Therapeutic Resistance in G-CSF Producing Lung Cancer With EGFR Mutation.

Background/Aim: Granulocyte colony-stimulating factor (G-CSF)-producing neoplasms are relatively rare; however, little is known on the clinical features of G-CSF-producing lung cancer harboring activating epidermal growth factor receptor (EGFR) mutations. Case Report: A 66-year-old female was definitively diagnosed with G-CSF-producing lung cancer that was positive for EGFR mutations. She repeatedly received epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as osimertinib and afatinib. However, she developed resistance to these molecular-targeting drugs within 2 to 3 months after immediate shrinkage. Thus, the patient was treated with chemoimmunotherapy including bevacizumab, and demonstrated a slight survival benefit. Conclusion: Overall, G-CSF-producing lung cancers positive for EGFR mutations were resistant to different treatment modalities. Clinicians should be attentive to the potential resistance of G-CSF-producing EGFR mutant lung cancer to EGFR-TKI therapy.

Progression to Lymph Node Metastasis After Spontaneous Regression of Pulmonary Adenocarcinoma Following Biopsy.

BACKGROUND/AIM: Spontaneous regression (SR) of cancer, which indicates the natural disappearance of malignant tumors, is rare. Little is known about the mechanisms underlying SR; however, immunological reactions, infections, injuries, and medications have been presumed. Among previously reported cases of SR, lung cancer cases have been extremely limited. CASE REPORT: Here, we present a case of lymph node metastasis exacerbation after SR of a primary adenocarcinoma following a biopsy. After complete disappearance of the primary site tumor, metastatic lymph nodes in the mediastinum gradually increased in size as a single lesion. Local treatment with resection and radiotherapy was effective for this metastasis, without recurrence for >3 years. CONCLUSION: This is an interesting case of SR of pulmonary adenocarcinoma with inconsistent features in the primary and metastatic lesions. When physicians encounter exacerbation of metastatic sites with SR of the primary site in lung cancer, local intervention may be considered as a curative treatment.

Metabolic Tumor Volume as Significant Predictor for Chemotherapy Containing PD-L1 Blocker in Extensive Stage Small Cell Lung Cancer.

BACKGROUND/AIM: Chemo-immunotherapy, including the programmed death ligand 1 (PD-L1) antibody, is an effective treatment for patients with extensive-stage small-cell lung cancer (ES-SCLC). However, no biomarker has been established for the prediction of chemo-immunotherapy. Therefore, we investigated the potential of 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) as a predictive marker. PATIENTS AND METHODS: Forty-six patients with ES-SCLC who received 18F-FDG-PET immediately before combined platinum-based chemotherapy with PD-L1 blockade as a first-line treatment were eligible, and the maximum standard uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) on 18F-FDG uptake were evaluated. RESULTS: PD-L1 and tumor infiltrative lymphocytes (TILs) were immunohistochemically analyzed in 36 of the 46 patients. A high MTV was significantly associated with poor performance status and low albumin levels, and there was a significant association between low albumin and high TLG. Univariate analysis identified sex, Brinkman index, and MTV as significant predictors of progression-free survival (PFS), and sex, SUVmax, MTV, and TLG as significant factors of overall survival (OS). Multivariate analysis revealed that sex, Brinkman index, and MTV were independent prognostic factors for PFS, and sex, SUVmax, MTV, and TLG were significant predictors of OS. SUVmax was significantly higher in patients with positive PD-L1 expression than in those with negative expression but was not significantly different between positive and negative TILs. Moreover, the levels of MTV and TLG were not closely associated with the levels of PD-L1 and TILs. CONCLUSION: MTV or TLG metabolic tumor activity is suitable for the prediction of chemo-immunotherapy outcomes in patients with ES-SCLC.

Phase I Study Evaluating the Combination of Afatinib with Carboplatin and Pemetrexed After First-line EGFR-TKIs.

