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.

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.

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.

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.

[Expression of telomerase activity in thymoma and thymiccarcinoma tissues; a clinicopathological study].

BACKGROUND: Telomerase is a nucleoprotein complex that caps the physical termini of all eukaryotic chromosomes. It is suggested that telomerase play important roles in unlimited cell division acquisition of the malignant phenotype. We studied the relation of telomerase activity in thymoma and thymic carcinoma to the clinicopathological features of these lesions. METHODS: Tissue specimens were surgically resected from patients with thymoma and thymic carcinoma. Telomerase activity was evaluated according to a modified telomeric repeat amplification protocol (TRAP) assay. RESULTS: Telomerase activity was detected in all thymic epithelial tumors. The activity (mean +/- SD: unit/microgram.protein) in thymoma (n = 17) was significantly higher than that in thymic carcinoma (n = 7) [431.8 +/- 400.1 vs. 68.8 +/- 39.8: p < 0.01]. Telomerase activities in thymoma and thymic carcinoma were significantly higher than that in primary lung adenocarcinoma (33.5 +/- 39.2: n = 47), studied as control (p < 0.01). In patients with thymoma, telomerase activity did not correlate with tumor stage according to Masaoka classification (p = 0.776). In patients with thymic carcinoma, however, telomerase activity positively correlated with tumor stage (p = 0.02). In thymoma, telomerase activity positively correlated with the ratio of induced lymphocytes according to Rosai's classification (p = 0.045). CONCLUSION: In thymoma, telomerase activity reflects the presence of immature T-cell lymphocytes in tumor tissue rather than tumor stage or malignant phenotype. In thymic carcinoma, telomerase activity derived directly from cancer cells may relate to tumor stage.

[Clinical analysis of surgically resected multiple primary lung cancer].

Synchronous and metachronous lung cancer is occasionally encountered. Frequency of the occurrence is increasing because of recent progress of imaging technique such as high resolution CT and CT based annual lung survey. We analyzed clinical characteristics of both synchronous and metachronous lung cancer treated surgically in our facility. There were 20 cases of multiple lung cancer cases, which is consisted of 12 synchronous multiple lung cancer cases and 8 metachronous lung cancer cases. Mean age was 62 years old and there were 14 male and 6 female cases. Among synchronous group, 8 cases have multiple shadow in ipsilateral hemithorax and 4 cases in both side. Surgery was carried out according to the extent of the disease and lung reserve. Associated cancer was diagnosed stage IA or IB in all cases. Five-year survival was 58.9%. Meanwhile, as regards to metachronous group, mean interval between first cancer and second cancer was 73 months. Seven cases have contralateral second primary lung cancer and one case has ipsilateral second primary lung cancer. In 3 cases, histology of the first and the second disease were different and in 5 cases that were the same. The first procedures were complete resection with systemic mediastinal LN dissection. The second procedures were determined based on the lung reserve. Pathological stage of the second disease were either stage IA or IB. There were no operative mortality and 5 years survival was 75%. Since there is no operative mortality and the outcome seems satisfactory when the patient has enough lung reserve, aggressive surgical resection should be considered in the case of multiple primary lung cancer. There is an increasing chance of synchronous multiple primary lung cancer because of improvement of imaging system. We have to prepare new therapeutic strategy for those patients.

Hemoglobin-vesicles as oxygen carriers: influence on phagocytic activity and histopathological changes in reticuloendothelial system.

Hemoglobin-vesicles (HbV) have been developed for use as artificial oxygen carriers (particle diameter, 250 nm) in which a purified Hb solution is encapsulated with a phospholipid bilayer membrane. The influence of HbV on the reticuloendothelial system was studied by carbon clearance measurements and histopathological examination. The HbV suspension ([Hb] = 10 g/dl) was intravenously infused in male Wistar rats at dose rates of 10 and 20 ml/kg, and the phagocytic activity was measured by monitoring the rate of carbon clearance at 8 hours and at 1, 3, 7, and 14 days after infusion. The phagocytic activity transiently decreased one day after infusion by about 40%, but it recovered and was enhanced at 3 days, showing a maximum of about twice the quiescent level at 7 days, and then returned to the normal value at 14 days. The initial transient decreased activity indicates a partly, but not completely, suppressed defensive function of the body. The succeeding increased phagocytic activity corresponds to the increased metabolism of HbV. The histopathological examination with anti-human Hb antibody, hematoxylin/eosin, and oil red O stainings showed that HbV was metabolized within 7 days. Hemosiderin was very slightly confirmed with Berlin blue staining at 3 and 7 days in liver and spleen, though they completely disappeared at 14 days, indicating that the heme metabolism, excretion or recycling of iron proceeded smoothly and iron deposition was minimal. Electron microscopic examination of the spleen and liver tissues clearly demonstrated the particles of HbV with a diameter of about 1/40 of red blood cells in capillaries, and in phagosomes as entrapped in the spleen macrophages and Kupffer cells one day after infusion. The vesicular structure could not be observed at 7 days. Even though the infusion of HbV modified the phagocytic activity for 2 weeks, it does not seem to cause any irreversible damage to the phagocytic organs. These results offer important information for evaluating the safety issues of HbV for clinical use.

[Surgical indications for lung cancer: influence of the M factor].

