although VC is considered radioresistant, concrete evidence for this is absent. METHODS: We obtained data on VC treated with surgery or radiation from the Surveillance, Epidemiology, and End Results database. Treatment selection bias was reduced by propensity score matching. Overall survival (OS) and disease-specific survival (DSS) rates were estimated using the Kaplan-Meier method. Hazard ratios (HRs) were estimated using Cox proportional hazards models. RESULTS: Five-year OS rates in the radiation and surgery groups were 72.7% and 72.0%, respectively (P = 0.111); five-year DSS rates in the same were 86.7% and 88.4%, respectively (P = 0.234). HRs of radiation compared with surgery were 1.68 (95% confidence interval (CI), 0.96-2.95) for OS and 1.95 (95% CI, 0.69-5.53) for DSS. CONCLUSIONS: Similar prognoses were observed in patients with VC treated with radiation and surgery. VC can be treated using radiation.

Preferential Selection of Low-Frequency, Lipopolysaccharide-Modified, Colistin-Resistant Mutants with a Combination of Antimicrobials in Acinetobacter baumannii.

Colistin, which targets lipopolysaccharide (LPS), is used as a last-resort drug against severe infections caused by drug-resistant Acinetobacter baumannii. However, A. baumannii possesses two colistin-resistance mechanisms. LPS modification caused by mutations in pmrAB genes is often observed in clinical isolates of multidrug-resistant Gram-negative pathogens. In addition to LPS modification, A. baumannii has a unique colistin resistance mechanism, a complete loss of LPS due to mutations in the lpxACD genes, which are involved in LPS biosynthesis. This study aimed to elucidate the detailed mechanism of the emergence of colistin-resistant A. baumannii using strains with the same genetic background. Various colistin-resistant strains were generated experimentally using colistin alone and in combination with other antimicrobials, such as meropenem and ciprofloxacin, and the mutation spectrum was analyzed. In vitro selection of A. baumannii in the presence of colistin led to the emergence of strains harboring mutations in lpxACD genes, resulting in LPS-deficient colistin-resistant strains. However, combination of colistin with other antimicrobials led to the selection of pmrAB mutant strains, resulting in strains with modified LPS (LPS-modified strains). Further, the LPS-deficient strains showed decreased fitness and increased susceptibility to many antibiotics and disinfectants. As LPS-deficient strains have a higher biological cost than LPS-modified strains, our findings suggested that pmrAB mutants are more likely to be isolated in clinical settings. We provide novel insights into the mechanisms of resistance to colistin and provide substantial solutions along with precautions for facilitating current research and treatment of colistin-resistant A. baumannii infections. IMPORTANCE Acinetobacter baumannii has developed resistance to various antimicrobial drugs, and its drug-resistant strains cause nosocomial infections. Controlling these infections has become a global clinical challenge. Carbapenem antibiotics are the frontline treatment drugs for infectious diseases caused by A. baumannii. For patients with infections caused by carbapenem-resistant A. baumannii, colistin-based therapy is often the only treatment option. However, A. baumannii readily acquires resistance to colistin. Many patients infected with colistin-resistant A. baumannii undergo colistin treatment before isolation of the colistin-resistant strain, and it is hypothesized that colistin resistance predominantly emerges under selective pressure during colistin therapy. Although the concomitant use of colistin and carbapenems has been reported to have a synergistic effect in vitro against carbapenem-resistant A. baumannii strains, our observations strongly suggest the need for attention to the emergence of strains with a modified lipopolysaccharide during treatment.

COVID-19 vaccine-induced Recurrence of the Radiation Recall Phenomenon in the Laryngeal Mucosa Due to a VEGF Inhibitor.