BACKGROUND/AIM: Promising reports have described the combination of first-generation epidermal growth factor receptor tyrosine-kinase inhibitors (EGFR-TKIs) with carboplatin plus pemetrexed or bevacizumab. However, no analysis of afatinib with platinum-doublet chemotherapies has been performed. PATIENTS AND METHODS: We evaluated the safety and antitumor efficacy of afatinib combined with carboplatin and pemetrexed in EGFR-mutated non-small-cell lung cancer (NSCLC) patients who progressed during first-generation EGFR-TKIs. RESULTS: Ten patients received 20 or 30 mg/day afatinib with carboplatin (area under the curve, 5) and pemetrexed (500 mg/m2). Dose-limiting toxicities included delay of afatinib ≥14 days, grade 3 diarrhea, grade 3 hypokalemia, grade 3 serum amylase increase and grade 4 thrombocytopenia. The recommended dose of afatinib was 20 mg/day in this combination therapy. Overall response rate was 30% and median progression-free survival was 13.7 months. CONCLUSION: This is the first study to investigate the combination of afatinib, carboplatin and pemetrexed. At the recommended dose, this combination was well tolerated and had a good clinical efficacy.

Lack of antibodies against the antigen domain 2 epitope of cytomegalovirus (CMV) glycoprotein B is associated with CMV disease after renal transplantation in recipients having the same glycoprotein H serotypes as their donors.

Cytomegalovirus (CMV) reinfection of seropositive individuals has been associated with adverse outcomes in organ transplantation and is a frequent cause of congenital infection. Previously we demonstrated that mismatching of CMV glycoprotein H (gH) serotypes was associated with CMV disease after renal transplantation. Because the antigen domain 2 (AD2) epitope of glycoprotein B (gB) is conserved among CMV isolates and is one of the known targets of neutralizing antibodies, in this study we investigated whether antibodies against the epitope contribute to protection from CMV reinfection in renal transplantation, irrespective of gH serological matching. For this purpose, the gB and gH serology and clinical outcomes were analyzed retrospectively for 77 transplant recipients in the donor positive/recipient positive setting, who were managed by preemptive strategy. We found that there was a good negative correlation between the numbers of antigenemia-positive cells and the levels of antibodies against gB AD2 in the CMV-gH antibody matched group, but not in the CMV-gH antibody mismatched group. None of the recipients with antibodies against both gB AD2 and strain-specific epitopes of gH have experienced CMV disease during 6 month after transplantation, while 28% of those who lacked either/both antibody response needed preemptive therapy. Because the outcome was statistically significant, antibodies against gB AD2 can be a useful indicator to predict emergence of CMV disease for preemptive therapy, in addition to antibodies against the mismatched gH types.

Urinary urgency - translating the evidence base into daily clinical practice.

AIM: To consider the currently available knowledge and understanding of the symptom of urgency. MATERIALS & METHODS: Each faculty member reviewed the literature base of a different aspect of urgency and along with their personal clinical experience provided a base of evidence for discussion. RESULTS: This overview summarises relevant published literature and the current clinical experience of the authors. DISCUSSION: Whilst the mechanisms producing the sensation of urgency are still not fully understood and we are working within a definition that may complicate measurement and treatment, our pressing need is to effectively manage our patients for whom the practical nature of urgency can be all too apparent. CONCLUSION: Health care professionals have an important role to play today in helping to alleviate the widespread problem of urgency and its consequences.

The role of autophagy in the heart.

Autophagy has evolved as a conserving process that uses bulk degradation and recycling of cytoplasmic components, such as long-lived proteins and organelles. In the heart, autophagy is important for the turnover of organelles at low basal levels under normal conditions and it is upregulated in response to stresses such as ischemia/reperfusion and in cardiovascular diseases such as heart failure. Cardiac remodeling involves increased rates of cardiomyocyte cell death and precedes heart failure. The simultaneously occurring multiple features of failing hearts include not only apoptosis and necrosis but also autophagy as well. However, it has been unclear as to whether autophagy is a sign of failed cardiomyocyte repair or is a suicide pathway for failing cardiomyocytes. The functional role of autophagy during ischemia/reperfusion in the heart is complex. It has also been unclear whether autophagy is protective or detrimental in response to ischemia/reperfusion in the heart. In this review, we will summarize the role of autophagy in the heart under both normal conditions and in response to stress.

