A phase II trial of paclitaxel plus biweekly cetuximab for patients with recurrent or metastatic head and neck cancer previously treated with both platinum-based chemotherapy and anti-PD-1 antibody.

BACKGROUND: An important unmet need for new treatment options remains for patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M-HNSCC) previously treated with both platinum-based chemotherapy and anti-programmed cell death protein 1 (PD-1) antibody. Retrospective studies suggest that previous treatment with immune checkpoint inhibitor might augment the efficacy of subsequent chemotherapy. Here, we conducted a phase II trial aimed to evaluate the efficacy and safety of paclitaxel plus biweekly cetuximab for patients in this setting. PATIENTS AND METHODS: This was a single-arm, multicenter, phase II trial. Key eligibility criteria were R/M-HNSCC, and previous treatment with both platinum-based chemotherapy and PD-1 antibody. Paclitaxel plus biweekly cetuximab consisted of weekly paclitaxel 100 mg/m2 (days 1, 8, 15) and biweekly cetuximab 500 mg/m2 (days 1, 15) with a cycle of 28 days until progression or unacceptable toxicity. Primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and adverse events (AEs) (Common Terminology Criteria for Adverse Events version 5.0). RESULTS: Between August 2020 and August 2022, 35 patients were enrolled, of whom 33 were assessable for response. ORR was 69.6% (95% confidence interval 51.2% to 84.4%). With a median follow-up period for survivors of 16.6 months, median PFS and OS were 5.5 and 13.3 months, respectively. DCR was 93.7%. Twenty-three patients (65%) experienced grade 3 or 4 AEs, including neutropenia (34%), infection (14%), leukopenia (11%), mucositis (8%), and pneumonitis (8%). Eight patients discontinued study treatment due to treatment-related AEs, and no treatment-related death was observed. CONCLUSIONS: Paclitaxel plus biweekly cetuximab showed highly encouraging efficacy and manageable toxicities in R/M-HNSCC patients previously treated with both platinum-based chemotherapy and PD-1 antibody. This combination therapy warrants further investigation in this setting.

Pan-Asian adaptation of the EHNS-ESMO-ESTRO Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with squamous cell carcinoma of the head and neck.

The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of squamous cell carcinoma (SCC) of the oral cavity, larynx, oropharynx and hypopharynx was published in 2020. It was therefore decided by both the ESMO and the Korean Society of Medical Oncology (KSMO) to convene a special, virtual guidelines meeting in July 2021 to adapt the ESMO 2020 guidelines to consider the potential ethnic differences associated with the treatment of SCCs of the head and neck (SCCHN) in Asian patients. These guidelines represent the consensus opinions reached by experts in the treatment of patients with SCCHN (excluding nasopharyngeal carcinomas) representing the oncological societies of Korea (KSMO), China (CSCO), India (ISMPO), Japan (JSMO), Malaysia (MOS), Singapore (SSO) and Taiwan (TOS). The voting was based on scientific evidence and was independent of the current treatment practices and drug access restrictions in the different Asian countries. The latter was discussed when appropriate. This manuscript provides a series of expert recommendations (Clinical Practice Guidelines) which can be used to provide guidance to health care providers and clinicians for the optimisation of the diagnosis, treatment and management of patients with SCC of the oral cavity, larynx, oropharynx and hypopharynx across Asia.

New proposal to revise the classification for squamous cell carcinoma of the external auditory canal and middle ear.

BACKGROUND: The prognosis of patients with advanced squamous cell carcinoma of the external auditory canal and middle ear has been improved by advances in skull base surgery and multidrug chemoradiotherapy during the last two decades. METHODS: Ninety-five patients with squamous cell carcinoma of the external auditory canal and middle ear who were treated between 1998 and 2017 were enrolled. The number of patients with tumour stages T1, T2, T3 and T4 was 15, 22, 24 and 34, respectively. Oncological outcomes and prognostic factors were retrospectively investigated. RESULTS: Among patients with T4 disease, invasion of the brain (p = 0.024), carotid artery (p = 0.049) and/or jugular vein (p = 0.040) were significant predictors of poor prognosis. The five-year overall survival rate of patients with at least one of these factors (T4b) was significantly lower than that of patients without these factors (T4a) (25.5 vs 65.5 per cent, p = 0.049). CONCLUSION: It is proposed that stage T4 be subclassified into T4a and T4b according to the prognostic factors.

Effect of tumor burden and growth rate on treatment outcomes of nivolumab in head and neck cancer.

