Safety and efficacy of nivolumab and standard chemotherapy drug combination in patients with advanced non-small-cell lung cancer: a four arms phase Ib study.

BACKGROUND: The human IgG4 monoclonal antibody nivolumab targets programmed cell death-1 (PD-1) and promotes antitumor response by blocking the interaction of PD-1 with its ligands. This single-center phase Ib study investigated the tolerability, safety, and pharmacokinetics of nivolumab combined with standard chemotherapy in patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients who had stage IIIB without indication for definitive radiotherapy, stage IV, or recurrent NSCLC were eligible. Regimens were nivolumab 10 mg/kg + gemcitabine/cisplatin (arm A), pemetrexed/cisplatin (arm B), paclitaxel/carboplatin/bevacizumab (arm C), or docetaxel (arm D). Regimens A, B, and D were repeated every 3 weeks for up to four cycles and regimen C was repeated for up to six cycles; nivolumab alone (arm A), with pemetrexed (arm B), bevacizumab (arm C), or docetaxel (arm D) was continued every 3 weeks as maintenance therapy until disease progression or unacceptable toxicity. Dose-limiting toxicity (DLT) was evaluated during the first treatment cycle. RESULTS: As of March 2014, six patients were enrolled in each arm. The combination of nivolumab 10 mg/kg and chemotherapy was well tolerated. DLT was observed in only one patient in arm A (alanine aminotransferase increased). Select adverse events (those with a potential immunologic cause) of any grade were observed in six, four, six, and five patients in arms A, B, C, and D, respectively. Three, three, six, and one patient achieved partial response while median progression-free survival was 6.28, 9.63 months, not reached, and 3.15 months in arms A, B, C, and D, respectively. CONCLUSIONS: Combination of nivolumab 10 mg/kg and chemotherapy showed an acceptable toxicity profile and encouraging antitumor activity in patients with advanced NSCLC. CLINICAL TRIALS NUMBER: Japanese Pharmaceutical Information Center Clinical Trials Information (JapicCTI)-132071.

Comparison of clinical outcomes of osimertinib and first-generation EGFR-tyrosine kinase inhibitors (TKIs) in TKI-untreated EGFR-mutated non-small-cell lung cancer with leptomeningeal metastases.

BACKGROUND: Leptomeningeal metastases (LM) are devastating complications of epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC). Although osimertinib, a third-generation EGFR-tyrosine kinase inhibitor (TKI), has better penetration into the central nervous system than first-generation EGFR-TKIs, data on the distinct activity of EGFR-TKIs in untreated advanced EGFR-mutated NSCLC with LM are lacking. PATIENTS AND METHODS: We retrospectively reviewed patients treated with EGFR-TKIs for TKI-untreated common EGFR-mutated NSCLC with LM between July 2002 and July 2021 at the National Cancer Center Hospital. The patients were divided into two groups: patients treated with osimertinib (Osi group) and those treated with gefitinib or erlotinib [first-generation (1G)-TKI group]. RESULTS: Of the 967 patients, 71 were eligible, including 29 in the Osi group and 42 in the 1G-TKI group. The median progression-free survival (PFS) and overall survival (OS) in the Osi group were better than those in the 1G-TKI group (PFS: 16.9 months versus 8.6 months, P = 0.007, and OS: 26.6 months versus 20.0 months, P = 0.158). The LM-overall response rate (ORR) and LM-PFS were significantly better in the Osi group than in the 1G-TKI group (LM-ORR: 62.5% versus 25.7%, P = 0.007; LM-PFS: 23.4 months versus 12.1 months, P = 0.021). In the subgroup analysis of EGFR mutation status, LM-PFS for patients with exon 19 deletion was significantly longer in the Osi group than in the 1G-TKI group (32.7 months versus 13.4 months, P = 0.013), whereas those with L858R mutation in exon 21 did not differ between the two groups. In the multivariate analysis, osimertinib and exon 19 deletion were significant factors for better LM-PFS and OS. CONCLUSION: Osimertinib can be more effective for untreated common EGFR-mutated NSCLC patients with LM, especially those with exon 19 deletion, compared to first-generation TKIs.