Epidemiological observations on bluetongue in sheep and cattle in Japan.

Bluetongue (BT) first occurred in Japan between late August and October 1994 in 23 cattle in three prefectures of the northern Kanto region, and between the end of October and mid-November in 23 Suffolk sheep in the same region. The affected cattle had fever, deglutitive difficulty, hyper-salivation, facial oedema, scabbing of the corner of the mouth and dysphagia. The BT virus (BTV) was isolated from blood cells of the affected sheep. Surveillance for BTV antibody conducted by prefectures in the affected region has detected seroconversion to BTV in some prefectures every year thereafter. In the autumn of 2001, again in the northern Kanto region, 45 sheep developed BT, and BTV was isolated. It is considered important that Japan has imported numerous cattle from Australia, the United States of America (USA), and New Zealand every year. In particular, BTV was isolated from cattle imported from the USA during quarantine although some of the serotypes isolated are not present in the USA. Furthermore, BTV is not present in New Zealand. The third RNA segment encoding the serogroup-specific VP3 protein of Japanese BTV isolates and reverse transcriptase-polymerase chain reaction (RT-PCR) positive blood cells was amplified by RT-PCR. Molecular phylogenetic analysis of the third RNA segment based on the sequence homology of the PCR products led to the classification of Japanese BTV isolates into two major groups.

Correlation between serum phospholipase A(2) IIA levels and histological activity in patients with ulcerative colitis.

BACKGROUND AND AIMS: Phospholipase A(2) (PLA(2)) participates in the regulation of phospholipid metabolism and biosynthesis of eicosanoids, serum levels of PLA(2) are suggested to reflect the disease activity in patients with ulcerative colitis (UC). We examined the relationship between histological disease activity and serum levels of PLA(2) IIA and also clarified mucosal production sites of PLA(2) IIA by immunohistochemistry. PATIENTS AND METHODS: Serum samples from 44 patients with UC, 125 with Crohn's diseases (CD), and 68 controls were studied. Biopsy specimens of colonic mucosa obtained from 23 patients with UC were used for assessment of histological activity. The histological score was determined active (1) or inactive (0), and the sum of each histological score from ten segments of the large intestine was assessed as disease activity. The levels of PLA(2) IIA in sera were measured by a radioimmunoassay kit using a specific monoclonal antibody; immunohistochemical study was performed using the same monoclonal antibody. RESULTS: The serum PLA(2) IIA levels in patients with UC and CD were significantly higher than those of controls. Serum PLA(2) IIA levels in UC were closely correlated with histological disease activity. Immunohistochemical study showed the production of PLA(2) IIA by the polymorphonuclear cells, macrophages, and colonic epithelial cells. CONCLUSION: Serum PLA(2) IIA is a good candidate for assessing disease activity in UC as one of clinical laboratory tests.

The healing process of infarct-related plaques. Insights from 18 months of serial angioscopic follow-up.

OBJECTIVES: To clarify the healing process of disrupted culprit plaques of acute myocardial infarction (MI), we serially observed the culprit plaques for 18 months after the onset of acute MI by angioscopy. BACKGROUND: Although it has been reported that disruption of the yellow plaque and subsequent thrombosis cause acute MI and that the thrombogenicity of the plaque lasts for a month, the healing process of the plaque after disruption has not been clarified. METHODS: Eighty-five patients with acute MI were prospectively and consecutively enrolled. Angioscopic studies were performed immediately and at 1, 6 and 18 months after successful reperfusion. The prevalence of yellow plaques and thrombus was examined. The color grade of the plaque was determined as 0 (white), 1 (light yellow), 2 (yellow) or 3 (bright yellow). RESULTS: Although yellow plaque was present at the culprit lesion in most patients throughout follow-up, its color grade was reduced from one to six months (1.9 +/- 0.6 vs. 1.1 +/- 0.7, p = 0.0003) after reperfusion, especially in the patients without hyperlipidemia (HL). The incidence of thrombus was 92.5% immediately after reperfusion, which was reduced significantly to 63.8%, 4.8% and 11.8% at 1, 6 and 18 months, respectively. The incidence of thrombus (77.8% vs. 45.0%, p = 0.03) at one month was higher in the patients with diabetes mellitus (DM). CONCLUSIONS: The healing process of yellow plaques at the culprit lesions of MI was detected by angioscopy as reductions of color grade and thrombogenicity at six months and partially at one month after the onset of acute MI. This healing process appears to deteriorate by complicating cases of DM or HL.