BACKGROUND: Nivolumab improves overall survival (OS) in patients with platinum-refractory recurrent and metastatic head and neck squamous cell carcinoma (R/M HNSCC). In one study, however, Kaplan-Meier OS and progression-free survival (PFS) curves for the nivolumab and cytotoxic agent arms crossed at 3-6 months, suggesting that patients with initial resistance to immunotherapy might have better outcomes with cytotoxic treatment. Here, we explored the conditions and candidates which are predictive of nivolumab outcomes in R/M HNSCC. METHODS: We retrospectively reviewed the clinical records of 27 consecutive R/M HNSCC patients treated with nivolumab from 2014 to 2018. Tumor size was evaluated by RECIST ver.1.1. Tumor growth rate (Gr) was defined as 3log(D0/Dpre)/t, where D0 and Dpre are the sum of the diameters of the target lesions (SumTLs) at baseline and pre-baseline, and t is time, with 1t defined as 4 weeks. RESULTS: Twenty-five patients were enrolled. Survival was significantly worse in patients with disease progression within 3 months. Outcomes appeared poorer in patients with higher pre-treatment Gr and bigger SumTLs at baseline. We therefore explored the association between prognosis, Gr and SumTLs. Recursive partitioning analysis showed that the characteristics of patients with disease progression after 3 months were Gr < 0.76 and SumTLs < 31.0 mm. Further, Gr < 0.76 and SumTLs < 31.0 mm was associated with significantly longer PFS (p = 0.01) and OS (p < 0.01). CONCLUSIONS: These results suggest that Gr and SumTLs at baseline are significantly associated with OS and PFS in R/M HNSCC patients treated with nivolumab.

Phase II trial of combination treatment with paclitaxel, carboplatin and cetuximab (PCE) as first-line treatment in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (CSPOR-HN02).

Background: The standard of care for first-line treatment of recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) is combination treatment with platinum, 5-FU and cetuximab (PFE). However, this regimen requires hospitalization to ensure proper hydration and continuous infusion of 5-FU, and causes severe nausea and anorexia. We evaluated the efficacy and safety of paclitaxel, carboplatin and cetuximab (PCE) as first-line treatment in patients with R/M SCCHN. Patients and methods: Eligibility criteria included recurrent and/or metastatic, histologically proven SCC of the oropharynx, oral cavity, hypopharynx or larynx; PS 0-1; adequate organ function; no suitable local therapy for R/M SCCHN; and no prior systemic chemotherapy for R/M SCCHN. Chemotherapy consisted of paclitaxel 100 mg/m2 on days 1, 8; carboplatin area under the blood concentration-time curve 2.5 on days 1, 8, repeated every 3 weeks for up to 6 cycles; and cetuximab at an initial dose of 400 mg/m2, followed by 250 mg/m2 weekly until disease progression or unacceptable toxicities. Primary end point was overall response rate. Secondary end points were safety, treatment completion rate, progression-free survival, overall survival, and clinical benefit rate. Planned sample size was 45 patients. Results: Forty-seven subjects were accrued from July 2013 to October 2014. Of 45 evaluable, 40 were male; median age was 63 years; Eastern Cooperative Oncology Group Performance Status was 0/1 in 23/22 cases; site was the hypopharynx/oropharynx/oral cavity/larynx in 17/11/10/7 cases; and 36/9 cases were smokers/nonsmokers, respectively. Overall response rate, the primary end point, was 40%. Median overall survival was 14.7 months and progression-free survival was 5.2 months. Grade 3/4 adverse events included neutropenia (68%), skin reaction (15%), fatigue (9%) and febrile neutropenia (9%). A potentially treatment-related death occurred in one patient with intestinal pneumonia. Conclusions: The PCE regimen shows promising activity with acceptable toxicity in the outpatient clinic. Further studies are needed to compare PCE with PFE in this population. Registered clinical trial number: UMIN000010507.

Changes in event-related potentials associated with postural adaptation during floor oscillation.

