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.

The relationships of proteinuria, serum creatinine, glomerular filtration rate with cardiovascular disease mortality in Japanese general population.

Proteinuria, high serum creatinine, and reduced glomerular filtration rate (GFR) have been associated with increased mortality from cardiovascular disease (CVD) and all causes. However, the combined effect of proteinuria with serum creatinine and GFR on CVD or all-cause mortality has not been well investigated. We conducted a 10-year prospective cohort study of 30,764 men and 60,668 women aged 40-79 years who participated in annual health checkups in 1993. The Cox proportional hazards model was used to estimate the relative risk (RR) after adjusting for age, smoking, and other cardiovascular risk factors. The multivariable RR (95% confidence interval (CI)) of CVD death for positive vs negative proteinuria was 1.38 (1.05-1.79) among men and 2.15 (1.64-2.81) among women. The respective RR for the highest vs lowest creatinine groups (> or = 1.3 vs < or = 0.8 mg/dl for men and > or = 1.1 vs < or = 0.6 mg/dl for women) was 1.56 (1.19-2.04) among men and 2.15 (1.58-2.93) among women. The respective RR for GFR < 60 vs > r = 100 ml/min/1.73 m2 was 1.65 (1.25-2.18) among men and 1.81 (1.39-2.36) among women. For individuals with proteinuria combined by hypercreatininemia or reduced GFR, the risk of CVD death was two-fold higher in men and 4-6-fold higher in women compared to those without proteinuria and with normal creatinine level or GFR. Similar associations were observed for stroke, coronary heart disease, and all-cause mortality. Proteinuria, and hypercreatininemia or reduced GFR and their combination were significant predictors of CVD and all-cause mortality.

The effect of interaction between hepatitis C virus and cigarette smoking on the risk of hepatocellular carcinoma.

We evaluated the interaction between hepatitis C virus (HCV) and cigarette smoking on death from hepatocellular cancer in The Japan Collaborative Cohort Study. The odds ratio of death from HCC for smoking was 9.60 (1.50-61.35) and 1.71(0.58-5.08) among anti-HCV positive and negative individuals, respectively.

Coffee and risk of death from hepatocellular carcinoma in a large cohort study in Japan.

We examined the relation between coffee drinking and hepatocellular carcinoma (HCC) mortality in the Japan Collaborative Cohort Study for Evaluation of Cancer Risk (JACC Study). In total, 110,688 cohort members (46,399 male and 64,289 female subjects) aged 40-79 years were grouped by coffee intake into three categories: one or more cups per day, less than one cup per day and non-coffee drinkers. Cox proportional hazards model by SAS was used to obtain hazard ratio of HCC mortality for each coffee consumption categories. The hazard ratios were adjusted for age, gender, educational status, history of diabetes and liver diseases, smoking habits and alcohol. The hazard ratio of death due to HCC for drinkers of one and more cups of coffee per day, compared with non-coffee drinkers, was 0.50 (95% confidence interval 0.31-0.79), and the ratio for drinkers of less than one cup per day was 0.83 (95% confidence interval 0.54-1.25). Our data confirmed an inverse association between coffee consumption and HCC mortality.

Combination of boron and gadolinium compounds for neutron capture therapy. An in vitro study.

In neutron capture therapy, the therapeutic effect of the boron compound is based on alpha particles produced by the B(n, alpha) reaction while with the gadolinium compound the main radiation effect is from gamma rays derived from the Gd(n, gamma) reaction. The uptake and distribution within the tumor may be different among these compounds. Thus, the combination of the boron and gadolinium compounds may be beneficial for enhancing the radiation dose to the tumor. Chinese hamster fibroblast V79 cells were used. For the neutron targeting compounds, 10B (BSH) at 0, 5, 10, and 15 ppm, and 157Gd (Gd-BOPTA) at 0, 800, 1600, 2400, 3200, and 4800 ppm, were combined. The neutron irradiation was performed with thermal neutrons for 30 min. (neutron flux: 0.84 x 10(8) n/cm2/s in free air). The combination of the boron and gadolinium compounds showed an additive effect when the gadolinium concentration was lower than 1600 ppm. This additive effect decreased as a function of gadolinium concentration at 2400 ppm and resulted in no additive effect at more than 3200 ppm of gadolinium. In conclusion, the combination of the boron and gadolinium compounds can enhance the therapeutic effect with an optimum concentration ratio. When the gadolinium concentration is too high, it may weaken the boron neutron capture reaction due to the high cross-section of gadolinium compound against neutrons.

Cervical spondylosis with thoracic level Brown-Séquard syndrome.

Brown-Sequard Syndrome (BSS) caused by cervical spondylosis (CS) is rare. About 70% of patients with CS presenting with BSS show lesion-dermatome discrepancy, which may be due to spinal cord lamination. From the clinical point of view, this discrepancy should be carefully evaluated and these patients should be treated as an emergency.

Normal pressure hydrocephalus after gamma knife radiosurgery for cerebellopontine angle meningioma.