Essential role for extracellular Ca(2+) in JNK activation by mechanical stretch in bladder smooth muscle cells.

Mechanical stretch has been implicated in phenotypic changes as an adaptive response to stretch stress physically loaded in bladder smooth muscle cells (BSMCs). To investigate stretch-induced signaling, we examined the mitogen-activated protein kinase (MAPK) family using rat primary BSMCs. When BSMCs were subjected to sustained mechanical stretch using collagen-coated silicon membranes, activation of c-Jun NH(2)-terminal kinase (JNK) was most relevant among three subsets of MAPK family members: the activity was elevated from 5 min after stretch and peaked at 10 min with an 11-fold increase. Activation of p38 was weak compared with that of JNK, and ERK was not activated at all. JNK activation by mechanical stretch was totally dependent on extracellular Ca(2+) and inhibited by Gd(3+), a blocker of stretch-activated (SA) ion channels. Nifedipine and verapamil, inhibitors for voltage-dependent Ca(2+) channels, had no effect on this JNK activation. Moreover, none of the inhibitors pertussis toxin, genistein, wortmannin, or calphostin C affected stretch-induced JNK activation, indicating that G protein-coupled and tyrosine kinase receptors are unlikely to be involved in this JNK activation. On the other hand, W-7, a calmodulin inhibitor, and cyclosporin A, a calcineurin inhibitor, prevented JNK activation by stretch. These results suggest a novel pathway for stretch-induced activation of JNK in BSMCs: mechanical stretch evokes Ca(2+) influx via Gd(3+)-sensitive SA Ca(2+) channels, resulting in JNK activation under regulation in part by calmodulin and calcineurin.

A new portable measuring cup for voided volume.

When recording daily urine volumes for the frequency-volume chart, a patient must measure voided urine volume throughout the whole day. Unless the patient stays at home, the conventional 500-mL paper or plastic cup must be carried with at all times, which can be very embarrassing and troublesome for the patient, so a collapsible, portable measuring cup has been developed. To determine the measuring accuracy of the new cup, the visual estimate was compared with the actual volume. The cup was found to be a highly accurate and useful container for measuring voided urine volume.

Endogenous nitric oxide-mediated relaxation and nitrinergic innervation in the rabbit prostate: the changes with aging.

BACKGROUND: Nitric oxide (NO) plays the key role in the non-adrenergic non-cholinergic (NANC) nerve-mediated relaxation of prostate. We tried to determine whether nitrinergic innervation of the prostate is reduced with aging, and whether a reduction of this innervation alters the relaxant properties of prostatic tissue. METHODS: The prostate isolated from young rabbits at the age of 3 months and aged rabbits at the age of 24 months was used. Pharmacologic experiments using electrical field stimulation (EFS) were performed on strips of prostate. Nitrinergic nerves were identified histochemically by the presence of NADPH diaphorase reactivity. RESULTS: The prostate weighed 0.34 +/- 0.06 g in the young and 0.78 +/- 0.13 g in the aged (P < 0.01). Electrical stimulation caused frequency-dependent relaxation that was inhibited by N-nitro-L-arginine and increased by L-arginine. Maximum relaxant rates of noradrenaline-induced tone were 41.3 +/- 1.8% and 22.7 +/- 0.6% in the young and the aged (P < 0.01), respectively. Exogenous NO caused concentration-dependent relaxation of the prostate. Both relaxation induced by electrical stimulation and exogenous NO were inhibited by LY83583 (a guanylate cyclase inhibitor). In all specimens, NADPH diaphorase activity was observed in the smooth muscle layer of the prostatic stroma and capsule. However, NADPH diaphorase positive nerves were significantly less in the aged than in the young (P < 0.01). CONCLUSIONS: As a result of these findings, it is suggested that both NO-mediated relaxation and nitrinergic innervation are reduced with aging in this animal model.