The event-related potential (ERP) mainly reflecting activation of the frontal lobe was measured during periodic floor oscillation, and changes in postural preparation and attention to the postural disturbance according to this adaptation were investigated. The experiment consisted of two tasks with eyes closed: adaptation to floor oscillation and finger flexion coinciding with the anterior and posterior reversals of oscillation. Subjects were 20 healthy young adults. They maintained a standing posture for 1 min (1 trial) on the force platform which oscillated in the anteroposterior direction at 0.5 Hz and an amplitude of 2.5 cm. ERP from a Cz electrode, activity of postural muscles and the center of foot pressure in the anteroposterior direction (CoPy) were analyzed. In the adaptation task, the speeds of CoPy fluctuation gradually decreased and reached a plateau between 4th and 14th trials, with inter-subject differences. Posterior postural muscles were activated in response to the anterior reversal of oscillation according to adaptation and also in the finger flexion task, with the largest activation of the gastrocnemius (GcM). A negative ERP peak was observed to occur locally around the anterior reversal of oscillation after adaptation. The peak ERP time had the strongest positive correlation with the peak activation time of the GcM, and the amplitude of the negative peak decreased with adaptation. In the finger flexion task, a negative ERP peak was observed around each target point. This negative peak was related to the anticipatory attention directed to the reversal point and to motor preparation for finger flexion. It is conceivable that the increasing negative ERP in the adaptation task reflects the dynamics of motor preparation and attention mainly for the anterior reversal, where the negative ERP peak is closely related to anticipatory information processing of somatosensory stimuli arising around the time of the reversal.

Phase I trial of combination chemotherapy with docetaxel, cisplatin and S-1 (TPS) in patients with locally advanced or recurrent/metastatic head and neck cancer.

BACKGROUND: we investigated the maximum tolerated dose (MTD) of combination therapy with docetaxel, cisplatin, and S-1 (TPS) in patients with locally advanced or recurrent/metastatic head and neck cancer (HNC). PATIENTS AND METHODS: treatment consisted of docetaxel (Taxotere) at doses of 50, 60, and 70 mg/m(2); cisplatin at 70 mg·m(2)/day on day 1; and S-1 twice daily on days 1-14 at doses of 40, 60, and 80 mg·m(2)/day, repeated every 3 or 4 weeks. RESULTS: forty patients were enrolled. MTD was not reached until level 4. Subjects at expanded dose were limited to patients with locally advanced disease. Two dose-limiting toxic effects (DLTs) were observed at dose level 5 (TPS: 70/70/80 mg·m(2)/day, every 3 weeks), namely one grade 3 infection and one grade 3 hyperbilirubinemia, establishing this as the MTD. Of 12 patients treated at dose level 6 (TPS: 70/70/60 mg·m(2)/day, every 3 weeks), 2 DLTs were seen. Six achieved a complete response and 22 a partial response, giving a response rate of 70%. CONCLUSIONS: TPS was well tolerated. The recommended phase II dose as induction chemotherapy for locally advanced HNC was determined as 70/70/60 mg·m(2)/day every 3 weeks. Antitumor activity was highly promising and warrants further investigation.

Saccades and prefrontal hemodynamics in basketball players.

We investigated saccade performance and prefrontal hemodynamics in basketball players with different skill levels. Subjects were 27 undergraduate basketball players and 13 non-athlete undergraduates (control group: CON). The players were divided into two groups: those who had played in the National Athletic Meet during high school or played regularly (n=13, elite group: ELI) and those who were bench warmers (n=14, skilled group: SKI). Horizontal eye movement and oxy-, deoxy-, and total-hemoglobin (Hb) concentration in the prefrontal cortex during pro- and anti-saccade were measured using electro-oculography and near-infrared spectroscopy, respectively. Only error rate in anti-saccade was less in ELI (4.8+/-4.0%) than SKI (13.7+/-12.6%) and CON (13.9+/-8.3%) (p<0.05). In ELI alone, oxy- (-0.15+/-0.18 mmol*mm) and total-Hb (-0.12+/-0.15 mmol*mm) during anti-saccade decreased significantly compared with that during rest (p<0.05), while those in CON significantly increased (oxy-Hb: 0.17+/-0.15 mmol*mm, total-Hb: 0.14+/-0.14 mmol*mm) (p<0.05). These results suggest that inhibition of eye movement to a visual target changes from voluntary to automatic through the motor learning of basketball.

Relationship between C-reactive protein and visceral adipose tissue in healthy Japanese subjects.