Purpose: The radiation recall phenomenon (RRP) is a rare and unexpected late complication of radiation therapy (RT). Although predominantly in the skin, RRP of the upper respiratory tract has also been reported. In general, RRP is caused by anticancer agents, and the COVID-19 vaccine has also been reported to cause RRP in recent years. Methods and Materials: A 50-year-old woman who had received RT around the larynx 3 years prior and was receiving a docetaxel + ramucirumab (RAM) regimen experienced recurrent sore throat. The administration of RAM was discontinued after a gastroscopic examination revealed mucosal bleeding from around the larynx, which was thought to be RRP caused by RAM, a vascular endothelial growth factor inhibitor. Results: After the remission of the RRP, the patient received a COVID-19 vaccine (Pfizer-BioNTech). Five days later, the appearance of cough and recurrence of sore throat worsened with time, and marked stridor was observed. The patient was admitted, and steroid pulse therapy was administered for 3 days starting on day 18 after vaccination. On day 50 after vaccination, edema of the vocal cords improved. Conclusions: When administering COVID-19 vaccines, considering that these vaccines may cause RRP is important, because RRP can be fatal in patients with a history of RT in the laryngeal region and treated with vascular endothelial growth factor inhibitors.

Predictive significance of body composition indices in patients with head and neck squamous cell carcinoma treated with nivolumab: A multicenter retrospective study.

BACKGROUND: The identification of predictive factors is imperative for identifying patients with optimal responses to nivolumab. We aimed to determine whether body composition parameters can predict treatment outcomes in patients with head and neck squamous cell carcinoma (HNSCC) treated with nivolumab. METHOD: We performed a multicenter retrospective chart review of patients with recurrent and/or metastatic HNSCC treated with nivolumab between 2017 and 2020. Computed tomography images and anthropometric measures were used to determine the skeletal muscle index (SMI), subcutaneous adipose index, visceral adipose index (VAI), and body mass index. Objective response, overall survival (OS), progression-free survival (PFS), and severe immune-related adverse events (irAEs) were the main outcomes. Odds ratios (ORs) and hazard ratios (HRs) for low-index groups compared with high-index groups were calculated for these outcomes. RESULTS: Our study comprised 114 patients with a median follow-up period of 23.1 months. Low SMI and low VAI were significantly associated with poor disease control [OR: 0.39, 95% confidence interval (CI): 0.15-0.97] and poor response (OR: 0.38, 95% CI: 0.15-0.94), respectively. Low SMI independently predicted poor OS (HR: 2.06, 95% CI: 1.16-3.67), poor PFS (HR: 1.74, 95% CI: 1.04-2.92), and increased incidence of irAEs (OR: 6.00, 95% CI: 1.04-34.61). Low VAI independently predicted poor PFS (HR 2.07, 95% CI: 1.15-3.73). CONCLUSION: The SMI and VAI are predictive factors of nivolumab therapy in patients with HNSCC. Body composition indices should be assessed before nivolumab treatment for achieving optimal responses to nivolumab.

Neutrophil-to-lymphocyte ratio as a prognostic marker for head and neck squamous cell carcinoma treated with immune checkpoint inhibitors: Meta-analysis.

We investigated the prognostic impact of the neutrophil-to-lymphocyte ratio (NLR) in patients with head and neck squamous cell carcinoma (HNSCC) treated with immune checkpoint inhibitors (ICIs). We systematically searched electronic databases and identified articles reporting an association between NLR and treatment results in patients with HNSCC treated with ICIs. Hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS) and odds ratios (ORs) for response and disease control were extracted. Pooled HRs and ORs were estimated using random-effects models. Fourteen studies involving 929 patients were included. A higher NLR was associated with poor OS (HR 2.03, 95% confidence interval [CI] 1.50-2.74), PFS (HR 2.15, 95% CI 1.44-3.21), response (OR 0.49, 95% CI 0.26-0.93), and disease control (OR 0.30, 95% CI 0.12-0.74). The NLR predicts treatment results with ICIs in patients with HNSCC.

Predominance of ST8 and CC1/spa-t1784 methicillin-resistant Staphylococcus aureus isolates in Japan and their genomic characteristics.