There are no reports of hydrocephalus following radiosurgery for a meningioma. We report on a case where gamma knife therapy for a 4 cm diameter right cerebellopontine meningioma accelerated hydrocephalus three months post treatment. Examination of the cerebrospinal fluid (CSF) revealed a high protein level and thus, CSF malabsorption and CSF obstruction might have occurred after the radio surgery. It is important to consider this pathology, and the need for long term follow up.

Kernohan's phenomenon associated with left ruptured occipital arteriovenous malformation.

A 23-year-old woman presented with ipsilateral hemiparesia due to rupture of a left occipital arteriovenous malformation (AVM). Emergency decompression (the onset-operation interval was 46 minutes,) was carried out and the patient could leave the hospital upon recovery without neurological deficits. In general, Kernohan's phenomenon is caused by the gradual displacement of the cerebral peduncle against the tentorial edge caused by compression by the contralateral mass. This phenomenon is very rare among the cases with spontaneous intracranial hemorrhage and only three cases including the present one have been reported in the literature. In all cases the onset-operation intervals of were very short. Kernohan's phenomenon associated with a ruptured AVM is a rare condition and emergency decompression is required.

Pitch perception abnormality as a side effect of carbamazepine.

Carbamazepine (CBZ) is frequently used to treat patients with epilepsy, neuralgia, psychiatric diseases, etc. We prescribe it with care due to its side effects, mainly such as dizziness, sleepiness and cerebellar symptoms. But pitch perception abnormality is an uncommon side effect. We describe the case of a 12-year-old girl who exhibited half tone lowered pitch perception abnormality caused by CBZ. As CBZ acts as a central nervous system (CNS) inhibitor, we speculate that CBZ inhibits CNS and patients misperceive notes. We must prescribe CBZ with care to prevent pitch perception abnormalities.

Retreatment of cerebral aneurysms after guglielmi detachable coil embolization.

SUMMARY: Of 175 patients with 181 aneurysms initially treated with Guglielmi Detachable Coils (GDC), 25 were retreated. All retreatments except one were performed on previously ruptured aneurysms. Thirteen aneurysms were retreated because of recurrence, and 12 aneurysms were retreated to complete initial insufficient embolization. Sixteen patients underwent re-embolization and 9 patients were operated upon surgically. No complications related to the retreatment were experienced. We consider that repeat embolization should be attempted before considering surgical treatment in case that additional therapy is required. However, it is difficult to retreat aneurysms having wide necks. In regard to surgical clipping, aneurysms without a coil in the neck are easier to treat with primary clipping, whereas aneurysms with a coil mass in the neck are difficult to surgical clip. We have never used temporary clipping and coil extraction if the distance between the coil and the parent artery was wider than 2 mm. Emerging new embolic agents or devices and technical improvement might decrease the need for retreatment and increase long-term efficacy after endovascular treatment.

Awakenings from persistent vegetative state: report of three cases with parkinsonism and brain stem lesions on MRI.

Three patients with a persistent vegetative state after severe head injury are reported. They recovered from a prolonged disturbance of consciousness after the administration of levodopa. These patients all had parkinsonian features. On magnetic resonance imaging, the distribution of lesions implied a diffuse axonal injury involving the substantia nigra or ventral tegmental area. The existence of patients whose dopaminergic systems may have been selectively damaged by a severe head injury should be recognised because such individuals may respond to levodopa treatment.

Perfusion-weighted MRI of spinal dural arteriovenous fistula.

A 72-year-old woman was admitted with rapidly progressive paraplegia and sphincter disturbance. T2-weighted images of the thoracic spine showed intramedullary high signal with flow voids suggesting dilated medullary veins. Conventional spinal angiography demonstrated a dural arteriovenous fistula draining into perimedullary veins. Perfusion-weighted MRI demonstrated a prolonged mean transit time and increased blood volume in the high-signal area. The loss of normal perfusion gradient and venous hypertension and were thought to produce these differences. The time-to-peak was almost identical in the high-signal and isointense areas, although the bolus of contrast medium arrived earlier in the former. Arteriovenous shunting was thought to cause faster inflow. These changes may have resulted in increased blood volume in the spinal cord. The high signal has been attributed to oedema due to venous congestion, but there has been no histological confirmation. Perfusion MRI in this case supports this hypothesis.

The antioxidant EPC-K1 ameliorates brain injury by inhibiting lipid peroxidation in a rat model of transient focal cerebral ischaemia.

BACKGROUND: Cerebral ischaemia-reperfusion injury is associated with the generation of reactive oxygen species during the early phases of reoxygenation. EPC-K1, a phosphate diester of vitamins C and E, has been reported to possess potent hydroxyl radical scavenging activity. This study was performed to investigate the effectiveness of EPC-K1 in attenuating cerebral ischaemia-reperfusion injury in a rat model of transient focal cerebral ischaemia. METHOD: We evaluated the efficacy of EPC-K1 by measuring the concentration of cerebral thiobarbituric acid reactive substances (TBARS), an indicator of the extent of lipid peroxidation by free radicals, and infarct size in rats subjected to one hour of cerebral ischaemia and 4, 24, or 72 hours of reperfusion. FINDINGS: EPC-K1 significantly reduced both the cerebral TBARS level and the infarct size in a rat model of transient focal cerebral ischaemia. These results indicate that EPC-K1 administration during the early stages of reperfusion ameliorates ischaemic brain injury by inhibiting lipid peroxidation. INTERPRETATION: This report is the first to describe the protective mechanism of EPC-K1 by measuring both the TBARS level and infarct size in a rat model of transient focal cerebral ischaemia, and may suggest a potential clinical approach for the treatment of ischaemic cerebrovascular disease.

