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Although diffuse cysts in the lung can be found in many diseases, they are uncommon in metastatic lung adenocarcinoma. They are even more unusual after the administration of immune checkpoint inhibitors. A case of lung adenocarcinoma that developed diffuse cysts in the lungs during treatment with nivolumab is reported. The patient was a 60-year-old woman with postoperative recurrent lung adenocarcinoma in mediastinal lymph nodes and pleural dissemination. After first-line treatment with cisplatin, pemetrexed, and bevacizumab, computed tomography (CT) showed disease progression. Treatment was then switched to nivolumab. After 5 courses of nivolumab, CT showed multiple ground-glass nodules in her lungs. After 4 more courses of nivolumab, the ground-glass nodules increased in size, and cystic air spaces appeared in their centers. The patient did not have any symptoms. Laboratory tests showed no evidence of infection or nivolumab-induced pneumonitis. Sialyl Lewis X-i antigen increased, and positron emission tomography showed abnormal uptake of 18 F-fluorodeoxyglucose in these lesions. Considering this evidence, the cystic lesions were diagnosed as multiple lung metastases. Various differential diagnoses should be considered when diffuse cystic lesions are found in the lungs after the administration of immune checkpoint inhibitors., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2021 by S. Karger AG, Basel.)

Large cell neuroendocrine carcinoma (LCNEC) of the lung with epidermal growth factor receptor ( EGFR ) mutation is rare, and few cases have been treated with EGFR tyrosine kinase inhibitors (TKIs). We report the treatment of combined LCNEC with adenocarcinoma harboring an EGFR mutation with EGFR-TKIs and bevacizumab. Our patient was a 70-year-old asymptomatic woman who underwent surgical resection of the lung for combined LCNEC with adenocarcinoma harboring an activating EGFR mutation 11 months previously. Magnetic resonance imaging (MRI) and positron emission tomography revealed metastatic lesions in the brain and lung. The patient was diagnosed with recurrence of combined LCNEC with adenocarcinoma. The brain lesion was irradiated, followed by administration of afatinib. Eight months after irradiation, brain MRI revealed ringed enhancement and perilesional edema after radiotherapy without new metastatic lesions. We switched treatment to erlotinib and bevacizumab, resulting in maintenance of stable disease for 10 months. Overall, the disease was controlled for 18 months with EGFR-TKIs and bevacizumab. Combination treatment with EGFR-TKIs and bevacizumab could be a treatment option for LCNEC of the lung harboring EGFR mutations, especially with brain metastasis., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2020 by S. Karger AG, Basel.)

Background: Tolvaptan was approved for the treatment of autosomal dominant polycystic kidney disease (ADPKD). However, the official indication of "rapidly progressive disease" is described differently in the clinical guidelines. We aim to define "rapidly progressive disease" by risk of ESRD, which is evaluated using estimated height-adjusted total kidney volume (HtTKV) growth rate., Methods: The risk of ESRD was retrospectively analyzed in 617 initially non-ESRD adults with ADPKD and observed with standard of care between 2007 and 2018. The estimated annual growth rate of the HtTKV, termed as eHTKV-α (%/year), is derived from the following equation: [HtTKV at age t] = K(1 + eHTKV-α/100)t, where K = 150 mL/m is used in Mayo Imaging Classification and K = 130 mL/m is proposed for individually stable eHTKV-α value from baseline. The accuracy of eHTKV-α to predict ESRD for censored ages was analyzed using time-dependent receiver-operating characteristic curves (ROC). The cutoff point of initially measured eHTKV-α to predict ESRD was assessed using Kaplan-Meier and Cox's proportional hazards models. Performance characteristics of the cutoff point for censored ages were calculated using time-dependent ROC and validated by the bootstrap method., Results: The area under the time-dependent ROC of eHTKV-α to predict ESRD at age 65 was 0.89 ± 0.04 (K = 130). The mean renal survival was less than 70 years at eHTKV-α ≥4.0%/year (K = 130). Mean renal survival was approximately 12 years shorter, and hazard ratio of ESRD was more than 5-time higher at this cutoff point than at lower point. Time-dependent sensitivity for age 65 and cutoff point of 4.0%/year (K = 130) was 93.4 ± 0.3%. Between cutoff points ≥4.0%/year (K = 130) and ≥3.5%/year (K = 150), there was no significant difference in performance characteristics and accuracy to predict ESRD., Conclusion: eHTKV-α well predicts ESRD. Initially, measured eHTKV-α ≥4.0%/year (K = 130) defines high-risk ESRD. Without additional conditions, a single eHTKV-α cutoff point identifies subjects that are most likely to benefit from tolvaptan., (© 2020 The Author(s) Published by S. Karger AG, Basel.)