Adrenal function in patients with community-acquired pneumonia.

Adrenal insufficiency is believed to occur frequently in severe sepsis and septic shock. The aim of the present study was to determine whether adrenal function is also related to the severity of community-acquired pneumonia (CAP). In total, 64 Japanese patients with CAP were consecutively enrolled in the present study, which was carried out during 2005-2006. Serum adrenocorticotropic hormone (ACTH) and cortisol were measured in each subject, as was the response of cortisol secretion when 250 mug of cosyntropin was administered. Analyses were performed comparing these values with the score calculated according to the Pneumonia Patient Outcomes Research Team (PORT) cohort study, the number of in-hospital deaths and the length of hospital stay. As the PORT score increased, serum ACTH and cortisol also increased, while the response of cortisol secretion to the administration of cosyntropin decreased. In the analysis by receiver operating characteristic curves, adrenal dysfunction was related significantly to both the number of in-hospital deaths and the length of hospital stay. Adrenal dysfunction was shown to correlate with the Pneumonia Patient Outcomes Research Team score and the clinical outcomes, while adrenal insufficiency defined by the cosyntropin stimulation test was rare in the present study.

Haemoglobin-vesicles as artificial oxygen carriers: present situation and future visions.

During the long history of development of haemoglobin (Hb)-based O2 carriers (HBOCs), many side effects of Hb molecules have become apparent. They imply the physiological importance of the cellular structure of red blood cells. Hb-vesicles (HbV) are artificial O2 carriers that encapsulate concentrated Hb solution with a thin lipid membrane. We have overcome the intrinsic issues of the suspension of HbV as a molecular assembly, such as stability for storage and in blood circulation, blood compatibility and prompt degradation in the reticuloendothelial system. Animal tests clarified the efficacy of HbV as a transfusion alternative and the possibility for other clinical applications. The results of ongoing HbV research make us confident in advancing further development of HbV, with the expectation of its eventual realization.

Novel homozygous mutation of the caveolin-3 gene in rippling muscle disease with extraocular muscle paresis.

We describe a 39-year-old Japanese man with rippling muscle disease who carried a novel homozygous mutation (Trp70 to a stop codon) in the caveolin-3 gene. The patient also had extraocular muscle paresis showing atrophy of the extraocular muscles on orbital MRI. The involvement of the extraocular muscles of patients with caveolinopathy is discussed.

Association of HTLV-I antibody profile of asymptomatic carriers with proviral DNA levels of peripheral blood mononuclear cells.

The human T-lymphotropic virus type I (HTLV-I) antibody profile of 216 asymptomatic carriers in Miyazaki, Japan, was analyzed in conjunction with the HTLV-I proviral DNA levels in their peripheral blood mononuclear cells (PBMC) determined by the semiquantitative polymerase chain reaction (PCR) method. The geometric mean HTLV-I titer by particle agglutination assay (PA) of 58 subjects (27%) with a high DNA level was 1:1, 240; 94 (44%) with a medium DNA level, 1:740; 38 (18%) with a low level, 1:476; and, 26 (12%) with an undetectable level, 1:263. Moreover, when the subjects were divided into four groups according to titer from high to low, the correlation between DNA level and antibody titer level was highly significant (p < 0.0001). HTLV-I antibody subclass by Western blot (WB) was determined for 78 randomly selected samples from these carriers. Immunoglobulin (Ig) M antibody was detected in 35 (45%). The mean PA antibody titer was higher in carriers with IgM antibody than in those without, at each detectable proviral DNA level. These findings suggest that HTLV-I antibody titer is related to proviral DNA level and also to the presence of IgM antibodies among those with proviral DNA of the same level. Seven carriers (9%) were negative for IgG antibody by WB, among whom the proviral DNA level was low or undetectable and the PA titer was also low. Three of these were positive only for IgM antibody.