Intraoperative angiography in the surgical treatment of cerebral arteriovenous malformations and fistulas.

BACKGROUND: The role of intraoperative angiography in the surgical treatment of cerebrovascular malformations remains controversial. The authors report on their experiences with intraoperative angiography in a series of 20 cases with cerebrovascular malformation to determine whether the use of intraoperative angiography has a favorable impact on the surgical treatment of cerebrovascular malformations. METHODS: Intraoperative angiography was performed in the surgical resection of arteriovenous malformation in 18 patients and in the surgical obliteration of arteriovenous fistula in 2 patients. The incidence of unexpected findings, such as residual nidus, demonstrated by intraoperative angiography was determined. FINDINGS: High-quality subtraction images were obtained by intraoperative angiography in every case and the findings prompted an additional procedure in 1 case that displayed an unexpected residual nidus (5.6%). There were no complications from the intraoperative angiography procedure. INTERPRETATION: Intraoperative assessment of technical results prior to wound closure offers the neurosurgeon the opportunity to resect or obliterate a vascular malformation completely, obviating a second operation.

Combined minimally invasive approach using microsurgery and thoracoscopic surgery for resecting a dumbbell-type thoracic schwannoma.

We present a case of a thoracic schwannoma with an intravertebral component, a so-called "dumbbell-type" tumor, that was resected with a combined minimally invasive approach using microsurgery and thoracoscopic surgery simultaneously. A 31-year-old man was admitted to our hospital for treatment of a thoracic schwannoma 45 mm in maximal diameter at the level of the third thoracic vertebra. After the tumor was separated from intravertebral structures by using a microsurgical technique via the posterior approach with a hemilaminectomy and minimal unilateral facetectomy, the mass was removed completely by using video thoracoscopy. We stress that this approach should be the most useful and less invasive technique for treating the dumbbell-type of thoracic neurogenic tumor compared with a single or combination technique involving thoracotomy, multi-level laminectomy and costotransversectomy. Below, we make some notes on this technique from the neurosurgeon's standpoint.

Cell cycle dependence of boron uptake from two boron compounds used for clinical neutron capture therapy.

In neutron capture therapy, it is important that the boron is selectively uptaken by tumor cells. In the present study, we used flow cytometry to sort the cells in the G0/G1 phase and those in the G2/M phase, and the boron concentration in each fraction was measured with inductively coupled plasma atomic emission spectroscopy. The results revealed that sodium borocaptate and boronophenylalanine (BPA), were associated with higher rates of boron uptake in the G2/M than in the G0/G1 phase. However, the difference was more prominent in the case of BPA. The G2/M:G0/G1 ratio decreased as a function of exposure time in BPA containing culture medium, thereby indicating the cell cycle dependency of BPA uptake. Such heterogeneity of boron uptake by tumor cells should be considered for microdosimetry.

In-phantom two-dimensional thermal neutron distribution for intraoperative boron neutron capture therapy of brain tumours.

The aim of this study was to determine the in-phantom thermal neutron distribution derived from neutron beams for intraoperative boron neutron capture therapy (IOBNCT). Gold activation wires arranged in a cylindrical water phantom with (void-in-phantom) or without (standard phantom) a cylinder styrene form placed inside were irradiated by using the epithermal beam (ENB) and the mixed thermal-epithermal beam (TNB-1) at the Japan Research Reactor No 4. With ENB, we observed a flattened distribution of thermal neutron flux and a significantly enhanced thermal flux delivery at a depth compared with the results of using TNB-1. The thermal neutron distribution derived from both the ENB and TNB-1 was significantly improved in the void-in-phantom, and a double high dose area was formed lateral to the void. The flattened distribution in the circumference of the void was observed with the combination of ENB and the void-in-phantom. The measurement data suggest that the ENB may provide a clinical advantage in the form of an enhanced and flattened dose delivery to the marginal tissue of a post-operative cavity in which a residual and/or microscopically infiltrating tumour often occurs. The combination of the epithermal neutron beam and IOBNCT will improve the clinical results of BNCT for brain tumours.

Chronological change of brain abscess in (1)H magnetic resonance spectroscopy.

We studied chronological magnetic resonance spectral changes in brain abscesses before and after medical and/or surgical treatment. We examined five patients with MRI imaging and (1)H magnetic resonance spectroscopy (MRS) on two or more occasions, using two volume-of-interest patterns, and saw chronological changes related to the evolution of the abscess. A spectrum specific for brain abscess was found in three of the five cases, while two showed a single lactate peak in the first study. In two cases, phenylalanine or alanine appeared in the second study. We observed the disappearance of the specific spectra and a single lactate peak following surgery. Only one patient showed different spectra in different volume of interest.