Crizotinib, the first clinically available inhibitor of anaplastic lymphoma kinase (ALK) gene rearrangement, is generally well tolerated. In contrast, neutropenia induced by crizotinib is a commonly reported grade 3 or 4 adverse event. In such cases, interruption and dose reduction of crizotinib might be necessary for some patients with severe neutropenia. However, information concerning clinical experience and management of severe neutropenia is currently limited. In this report, the successful management of crizotinib-induced neutropenia by dose reduction of crizotinib in a patient with ALK-positive non-small cell lung cancer is described.

Background: Indisetron is a serotonin (5-hydroxytryptamine type 3) receptor antagonist that also antagonizes 5-hydroxytryptamine type 4 receptors. We designed a pilot study in order to explore the optimal dosing period for indisetron during modified FOLFOX6 (mFOLFOX6)., Patients and Methods: Forty-two chemotherapy-naive patients with advanced colorectal cancer scheduled to receive mFOLFOX6 were randomly assigned to either a 1- or 3-day indisetron regimen arm. The primary endpoint was complete protection from vomiting., Results: Proportions of patients with complete protection from vomiting were 85.7% [95% confidence interval (CI) 63.7-97.0] with the 3-day regimen and 81.0% (95% CI 58.1-94.6) with the 1-day regimen. Proportions of patients with complete protection from nausea were 47.6% in each arm (95% CI 25.7-70.2). No rescue therapy rates were 66.7% (95% CI 43.0-85.4) versus 57.1% (95% CI 34.0-78.2). No severe adverse events were observed in either arm., Conclusion: Both 1- and 3-day indisetron regimens were feasible for preventing nausea and vomiting induced by mFOLFOX6., (Copyright © 2012 S. Karger AG, Basel.)

Background/aims: The information available concerning the qualitative and quantitative clinical variables in cases with pathologically defined diabetic glomerulosclerosis (DGs) has been insufficient so far. In addition, the prevalence and composition of nondiabetic renal disease (NDRD) among proteinuric diabetics still remain to be delineated., Methods: The glomerular pathology, clinical correlates, and the prevalence of NDRD were retrospectively analyzed in 50 type 2 proteinuric diabetics who underwent a renal biopsy between 1990 and 2006. The patients were divided into two groups according to clinical and pathological features. Thereafter, the diagnostic contribution of the laboratory and clinical variables that were significant between the two groups were determined by logistic regression analysis., Results: There were 34 cases with pure DGs and 15 cases (30%) had NDRD with or without DGs. Although the difference in the prevalence of microscopic hematuria between these two groups was significant, it was no longer statistically significant when the patients were limited to nephrotic cases. We identified 14 hematuric cases with pathologically defined DGs, and they all had a significantly lower renal function than nonhematuric patients with DGs. The prevalence of nephrotic syndrome and retinopathy were significantly higher in the cases with hematuric DGs than in the cases with nonhematuric DGs. Based on a logistic regression analysis, the presence of nephrotic syndrome and known duration of diabetes were identified to be significant predictors for hematuria with DGs., Conclusions: Our observations suggest that the presence of hematuria may be a common feature for DGs with nephrotic syndrome., (Copyright 2008 S. Karger AG, Basel.)

Background: In this study, the membrane mechanisms of hyperkalemia caused by trimethoprim-sulfamethoxazole (TMP-SMX) combination antibiotics were assessed in the cortical collecting duct (CCD)., Methods: We used the microelectrode technique and flux measurements, and examined the effects of TMP and SMX on electrical properties of the apical and basolateral membranes in the rabbit CCD perfused in vitro., Results: TMP in the lumen caused increases in apical membrane voltage, fractional apical membrane resistance (fRA), and transepithelial resistance (RT), all effects which were completely inhibited by luminal amiloride, but not by luminal Ba2+. The luminal TMP inhibited both net Na+ reabsorption and K+ secretion in the CCD. TMP in the bath slightly but significantly depolarized transepithelial voltage and basolateral membrane voltage without influencing fRA or RT. SMX in the lumen or bath had no effect on barrier voltages or resistances., Conclusion: TMP mainly acts on the apical membrane of the CCD, inhibits the amiloride-sensitive macroscopic Na+ conductance in this membrane, and thereby decreases the net driving force for K+ exit across the membrane, resulting in an inhibition of K+ secretion. SMX in the lumen or bath had no effect on the CCD., (2006 S. Karger AG, Basel.)

