Nivolumab with carboplatin, paclitaxel, and bevacizumab for first-line treatment of advanced nonsquamous non-small-cell lung cancer.

BACKGROUND: This international, randomized, double-blind phase III study (ONO-4538-52/TASUKI-52) evaluated nivolumab with bevacizumab and cytotoxic chemotherapy as first-line treatment for nonsquamous non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Between June 2017 and July 2019, this study enrolled treatment-naïve patients with stage IIIB/IV or recurrent nonsquamous NSCLC without sensitizing EGFR, ALK, or ROS1 alterations. They were randomly assigned in a 1 : 1 ratio to receive nivolumab or placebo in combination with carboplatin, paclitaxel, and bevacizumab every 3 weeks for up to six cycles, followed by nivolumab/placebo with bevacizumab until progressive disease or unacceptable toxicity. The primary endpoint was progression-free survival (PFS) assessed by an independent radiology review committee (IRRC). RESULTS: Overall, 550 patients from Japan, Korea, and Taiwan were randomized; of these patients, 273 and 275 received the nivolumab and placebo combinations, respectively. In the present preplanned interim analysis with a median follow up of 13.7 months, the IRRC-assessed median PFS was significantly longer in the nivolumab arm than in the placebo arm (12.1 versus 8.1 months; hazard ratio 0.56; 96.4% confidence interval 0.43-0.71; P < 0.0001). The PFS benefit was observed across all patients with any programmed death-ligand 1 (PD-L1) expression levels including PD-L1-negative patients. The IRRC-assessed objective response rates were 61.5% and 50.5% in the nivolumab and placebo arms, respectively. The incidence of treatment-related adverse events of grade 3 or 4 was comparable between the two arms; treatment-related adverse events leading to death were observed in five and four patients in the nivolumab and placebo arms, respectively. CONCLUSION: The TASUKI-52 regimen should be considered a viable new treatment strategy for treatment-naïve patients with advanced nonsquamous NSCLC.

The relationship between central motor conduction time and spinal cord compression in patients with cervical spondylotic myelopathy.

STUDY DESIGN: Retrospective study. OBJECTIVES: Few studies have reported a relationship between central motor conduction time (CMCT), which evaluates corticospinal function, and degree of spinal cord compression in patients with myelopathy. Thus, there is no consensus on predicting the degree of prolonged CMCT on the basis of the degree of spinal cord compression. If a correlation exists between CMCT and spinal cord compression, then spinal cord compression may be a useful noninvasive clinical indicator of corticospinal function. Therefore, this study evaluated the relationship between CMCT and cervical spinal cord compression measured by magnetic resonance imaging (MRI) in patients with cervical spondylotic myelopathy (CSM). SETTING: Hiroshima University Hospital in Japan. METHODS: We studied 33 patients undergoing laminoplasty. Patients exhibited significant cervical spinal cord compression on both MRI and intraoperative electrophysiological examination. We assessed transcranial magnetic stimulation measurement of CMCT; spinal cord compression parameters such as area, lateral diameter, anteroposterior diameter and flattening of the spinal cord at the lesion site and C2/3 levels on MRI; and pre- versus postoperative Japanese Orthopaedic Association (JOA) scores. RESULTS: Correlations between CMCT and flattening as well as anteroposterior diameter of the spinal cord at the lesion level were observed. Strong correlations between CMCT and the ratio of the flattening and anteroposterior diameter parameters at the lesion level to that at the C2/3 level were also observed. CONCLUSIONS: Measurement of spinal cord compression may be useful for the evaluation of corticospinal function as a proxy for CMCT in patients with CSM.

Resection of spinous processes can cause spinal cord injury in patient with ossification of the posterior longitudinal ligament in the thoracic spine.

STUDY DESIGN: Case report. OBJECTIVE: To report intraoperative spinal cord injury by resection of spinous processes in a 73-year-old man with ossification of the posterior longitudinal ligament (OPLL) in the thoracic spine. METHODS: A 73-year-old man presented with cervicothoracic OPLL with bilateral numbness and clumsiness of his hand, weakness of his lower extremities and severe gait disturbance. His Japanese Orthopaedic Association (JOA) score was 7.5 out of 17. Cervical laminoplasty (C2-6), cervicothoracic laminectomy (C7-T10) and posterior fusion (C7-T10) were performed in the prone position with electrophysiologic monitoring of the spinal cord-evoked potentials (SCEPs). RESULTS: The spinal processes with supra- and interspinous ligaments between C7 and T10 were resected. After resection, the amplitude of SCEP waveforms decreased rapidly to <10% of control levels. Laminectomy was performed, and, after 80 min of SCEP deterioration, an instrumented fusion with correction for kyphosis was completed. The SCEP amplitude recovered gradually. Immediately after surgery, the patient suffered severe motor loss in both lower limbs. His neurological recovery progressed gradually from 2 days after surgery, and he was able to walk at 3 months after surgery. At 6 years after surgery, the JOA score was 11. CONCLUSION: Our results suggest that intraoperative spinal cord injury can occur before posterior decompression by resection of spinal processes with supra- and interspinous ligaments. The timing of the instrumented stabilization using a temporary rod is important and should be considered immediately after posterior exposure of the spine.