A new dysferlin gene mutation in two Japanese families with limb-girdle muscular dystrophy 2B and Miyoshi myopathy.

We found a new dysferlin gene mutation in two Japanese families, one with limb-girdle muscular dystrophy 2B and the other with Miyoshi myopathy. All patients in the limb-girdle muscular dystrophy 2B family showed apparent proximal dominant muscle atrophy and weakness, whereas a patient with Miyoshi myopathy in the second family showed distal muscle involvement at an early stage. The common clinical feature of all patients in both families was preferential involvement of calf muscles rather than the tibialis anterior muscle, which was confirmed by muscle computed tomography scan. All patients in both families shared the same homozygous alleles for chromosome 2p13 markers, and dysferlin gene analysis revealed a novel missense mutation, a G to A transition at nt 5882, which changed aspartic acid to asparagine at codon 1837. Allele-specific polymerase chain reaction analysis was used for confirmation of the mutation and for genotype analysis of the family members.

Measurement of tumor blood flow using colored dye extraction microspheres in two rat tumor models.

A technique that can measure tumor blood flow easily, accurately and economically is required to study tumor angiogenesis and angiogenesis inhibition. Using dye extraction colored microspheres, we measured tumor blood flow in Sato lung carcinoma (SLC) and ascites hepatoma LY80 in rats. Colored microspheres were infused into tumor-bearing rats via a catheter in the left ventricle. After removal of the tumor and the liver, the tissue samples were dissolved, and the microspheres were isolated. Dye was extracted, and the dye concentration was quantified by spectrophotometry. The dye concentration per gram of tumor was compared with that per gram of liver as follows (AU = absorbency units): [AU per gram of tumor] / [AU per gram of liver] X 100 = (%). Tumor blood flow corrected for wet weight was calculated as follows: [blood flow to tumor] = [AU per gram of tumor] X [reference withdrawal rate] / [AU per gram of reference blood]. Tumor blood flow rate was divided by tumor weight to yield ml. min-1g-1. The tumors were also examined histologically, and casts of the tumor vasculature were prepared with silicone rubber. Blood flow 2 weeks after transplantation was equivalent to 1/10 and 1/2 at 1 week in SLC and LY80 tumors, respectively (SLC, P=0.009, n=10; LY80, P=0.05, n=10). These decreases in tumor blood flow were associated with underlying pathological and vascular change. Blood flow in LY80 tumors negatively correlated with tumor volume (P=0.009, n=10). We concluded that the colored microsphere method, initially developed to measure organ blood flow, is also useful for estimating tumor blood flow in rats.

Traumatic pulmonary pseudocyst. Report of twelve cases.

Twelve cases of traumatic pulmonary pseudocyst were seen between January 1966 and July 1987 at Saiseikai Kanagawaken Hospital. The cause of the traumatic pulmonary pseudocyst was closed blunt chest trauma in all patients. For the first few days after the injury, computed tomographic scan was more useful in diagnosis than chest roentogenogram. Tube drainage of the pleural cavity was performed in 10 patients who had hemothorax or hemopneumothorax, and antibiotics were administered to all patients. No patient underwent a surgical procedure, and all traumatic pulmonary pseudocysts eventually resolved, without any specific treatment, within 1 to 4 months (average 1.8 month) after the trauma. We conclude that pulmonary resection is not indicated except in the rare instance in which the traumatic pulmonary pseudocyst becomes infected.

Epithelial myoepithelial tumour of the tracheal gland.

A case of epithelial myoepithelial tumour originating from the tracheal gland in a 57 year old woman is described. The tumour was removed by segmental tracheal resection and end-to-end anastomosis. Histologically, the tumour comprised clear cells and presented a monophasic pattern. Immunohistochemical analysis showed that the tumour cells were positive for both S-100 protein and smooth muscle actin. suggesting that this tumour resembles a subtype of epithelial-myoepithelial carcinoma described in the 1990 WHO international classification of salivary glands. Although some reports describe a clear cell dominant epithelial myoepithelial carcinoma, in this case local invasiveness or regional lymphnode metastasis was not proved through investigation. It is therefore concluded that this was an epithelial myoepithelial tumour rather than a carcinoma.