AIM: Recent studies have suggested that the elevated C-reactive protein (CRP) levels are associated with body fat, especially visceral adipose tissue, but most of them were investigated in Westerners who had higher body mass index (BMI) than Asians. To investigate the association between CRP concentrations, parameters of visceral obesity, the insulin resistance syndrome and carotid atherosclerosis in healthy Japanese who had a lower BMI than Westerners. METHODS: We explored the relationships between fatness and visceral obesity parameters [by anthropometry, bioelectrical impedance analysis and abdominal computed tomography (CT)] and CRP (high sensitivity) and examined their associations with components of insulin resistance syndrome, interleukin-6 (IL-6), tissue necrosis factor-alpha (TNF-alpha) and intima-media thickness (IMT) of common carotid arteries (CCAs) by ultrasonograms in 116 healthy Japanese subjects. RESULTS: In crude regression analyses, CRP was significantly associated with measures of obesity. After adjustment for age, gender and smoking, the association with CRP was stronger for parameters of visceral obesity (waist circumference, waist-to-hip ratio and visceral adipose tissue accumulation) than for other parameters of obesity. IL-6 and TNF-alpha were not associated with CRP. Blood pressure (BP), metabolic variables and CCA-IMT were also significantly associated with CRP. But, after being adjusted for age, gender, smoking and BMI, BP and high-density lipoprotein cholesterol (HDLc) were significantly associated. CONCLUSION: CRP level is associated with visceral adipose tissue and is significantly associated with the components of insulin resistance syndrome in healthy Japanese subjects. These data support a possible role of visceral adipose tissue in inflammation component of atherosclerosis, and further studies are needed to study the mechanism of CRP elevation caused by visceral adipose tissue.

Molecular cloning and sequence analysis of an endoinulinase gene from Penicillium sp. strain TN-88.

A genomic DNA segment and cDNAs encoding an extracellular endoinulinase of Penicillium sp. strain TN-88 were cloned and sequenced. Southern blot analysis indicated that the endoinulinase gene (inuC) was present as a single copy in the genome. An open reading frame, consisting of 1,545 bp, was not interrupted by introns, and it encoded a 25 amino acid signal peptide and a 490 amino acid mature protein. The mature protein contained three Cys residues and ten potential N-linked glycosylation sites. Three distinct transcriptional start points were observed at positions -242 (A), -215 (A), and -75 (C) from the start codon. The 5'-noncoding region had a putative TATA box at position -120 (TATATATA) and two contiguous CAAT sequences at -159 to -151. The deduced amino acid sequence showed 72 and 85% identities with those of Aspergillus niger and Penicillium purpurogenum endoinulinase genes, respectively. A neighbor-joining tree showed that fungal endoinulinases form a distinct cluster from other members of the beta-fructofuranosidase superfamily and that they are more closely related to bacterial levanases than to a fungal fructosyltransferase, yeast invertases, or a yeast exoinulinase.

In vivo isomerization of retinoic acids. Rapid isomer exchange and gene expression.

The in vivo isomerization of all-trans- and 9-cis-retinoic acids (RAs) was evaluated by high performance liquid chromatography after oral administration to rats. All-trans (2 ng/ml)- and 13-cis (1.8 ng/ml)-RAs, but not 9-cis-RA, were detected in the serum of normal rats. When an excess of either all-trans-RA or 9-cis-RA (100 micrograms/rat) was intragastrically administered to the retinoid-depleted rats, a rapid isomer exchange between 9-cis- and all-trans-RAs along with appearance of the administered RA occurred shortly after the dose (30 min). RA rapidly isomerized when an excess of either all-trans- or 9-cis-RA (1 mg/rat) was administered to normal rats. To examine whether the isomerized RAs elicit biological actions in vivo, the induction of target genes-[cellular retinol-binding protein type II (CRBP II) for 9-cis-RA and all-trans-retinoic acid receptor beta (RAR beta) for 9-cis- and all-trans-RAs] was determined. The degree of induction of the two genes did not differ 4 h after administration of either 9-cis-RA or all-trans-RA. However, unlike all-trans-RA, the RAR-specific synthetic retinoids did not induce the CRBP II gene. These results suggested that the apparent actions of 9-cis- and all-trans-RAs on gene expression in vivo may be mediated to some extent by the converted stereoisomer.

Plasma guanosine 3',5'-monophosphate responses to the cold pressor test in patients with vibration disease.

Plasma cyclic guanosine 3',5'-monophosphate (cyclic GMP) levels were determined during the cold pressor test (CPT) in 10 normal volunteers and 39 patients with vibration disease. The CPT caused no significant increase in plasma cyclic GMP in the controls. There was a sharp rise in plasma cyclic GMP during and after the CPT in patients with vibration disease. This increase was suppressed by simultaneous injection of phentolamine or atropine. In patients who had been treated with kallidinogenase or nicametate citrate for 3-6 months, the CPT caused no significant increase in plasma cyclic GMP. In 1 patient the plasma cyclic GMP was suppressed by dihydroergotamine. From these findings it is very likely that cholinergic or alpha-adrenergic receptor responses are enhanced in patients with vibration disease.