Utilization of a glucose/fructose/xylitol carbohydrate solution during surgery.

The utilization of a 4:2:1 mixture of glucose, fructose, and xylitol (GFX) was studied by indirect calorimetry in patients undergoing abdominal surgery. Sixteen patients undergoing gastrectomy under general anesthesia received GFX intravenously at 0.25 g/kg h-1 during surgery. VO2, VCO2, and RQ were measured continuously for 150 min using an Engström metabolic computer, and urea nitrogen excretion was determined at 30-min intervals during surgery. Blood levels of glucose, fructose, and xylitol plateaued after 1 h. The RQ decreased over the first 90 min from 0.84 +/- 0.06 to 0.75 +/- 0.05 and then gradually increased to 0.79 +/- 0.04 at 150 min. VO2 did not change significantly over the 150-min period. From the RQ, VO2, and nitrogen excretion data, carbohydrate oxidation was estimated. The amount of carbohydrate oxidized was 9.7 +/- 6.9 g during the first 30-min period, 3.5 +/- 5.2 g during the 60 to 90-min period, and 7.5 +/- 4.5 g in the 120 to 150-min study period. Simultaneously, lipid oxidation increased. These observations suggest that the GFX solution is adequately metabolized during surgery and therefore may be a suitable energy source for patients.

[Myxomatous stromal changes in bone marrow following chemotherapy of acute leukemia--immunohistochemical characteristics of matrix components].

Although fibrosis and gelatinous transformation of bone marrow stroma are well known, there have been few histopathological descriptions in the literature. We studied 16 cases of acute leukemia, and describe the myxomatous changes of bone marrow stroma observed at 2 or 3 weeks following chemotherapy. We analyzed the extracellular matrix components immunohistochemically, using monoclonal or polyclonal antibodies raised against collagens, proteoglycans (PG), fibronectin and laminin. We found that the major components of the myxomatous matrix were chondroitin 6-sulfate PG and large PG. The stainability resembles that of extracellular matrix components in long-term bone marrow culture. We suppose that the myxomatous matrix provides favorable conditions for hematopoiesis, because hematopoietic cells proliferate and differentiate as soon as such stromal changes occur.

[Anesthetic management of caesarean section for the delivery of quadruplets].

Multiple gestation pregnancies are accompanied with risks for both mother and fetuses. Morbidity and mortality of both of them are increased compared with singleton pregnancies. We have presented a case of a 30-year-old parturient with quadruplets. The pregnancy had been complicated by premature labour, anemia, toxemia, coagulopathy, pulmonary congestion and malpresentation. On the 29th week of pregnancy, an elective Caesarean section was scheduled. There is no ideal anesthetic technique for quadruplets. In this case general anesthesia was chosen, because she had coagulopathy. The anesthesia and postoperative course were uneventful. The patient and the four babies had no complication nor sequela on their discharge. The anesthetic considerations for multiple gestation pregnancies were also discussed.

[Anesthetic management in surgery of thoracic aortic aneurysms--a report of eleven cases].

Anesthetic management of patients with thoracic aneurysm is discussed. During a period of two years, 11 cases were observed; 7 cases of dissecting aneurysm and 4 cases of true aneurysm. Dissecting aneurysms were of DeBakey's type 1 in 5 cases and of DeBakey's type 2 in 2 cases. Four cases had hypertension. As many of these patients often have hypertension, it is important not to change the circulatory dynamics during induction of anesthesia. We employed high dose fentanyl in 9 cases and used nitroglycerin or nitroprusside to control systolic blood pressure at about 100-120 mmHg. Massive bleeding can occur during intraoperative period and it is important to secure a sufficient number of intravenous routes to protect the central nervous system during cardio-pulmonary bypass.