Eradication of Rickettsia tsutsugamushi from patients' blood by chemotherapy, as assessed by the polymerase chain reaction.

The presence of Rickettsia tsutsugamushi DNA in peripheral blood mononuclear cells of eight patients with tsutsugamushi disease was determined by the polymerase chain reaction during antibiotic treatment with minocycline or doxycycline. Rickettsia tsutsugamushi DNA was detectable in all samples from these patients collected the day before treatment began. After the initiation of chemotherapy, all samples tested positive on the third or fourth day, and one sample tested positive on the eighth day, showing a slow action of the drugs against the rickettsia within cells. Immune responses against R. tsutsugamushi also seemed to be important for eradication of the pathogens, as suggested by patients' high antibody titers.

Genotypic identification of Rickettsia tsutsugamushi by restriction fragment length polymorphism analysis of DNA amplified by the polymerase chain reaction.

We combined the nested polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) for genotypic identification of Rickettsia tsutsugamushi. Four primers were selected from the DNA sequence of the gene encoding a 56-kD serotype-specific antigen of the Karp strain. Nested PCR produced rickettsia-specific products of approximately 0.6 kb in the amplification of DNA prepared from three reference strains (Gilliam, Karp, and Kato) and two prototype strains (Irie and Hirano) prevalent in the Miyazaki Prefecture of Japan. When the nested PCR products obtained from these five strains were digested with Hha I, profiles specific to each strain were generated. Fourteen of 17 DNA samples of peripheral blood mononuclear cells from patients with scrub typhus tested positive in the nested-PCR, providing a rickettsia-specific band. The serotype of infected rickettsia of 10 patients were diagnosed as Irie and those of four patients were diagnosed as Hirano by indirect immunofluorescence methods. The fragment profiles of the PCR products of these 14 patients after digestion with Hha I corresponded closely with those serotypes. However, the PCR products from two of four samples, which were similar to Hirano strain by a serologic method and by the pattern of digestion with Hha I, produced different RFLP profiles upon further digestion with Hinf I and Alu I. These results may suggest that genetic variation exists within serotypes. Genotypic identification of R. tsutsugamushi by means of PCR-RFLP using three restriction enzymes is apparently useful.

Evaluation of the capabilities of a hemoglobin vesicle as an artificial oxygen carrier in a rat exchange transfusion model.

Encapsulation of hemoglobin within a liposome is one of the strategies in the development of artificial oxygen carriers. It maintains the oxygen transporting properties of hemoglobin and, at the same time, eliminates the side effects of cell free hemoglobin. Hemoglobin vesicles (HbV) are a type of liposome encapsulated hemoglobin. They have a particle size of approximately 250 nm, a hemoglobin concentration of 10 g/dl, and the oxygen affinity, P50, is regulated to 32 Torr. In this study the authors examined the oxygen transporting capability of HbV in vivo, by performing exchange transfusions in rats. Exchange transfusion (90% of the estimated circulatory volume) with HbV suspended in 5% albumin (containing 160 mEq/L, sodium and 107 mEq/L, chloride) was carried out in male Wistar rats. Mean arterial pressure and heart rate were monitored through the arterial catheter. Arterial blood samples for gas analyses were also obtained from the arterial catheter. Abdominal aortic blood flow was measured by an ultrasonic pulsed Doppler flowmeter as an indicator of cardiac output. The oxygen tension of blood withdrawn from the right atrium was measured as an indicator of mixed venous oxygen tension. These values were employed to calculate oxygen delivery and consumption. Renal cortical and skeletal muscle tissue oxygen tensions were monitored as indicators of tissue perfusion. Five percent albumin and washed rat red blood cells suspended in 5% albumin containing 10 g/dl of hemoglobin; were employed as controls. At the completion of a 90% exchange transfusion, renal cortical and skeletal muscle tissue oxygen tensions, along with oxygen delivery and consumption, were sustained almost equally well with the HbV suspension compared to the washed rat red blood cell suspension, but declined significantly with the albumin suspension. The results indicate that the oxygen transporting capability of HbV was almost equivalent to that of rat red blood cells.