[The voiding after the suburethral sling operation, obstructive or non-obstructive?].

To examine whether or not the suburethral sling operation produces obstruction during voiding, seven females who underwent the sling operation using synthetic material (Vesica Sling Kit) were studied postoperatively urodynamically. Uroflowmetry and residual urine measurement showed no overt voiding difficulties in any cases. However, in one case, a pressure flow study indicated equivocal and the position of the sling material was judged to be too proximal by fluoroscopic monitoring. In all other 6 cases pressure flow was shown to be non-obstructive. Fluoroscopic finding also demonstrated in these 6 cases an appropriate bladder neck opening at the time of voiding and the sling was positioned just from the bladder neck to mid-urethra. Thus, it is concluded that the suburethral sling operation produces no obstruction as long as the position of the sling material is carefully determined from bladder neck to mid-urethra and excessive tension is avoided.

Extensive development of vulnerable plaques as a pan-coronary process in patients with myocardial infarction: an angioscopic study.

OBJECTIVES: To test our hypothesis that the development of vulnerable plaques is not limited to the culprit lesions, but is a pan-coronary process, we directly observed all three major coronary arteries by angioscopy and evaluated the prevalence of yellow plaques in patients with myocardial infarction (MI). BACKGROUND: Although pathologic studies have suggested that the disruption of atheromatous plaque plays a major role in the development of acute MI, the prevalence of yellow plaques in the whole coronary arteries of patients with MI has not been clarified. METHODS: Thirty-two patients undergoing follow-up catheterization one month after the onset of MI were prospectively and consecutively enrolled in this study. The prevalence of yellow plaques and thrombus in the major coronary arteries was successfully evaluated in 20 patients (58 coronary arteries, 21 culprit lesions) by coronary angioscopy. The diameter stenosis (DS) of the culprit lesions and the maximal diameter stenosis (maxDS) of nonculprit segments were angiographically measured for each coronary artery. RESULTS: The DS of the culprit lesions and maxDS were 27 +/- 17% and 19 +/- 13%, respectively. Yellow plaques and thrombus were detected in 19 (90%) and 17 (81%) of 21 culprit lesions, respectively. Yellow plaques were equally prevalent in the infarct-related and non-infarct-related coronary arteries (3.7 +/- 1.6 vs. 3.4 +/- 1.8 plaques/artery). However, thrombus was only detected in the nonculprit segments of one (2%) coronary artery. CONCLUSIONS: In patients with MI, all three major coronary arteries are widely diseased and have multiple yellow though nondisrupted plaques. Acute MI may represent the pan-coronary process of vulnerable plaque development.

Influence of interleukin-10 on the interleukin-1 receptor antagonist/interleukin-1 beta ratio in the colonic mucosa of ulcerative colitis.

A decrease in the ratio of IL-1ra/IL-1 beta produced regionally by the colonic mucosa of patients with ulcerative colitis (UC) is believed to play a role in the pathogenesis of UC. To investigate factors influencing intramucosal IL-1ra/IL-1 beta ratios, we evaluated polymorphism of the IL-1ra gene and the production of mucosal cytokines in Japanese patients with UC. Colonic biopsy specimens of mucosal tissue were placed in organ cultures for 24 h. Then, the supernatant concentrations of IL-1 beta, IL-1ra, IL-8, IL-4, IL-10, and TGF-beta were assayed by ELISA. Genomic DNA was extracted from patient peripheral blood samples, then IL-1ra gene polymorphism was determined using PCR amplification. The mucosa from patients with active stage UC showed a tendency toward a decreased IL-1ra/IL-1 beta ratio. In the resolving stage, IL-1ra/IL-1 beta ratios increased with increasing IL-10 and TGF-beta concentrations. The addition of human recombinant IL-10 to the culture supernatants produced concentration-dependent inhibition of IL-1 beta. In Japanese patients with UC, the IL-1ra allele gene 2 phenotype had no effect on the IL-1ra/IL-1 beta ratio. Our findings suggest that a relative deficiency of IL-10 in patients with UC may contribute to persistent inflammatory changes.