[Effects of prostaglandin E1 and dibutyryl cyclic AMP on hemodynamics after cardiopulmonary bypass in valve replacement surgery].

In view of vasodilating action of prostaglandin E1 (PGE1) and dibutyryl cyclic AMP (DBcAMP) we investigated the effect of each agent on hemodynamics after weaning from cardiopulmonary bypass (CPB) comparing with the effect in control group. PGE1 and DBcAMP were administered to patients who underwent valve replacement surgery with continuous low dose infusion at an average rate of 0.026 micrograms.kg-1.min-1 and 7.25 micrograms.kg-1.min-1 respectively. Following result was obtained. In PGE1 administered group, a significant reduction in pulmonary vascular resistance (PVR) and a significant decrease in mean arterial pressure (MAP) were observed during CBP, while there were no significant differences in other parameters, such as platelet counts, differences between core and peripheral temperature (delta T), urine output, systemic vascular resistance (SVR), cardiac index (CI), right-to-left shunt (Qs/Qt), oxygen delivery (DO2) and oxygen consumption (VO2). However, CI and platelet counts tended to increase but delta T and SVR tended to decrease. In DBcAMP administered group, there were no significant differences in all parameters compared with those of control group, showing a tendency of less improvement in hemodynamics than in PGE1 group. We have shown that the use of PGE1 rather than DBcAMP as vasodilator agent seems advantageous during open-heart surgery in patients especially with severe pulmonary hypertension, but it tends to cause severe hypotension during CPB.

Reciprocal regulation of prothrombin secretion and tyrosine aminotransferase induction in hepatocytes.

Multicellular spheroids of hepatocytes are known to maintain liver functions for a long period. Rat hepatocytes were isolated to form spheroids by rotation culture and immobilized within calcium alginate. Immobilized spheroids had a much higher extent of tyrosine aminotransferase induction, which is one of the liver-specific differentiated functions, than immobilized non-aggregated cells, while the spheroids secreted significantly less prothrombin than non-aggregated cells. Co-culture of hepatocytes and non-parenchymal liver cells in a monolayer enhanced tyrosine aminotransferase induction and suppressed prothrombin secretion, while conditioned medium prepared from non-parenchymal cells greatly stimulated tyrosine aminotransferase induction and suppressed the prothrombin secretion and DNA synthesis in monolayer-cultured hepatocytes. Prothrombin secretion in hepatocytes was subjected to cell-density-dependent regulation. In a similar manner to other growth-related functions, prothrombin secretion was stimulated at low cell density. It has been reported that thrombin activates the zymogen of hepatocyte growth factor activator [Shimomura, T., Kondo, J., Ochiai, M., Naka, D., Miyazawa, K., Morimoto, Y. & Kitamura, N. (1993) J. Biol. Chem. 268, 22,927-22,932]. Therefore, prothrombin secretion could be one of the growth-related functions and involved in wound healing and liver regeneration.

Stimulation of liver functions in hierarchical co-culture of bone marrow cells and hepatocytes.

A hierarchial co-culture, in which rat hepatocytes and non-parenchymal liver cells (NPLCs) were separated by a collagen layer and which was designed to mimic the in vivo microenvironment, was carried out with the aim of developing a module for bio-artificial liver support. Compared with a monolayer co-culture and hepatocytes cultured alone in a monolayer, higher urea synthesis activity was maintained for 6 d in the hierarchical co-culture. When a rat hepatoma cell line H4-II-E-C3, which retains the induction of tyrosine aminotransferase (TAT), was co-cultured in a monolayer with NPLCs, dose-dependent stimulation of TAT induction was observed. In a hierarchical co-culture, NPLCs further stimulated TAT induction in H4-II-E-C3 cells. Since peritoneal macrophages could stimulate TAT induction in hepatocytes in both monolayer and hierarchical co-cultures, bone marrow cells, which can proliferate and differentiate into macrophages in vitro, were investigated as a possible substitute for NPLCs. Bone marrow cells isolated from rat femurs were cultivated in the presence of IL-3 and macrophage colony-stimulating factor (M-CSF), and co-cultured with hepatocytes. Urea synthesis and TAT induction of hepatocytes were stimulated in the co-culture. The co-culture of bone marrow and H4-II-E-C3 cells, both of which have proliferation ability in vitro, was also shown to be effective in stimulating liver functions. The hierarchical configuration, in which two cell types can communicate with the soluble factor(s) through a collagen layer, was found to be more effective than a monolayer in long-term co-culture.