Control of Fusarium Crown and Root Rot of Tomato with Hypovirulent Binucleate Rhizoctonia in Soil and Rock Wool Systems.

Hypovirulent binucleate Rhizoctonia (HBNR) isolates L2, W1, W7, and Rhv7 were studied as potential antagonists of Fusarium crown and root rot of tomato (FCRR) caused by Fusarium oxysporum f. sp. radicis-lycopersici, in either soil or hydroponic rock wool systems. Reduction of FCRR on tomato by HBNR isolates was different depending on the isolate, days after inoculation of pathogen, and experiments. In the greenhouse soil system, HBNR isolates significantly (P = 0.01) reduced vascular discoloration and discoloration of total roots systems by 90 to 100% and by 73 to 89%, respectively, in three experiments. Under field soil conditions, HBNR W1 provided significant (P = 0.05) reduction of vascular discoloration by 71%. In the rock wool system, all HBNR isolates except L2 in experiment 1 significantly reduced (P = 0.05) vascular discoloration by 18 to 100% in four experiments. Plants treated with all HBNR isolates had foliar symptoms reduced by 41 to 100% in four experiments under the rock wool system. Application of HBNR also resulted in increases of marketable and total yields of tomatoes as much as 70 and 73%, respectively, over the untreated plants. The number of colony forming units of F. oxysporum f. sp. radicis-lycopersici per gram fresh weight of roots and stems was significantly reduced (P = 0.05) in plants treated with HBNR in both soil and rock wool systems. HBNR was re-isolated at a high frequency from roots grown inside paper pots containing soil infested with HBNR, but rarely isolated from the roots grown in soil infested with only F. oxysporum f. sp. radicis-lycopersici outside the paper pots. HBNR was not re-isolated from the tomato stems. Stem extracts from HBNR-treated and pathogen-challenged plants in the rock wool system inhibited germination and production of budding cells of F. oxysporum f. sp. radicis-lycopersici.

Staple-line reinforcement with a new type of polyglycolic acid felt.

Although various materials have been used for reinforcement in lung-volume-reduction surgery to buttress pulmonary staple-line, absorbable materials are not available for use in thoracoscopic surgery. Moreover, even nonabsorbable types of reinforcements have been used only for lung volume reduction surgery. However, elderly patients with spontaneous pneumothorax secondary to emphysematous lung are well treated with staple-line reinforcement. The authors developed a new type of polyglycolic acid felt to buttress staple-line. This felt is absorbable, easier to cut with a stapler knife than is the conventional polyglycolic acid felt, and inexpensive enough to use for various types of thoracic surgeries for emphysematous lungs in Japan, and it can be attached to staplers with a small amount of fibrin glue. These strips were used to reinforce pulmonary staple lines for resection of emphysematous lungs in 14 patients: pulmonary emphysema (n = 1), bilateral giant bullae (n = 1), ipsilateral giant bullae (n = 6), spontaneous pneumothorax with multiple bullae in an emphysematous lung (n = 5), and lung cancer in a patient with pulmonary emphysema (n = 1). There were no air leaks during surgery. Air leaks were noted in three patients after surgery. In two patients, the air leaks stopped within 2 weeks. In one patient, the air leak was found to originate from an untouched lobe during reoperation. No infection or allergic reaction developed in a patient during a mean follow-up of 12 months (range, 1 to 24 months).

Cerebellar abscess associated with pulmonary arteriovenous fistula and hereditary hemorrhagic telangiectasia--case report.