OBJECTIVES: Methicillin-resistant Staphylococcus aureus (MRSA) has become a serious epidemiologic problem worldwide. In this study, we aimed to investigate recently isolated MRSA types and determine their characteristics. METHODS: We collected 164 strains isolated from 13 hospitals located in Tokyo and surrounding prefectures. In addition to drug resistance tests, we sequenced whole genomes of the prevalent MRSA clones and analysed their genomic characteristics, such as drug resistance genes, virulence factor genes, and genome arrangements. RESULTS: Multilocus sequencing typing showed that 51% of the SCCmecⅣ MRSA isolates belonged to clonal complex 1 (CC1). Staphylococcus protein A gene (spa) typing showed that 91% of these CC1 isolates could be categorised as t1784 type. These CC1/t1784 isolates possessed genes encoding erythromycin resistance protein, spectinomycin 9-adenylyltransferase, and staphylococcal enterotoxins (SEA, SEI, SEM), but not the pvl gene encoding Panton-Valentine leukocidin. Complete genomic analysis of nine CC1/t1784 isolates showed that they shared an intact phage, which carried no annotated virulence factor genes except for two encoding a hypothetical membrane protein and a teichoic acid biosynthesis protein. No significant genomic rearrangements were observed among the CC1/t1784 isolates. CONCLUSION: These data and previous reports indicate that this CC1/t1784 clone has been expanding rapidly in Japan without genomic changes.

Performance of oral HPV DNA, oral HPV mRNA and circulating tumor HPV DNA in the detection of HPV-related oropharyngeal cancer and cancer of unknown primary.

A biomarker that is useful for the detection of human papillomavirus (HPV)-related oropharyngeal cancer (OPC) and cancer of unknown primary (CUP) is indispensable. We evaluated the diagnostic performance of HPV DNA and mRNA in oral gargle samples and circulating tumor HPV16 DNA (ctHPV16DNA) in blood samples. Oral HPV DNA and mRNA were analyzed using commercially available HPV assays of the GENOSEARCH HPV31 and Aptima, respectively. ctHPV16DNA was analyzed using in-house droplet digital polymerase chain reaction. Seventy-four patients with OPC and eight patients with CUP were included. The sensitivity and specificity of oral HPV DNA, oral HPV mRNA, and ctHPV16DNA were 82% (95% confidence interval [CI] = 66-92) and 100% (95% CI = 88-100), 85% (95% CI = 69-94) and 94% (95% CI = 73-100), and 93% (95% CI = 81-99) and 97% (95% CI = 84-100), respectively, for HPV16-related OPC, while those were 20% (95% CI = 1-72) and 100% (95% CI = 3-100), 0% (95% CI = 0-52) and 100% (95% CI = 3-100), and 100% (95% CI = 54-100) and 100% (95% CI = 16-100), respectively, for HPV16-related CUP. The sensitivity of ctHPV16DNA for HPV16-related OPC was higher than that of oral biomarkers, though the difference was not statistically significant. ctHPV16DNA remarkably correlated with the anatomic extent of disease, total metabolic tumor volume and HPV16 copy number per tumor genome in patients with HPV16-related OPC/CUP, whereas oral biomarkers did not. In conclusion, ctHPV16DNA is a potentially promising biomarker for HPV16-related OPC, while further studies are required for HPV16-related CUP.

Prognostic impact of sarcopenia in patients with head and neck cancer treated with surgery or radiation: A meta-analysis.

BACKGROUND: The objective of this study was to compare the prognostic impact of sarcopenia in patients with head and neck cancer (HNC) treated with surgery or radiation. METHODS: We systematically searched electronic databases to identify articles reporting the impact of sarcopenia on the prognosis of patients with HNC. Hazard ratios (HRs) and 95% confidence intervals (CIs) for overall survival (OS), disease-free survival (DFS), and disease-specific survival (DSS) were extracted and pooled. HR according to treatment modality were estimated using random-effects models. Statistical analyses were carried out using the Comprehensive Meta-Analysis software. RESULTS: In total, 18 studies enrolling 3,233 patients were included. Sarcopenia was associated with poor OS in both surgery and radiotherapy groups (hazard ratio [HR] 2.50, 95% confidence interval [CI] 1.95-3.21; HR 1.63, 95% CI 1.40-1.90, respectively). The HR was significantly higher in the surgery group than in the radiotherapy group (p = 0.004), with similar results obtained for DFS (HR 2.59, 95% CI 1.56-4.31; HR 1.56, 95% CI 1.24-1.97 for the surgery and radiotherapy groups, respectively) and DSS (HR 2.96, 95% CI 0.73-11.95; HR 2.67, 95% CI 1.51-4.73 for the surgery and RT groups, respectively). CONCLUSIONS: Sarcopenia was a poor prognostic factor for HNC, regardless of the treatment modality. However, the adverse effects of sarcopenia on survival were more prominent in the surgery group than in the radiotherapy group. Sarcopenia assessment is required for appropriate treatment decision-making.