Effects of bradykinin on cytoplasmic calcium and motility in murine bladder tumor cells.

PURPOSE: Bradykinin is known to mobilize calcium from an intracellular or extracellular source in several tumor cells. We evaluated whether bradykinin increases cytoplasmic calcium concentration ([Ca2+]i) and evokes locomotory movement in bladder cancer cells. MATERIALS AND METHODS: We studied the bladder cancer cell lines MBT-2, MB-49 and HT-1376, and the prostate cancer cell line PC-3 was used as a control. [Ca2+]i was measured with the fluorescent calcium indicator fura-2/AM. Bradykinin induced cell contraction was studied on only MBT-2 cells by taking microscopic photographs. Matrigel coated transwell chambers were used to test the invasive behavior of cancer cells. RESULTS: Bradykinin induced a transient increase in [Ca2+]i in the 3 bladder cancer cell lines, which was suppressed by a specific blocker of B2 receptors, the B2 inhibitor. Bradykinin did not induce an increase in [Ca2+]i in PC-3 cells. MBT-2 cells showed a contractile response to bradykinin. ML-9, a myosin light chain kinase inhibitor, or W-7, a calmodulin antagonist, completely abolished this bradykinin induced contraction, although a bradykinin induced calcium transient was consistently observed. When bladder cancer cells were incubated with bradykinin, the number of cells which migrated through a matrigel coated filter was significantly greater than that of the control without bradykinin. This bradykinin induced chemo-invasion was completely blocked by the B2 inhibitor. Bradykinin did not evoke the chemotactic response in PC-3 cells. CONCLUSIONS: Bradykinin can increase [Ca2+]i transiently in bladder cancer cells, which is mediated by B2 receptors. The contractile response of MBT-2 cells to bradykinin appears to occur as a result of the actin-myosin interaction caused by increased calcium. In addition, bradykinin can induce locomotory movement of bladder cancer cells through B2 receptors. It is difficult to explain this chemotactic response only by the calcium mobilizing effect of bradykinin.

[Significance of interferon alpha therapy for advanced renal cell carcinoma. Fukushima Renal Cancer Study Group].

We ranked prognostic factors to retrospectively evaluate the clinical significance of interferon alpha (IFN-alpha) therapy in patients with Robson stage IVB renal cell carcinoma. A total of 44 Robson stage IVB renal cancer patients were divided into 2 groups, one with more than 6 months administration of IFN-alpha (3-7 times a week: group A) and another without any IFN-alpha administration. The distribution of these 2 groups was not randomized. In addition to IFN-alpha therapy, survival was analyzed with respect to performance status (PS), mass reductive nephrectomy, concomitant use of other cytotoxic therapies, the number of metastatic organs, growth type, site of metastasis and the period of diagnosis, using a multivariate method with Cox proportional hazards regression. The multivariate analysis showed administration of IFN-alpha to be the most significant factor influencing a good prognosis. Improved survival was also significantly correlated with slow growing type and good PS. Among group A, a significant favorable prognosis was obtained in patients with the responses of no change (NC), partial response (PR) and complete remission (CR) 6 months after initiating administration of IFN-alpha, as well as with good PS and a slow growing type carcinoma. We conclude that IFN-alpha therapy might improve the prognosis of patients with Robson stage IVB renal cell carcinoma, especially, in cases when a greater than NC response is obtained after 6 months administration of IFN-alpha.