The presence of distant metastasis indicates systemic dissemination of disease. Patients with lung cancer in this category are not usually considered candidates for surgical resection of the primary and metastatic sites, although newly emerging treatment modalities for lung cancer improve survival. We need to conduct clinical trials in patients with distant metastases. We conducted a retrospective analysis of the surgical outcome of 16 PM2 patients who are now classified as having M1 disease. The 3-16 year survival rate was 45% and 5-year survival rate 14% in our facility. Among the 11 patients had N2 disease and a poor prognosis. Long-term survival can be achieved if the histology shows low grade malignancy and there is no lymph node involvement (N0 status). Patients with solitary brain metastasis also have a poor outcome even after surgical resection of both the brain metastasis and primary lung cancer. In this group, surgical intervention should be restricted to those in whom the quality of life is expected to improve, since it has been reported that no improvement in survival can be expected. We should investigate which patient groups can achieve long-term survival when surgically treated. The TNM classification had better be revised so that patients who benefit from simultaneous lung and metastatic resection are classified in earlier-stage groups.

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).

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.

Proteasome expression in the skeletal muscles of patients with muscular dystrophy.

Previous investigators have suggested that proteolysis by calpain, a Ca2+-dependent protease, causes muscle fiber degradation in Duchenne and Becker muscular dystrophies (DMD/BMD). Recent evidence indicates that the nonlysosomal ATP-ubiquitin-dependent proteolytic complex (proteasomes) participates in muscle wasting during various catabolic states and in muscle fiber degradation in physiological or pathological conditions. To elucidate the possible role of proteasomes in dystrophic muscles, routine histochemistry and immunohistochemistry of 26S proteasomes were performed on muscle biopsy specimens obtained from patients with various neuromuscular disorders including DMD/BMD, polymyositis (PM), amyotrophic lateral sclerosis, and peripheral neuropathies, and on normal human muscle specimens. Immunohistochemically, proteasomes were located in the cytoplasm in normal human muscle, but their staining intensity was faint. Compared to control muscles, abnormal increases in both proteasomes and ubiquitin were demonstrated mainly in the cytoplasm of necrotic fibers and to a lesser extent in regenerative fibers in DMD/BMD and PM. Non-necrotic, atrophic fibers in all diseased muscles showed moderate or weak immunoreactions for the proteins; their staining intensities were stronger than those of control muscle fibers. Both proteins often colocalized well. Not all dystrophin-deficient muscle fibers showed a strong reaction for proteasomes. Our results showed increased proteasomes in necrotic and regenerative muscle fibers in DMD/ PMD, although this may not be disease-specific up-regulation. We suggest that the ATP-ubiquitin-dependent proteolytic pathway as well as the nonlysosomal calpain pathway may participate in muscle fiber degradation in muscular dystrophy.

[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.

Increased lysosome-related proteins in the skeletal muscles of distal myopathy with rimmed vacuoles.

Investigators have speculated that the degenerative process in distal myopathy with rimmed vacuoles (DMRV) mainly involves the lysosomal system. To investigate possible protein abnormalities related to intracellular lysosomal proteolytic pathways in DMRV-affected muscles, we performed immunohistochemical analyses of certain proteins in muscle biopsy specimens obtained from patients with various neuromuscular diseases, including DMRV, muscular dystrophy, polymyositis, and amyotrophic lateral sclerosis, and in normal human muscles specimens. Immunohistochemically, most muscle fibers in normal control specimens showed little or no reaction for clathrin and alpha- and gamma-subunits of adaptin-constituted adaptin proteins (AP)-1 and AP-2, respectively. Abnormal increases in these proteins were demonstrated mainly in the cytoplasm of atrophic fibers or in necrotic fibers in all diseased specimens. Particularly in DMRV-affected muscles, alpha- and gamma-adaptins were often observed inside or on the rims of vacuoles and in the cytoplasm of vacuolated fibers. Abnormal increases in Golgi-zone protein were also demonstrated in DMRV muscles. The rims of rimmed vacuoles were negative for kinectin, an endoplasmic reticulum-binding protein. Positive staining for both proteins, however, was sometimes seen inside the vacuoles in DMRV-affected fibers. These results suggest increased endocytosis at the plasma membrane as well as secretion involving transport from the trans-Golgi network of the Golgi apparatus in DMRV. Accumulation of various lysosome-related proteins within the rimmed vacuoles indicates at least some of these vacuoles may be autolysosomes.

Experimental lung transplantation using non-penetrating vascular clips for anastomosis of the pulmonary artery.

BACKGROUND: Reliable and rapid anastomosis is critical in lung transplantation. The purpose of this study is to show the appropriateness of sutureless anastomosis of the pulmonary artery using a nonpenetrating vascular clipping device. METHODS: The left lung was excised and the cranial lobe was transplanted autologously in 9 dogs. The anastomosis of the left main pulmonary artery (PA) (1 cm) was performed using a vascular clipping system. RESULTS: PA anastomosis was performed in 7 dogs in 8 to 13 minutes. The endovascular surface of the anastomotic site was smooth, and passage of silicone rubber through the anastomosis was good 14 or 28 days after surgery. Microscopic examination of the anastomotic sites showed excellent healing without evidence of intimal hyperplasia. CONCLUSIONS: The vascular clipping system facilitates anastomosis of the PA in lung transplant surgery.

[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.