Predictive impact of sarcopenia in solid cancers treated with immune checkpoint inhibitors: a meta-analysis.

Sarcopenia, which is characterized by a decrease in muscle quantity or quality, is commonly observed in patients with cancer. Recent research has reported contradictory results on the association between sarcopenia and the efficacy of immune checkpoint inhibitors (ICIs). We conducted a systematic review and meta-analysis to investigate this discrepancy. We systematically searched three electronic databases to identify articles reporting on the association between sarcopenia and treatment outcomes in patients with solid cancers who received ICIs. The outcomes assessed were hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS), and odds ratios (ORs) for objective response rate (ORR), disease control rate (DCR), and toxicity. Pooled estimates and their 95% confidence intervals (CIs) were calculated. A total of 2501 patients from 26 studies were analysed. Sarcopenia was observed in 44.7% (95% CI: 38.2-51.3) of the patients and was significantly associated with poor survival (HR = 1.55, 95% CI = 1.32-1.82 for OS and HR = 1.61, 95% CI = 1.35 to 1.93 for PFS). The HRs (95% CIs) for OS according to the diagnostic measures used were 1.97 (0.88-4.41) for psoas muscle index (PMI), 1.41 (0.87-2.28) for skeletal muscle density (SMD), and 1.43 (1.23-1.67) for skeletal mass index (SMI). The HRs (95% CIs) for PFS were 1.86 (1.08-3.21) for PMI, 1.27 (0.94-1.71) for SMD, and 1.38 (1.11-1.71) for SMI. Poor radiological response to ICI therapy was observed in patients with sarcopenia (OR = 0.52, 95% CI = 0.34-0.80 for ORR and OR = 0.45, 95% CI = 0.30-0.67 for DCR). The ORs for ORR (95% CIs) were 0.56 (0.15-2.05) for PMI and 0.78 (0.56-1.09) for SMI. The oncologic outcomes associated with melanoma and non-small cell lung cancer (NSCLC) were comparable with those observed overall (HR for OS = 2.02, 95% CI = 1.26-3.24 for melanoma and HR for OS = 1.61, 95% CI = 1.19-2.18 for NSCLC). In contrast, the occurrence of severe toxicity was not associated with sarcopenia (OR = 1.13, 95% CI = 0.51-2.52). Poor survival and poor response in patients with sarcopenia indicate a negative association between sarcopenia and efficacy of ICIs. Sarcopenia's predictive ability is consistent across various tumour types. For the selection of patients who may respond to ICIs pre-therapeutically, the presence of sarcopenia should be assessed in clinical practice.

Modified TPEx as First-line Treatment for Recurrent and/or Metastatic Head and Neck Cancer.

BACKGROUND/AIM: To retrospectively evaluate the efficacy and safety of modified TPEx (docetaxel 60 mg/m2 on day 1, cisplatin 60 mg/m2 on day 1, and weekly cetuximab 250 mg/m2 with loading dose of 400 mg/m2) followed by maintenance cetuximab as first-line treatment for inoperable recurrent and/or metastatic squamous cell carcinoma of the head and neck. PATIENTS AND METHODS: We analyzed 22 Japanese patients receiving modified TPEx every 21 days for four cycles with or without prophylactic granulocyte colony-stimulating factor (G-CSF). RESULTS: The best overall response rate was 55% [95% confidence interval (CI)=35-73]. The median progression-free survival and overall survival were 8.9 months (95%CI=3.9-10.2) and 14.3 months (95%CI=10.1-28.2), respectively. Without prophylactic G-CSF, Grade 3/4 neutropenia and febrile neutropenia was common (94% versus 20%; p=0.003 and 41% versus 0%; p=0.11, respectively). CONCLUSION: The modified TPEx is effective, while prophylactic G-CSF is essential.