A 57-year-old male with a past history of bilateral pulmonary arteriovenous fistulas (PAVFs) experienced a sudden onset of headache and gait disturbance. There was a family history of PAVF and recurrent epistaxis. He had diffuse telangiectasia of the tongue, and hereditary hemorrhagic telangiectasia was diagnosed. Neuroimaging revealed a brain abscess in the right cerebellar hemisphere, which was successfully aspirated under ultrasound guidance. The PAVFs were resected afterwards in two-staged operation. No recurrence of the abscess has been observed. Cerebral abscesses complicated by PAVF are usually supratentorial. Complete eradication of PAVF is essential because the brain abscess will sometimes recur if the PAVF is left untreated.

[A case of atopic myelitis].

A 35-year old woman was admitted to our hospital because of slowly increased numbness of lower truncus and the legs for 10 months. She showed atopic dermatitis on her nape and bilateral popliteal fossa, and signs and symptoms of anorexia nervosa, such as asitia, emaciation, and menopause. Neurologic examination revealed Lhermitte's sign, muscle weakness of bilateral hands, deep and superficial sensory disturbance below the Th 4 level of thoracic spinal cord, and increased tendon reflexes of four limbs. Laboratory data showed hyperIgEemia and high titer of mite antigen specific IgE in sera. Cervical MRI demonstrated abnormal intensity area located at the C6 to C7 segments (i.e. low intensity in T1 weighted images and high in T2). She also showed hypercalcemia and swelling of the parathyroid gland, and had been diagnosed primary hyperparathyroidism by scintigram of the parathyroid gland. We concluded that this case is thought to be atopic myelitis, which has been recently reported as acute myelitis associated with hyperIgEemia and atopic dermatitis proposed by Kira et al. (1997). The patient also had anorexia nervosa and primary hyperparathyroidism.

[A case of chronic hypertrophic cranial pachymeningitis causing cranial polyneuropathy and unilateral central retinal vein occlusion].

We presented a 70-year-old woman who developed unilateral visual loss due to central retinal vein occlusion caused by chronic hypertrophic cranial pachymeningitis. She had developed right blindness with optic atrophy due to chronic intracranial pachymeningitis one year before admission. In June 1999, she noticed visual loss of the left eye. On admission, neurological examination revealed left visual loss and sensory impairment in the first branch area of bilateral trigeminal nerves. Ophthalmological examination revealed central retinal vein occlusion of the left eye. Brain MRI showed dural thickening with gadolinium enhancement of the cavernous sinus near the left optic nerve and dilatation of the left supraorbital vein. There was no compression of the left optic nerve. We suggest that central retinal vein occlusion may be caused by compression of the supraorbital vein by dural thickening. This is the first case report of central retinal vein occlusion associated with chronic hypertrophic cranial pachymeningitis.

[A case of acute quadriplegic myopathy].

A 22-year-old man developed unconsciousness, severe quadriplegia and muscle atrophy, and had markedly elevated serum creatine kinase levels after using the high-dose steroid and nondepolarizing neuromuscular blocking agents during the course of sepsis and DIC. On neurological examination, he was lethargic. The patient had generalized muscle weakness and wasting, and diminished deep tendon reflexes. He weakly responsed to painful stimuli on the legs. The motor nerve conduction study demonstrated decreased CMAP (compound muscle action potential) amplitudes. Motor and sensory nerve conduction velocities and their distal latencies were normal. Muscle biopsy revealed marked muscle fiber atrophy predominantly in type 2 fibers and numerous basophilic and a few necrotic fibers. Some atrophic fibers had decreased to absent myosin adenosine triphosphatase activity in their center. Accordingly, he was diagnosed as having acute quadriplegic myopathy (AQM), which has been reported mainly in Western countries. The mechanism of muscle fiber degradation in this myopathy is still unknown. On immunohistochemical analysis to our patient, enzyme activities of various proteases such as calpain, cathepsin B, and proteasomes were increased in the sarcoplasm, especially in the atrophic fibers. We suggest that lysosomal cathepsin, nonlysosomal calpain, and ATP-ubiquitin-proteasome proteolytic pathways participate in muscle fiber degradation in AQM.