Background: We previously found that the Na(+)/H(+) exchanger 3 (NHE3) is localized in the apical membrane of the rat renal proximal tubule and thick ascending limb of Henle. In the present study, we examined the direct effect of glucagon on the opossum kidney P (OKP) cell Na(+)/H(+) antiporter, encoded by NHE3., Methods: Na(+)/H(+) antiporter activity was measured as the rate of cell pH recovery from an acid load using 2',7'-bis(carboxyethyl)-5(6)-carboxyfluorescein. Northern blot and Western blot analyses were performed using OKP NHE3 cDNA and anti-OKP-NHE3 antibodies., Results: Glucagon (1 ng/ml) acutely (1 h) inhibited, but chronically (24 h) activated NHE3 activity in OKP cells. These effects were blocked by either KT5720 or RpcAMP [protein kinase A (PKA) inhibitors], and mimicked by 10(-4) M dibutyryl-cAMP. Both NHE3 mRNA and protein abundance increased with the 24-hour incubation in glucagon or dibutyryl-cAMP. Cycloheximide did not prevent a significant increase in NHE3 activity at 24 h. We therefore examined NHE3 protein abundance in the surface membrane by the biotinylation method. cAMP or glucagon significantly increased NHE3 protein abundance in the surface membrane when incubated with cycloheximide for 24 h., Conclusions: Glucagon acutely inhibits but chronically activates NHE3 activity in OKP cells via a PKA-dependent pathway. Both protein-synthesis-dependent and -independent mechanisms play important roles in the chronic activation of NHE3., (Copyright 2002 S. Karger AG, Basel)

Background: Hemodialysis patients who had been treated with anti-platelet aggregation drugs, including ticlopidine, sometimes developed hypotension. The mechanism by which ticlopidine lowers the blood pressure in hemodialysis patients is unclear. To elucidate the mechanism of the action of this drug, we investigated cytokine-stimulated nitric oxide (NO) metabolism by ticlopidine in cultured rat vascular smooth muscle cells (VSMC)., Methods: Nitrite, a stable metabolite of NO, and intracellular cAMP and cGMP contents were assayed by the Griess method and enzyme immunoassay, respectively. iNOS mRNA and protein expressions were analyzed by Northern blotting and Western blotting., Results: Ticlopidine enhanced interleukin-1beta (IL-1beta)-induced nitrite production in a dose- and time-dependent manner. The mRNA and protein expressions of inducible NO synthase were upregulated by ticlopidine in a dose- and time-dependent manner. IL-1beta alone stimulated both intracellular cAMP and cGMP contents, and the addition of ticlopidine further enhanced their contents. KT 5720, a selective inhibitor of protein kinase A, but not KT 5823, a selective inhibitor of protein kinase G, abolished the enhancement of IL-1beta-induced nitrite production by ticlopidine. In addition, a phosphodiesterase inhibitor, isobutylmethylxanthine, enhanced IL-1beta and ticlopidine induced nitrite production., Conclusion: We concluded that ticlopidine enhanced the IL-1beta-induced NO production via cAMP and subsequent activation of protein kinase A in cultured rat VSMC., (Copyright 2002 S. Karger AG, Basel)

A 24-year-old Japanese woman with IgA nephropathy exhibited a decreased serum aldosterone level with normal plasma renin activity after toxemia of pregnancy. Our studies revealed selective hypoaldosteronism with normal adrenoglucocorticoid functions. Levels of serum corticosterone and deoxycorticosterone were normal. Resting plasma renin activity was normal, and plasma levels of total and inactive renin were increased. Rapid ACTH administration failed to stimulate any secretion of aldosterone, whereas it adequately increased serum cortisol, deoxycorticosterone, and corticosterone concentrations. Responses of both plasma renin activity and serum aldosterone level to the furosemide-posture challenge were blunted. Angiotensin II also failed to stimulate any secretion of aldosterone despite a progressive rise in blood pressure and an appropriate increase in serum corticosterone. These results suggest that combined defects of the conversion from inactive renin to active renin and aldosterone biosynthesis are the causes of selective hypoaldosteronism in our patient., (Copyright 2001 S. Karger AG, Basel)

Thiazolidinedione derivatives, new insulin-sensitizing antidiabetic agents, are expected to have potential clinical use. Since these drugs cause edema in a variable proportion of patients, we examined whether troglitazone (Tro) has direct action on Na+ transport of rabbit proximal straight tubule perfused in vitro. For this purpose, we measured basolateral membrane voltage (V(B)) by conventional microelectrode techniques and intracellular pH (pH(i)) by microscopic fluorescence spectrophotometry with a pH-sensitive fluorescent dye, 2', 7'-bis-2-carboxyethyl-5-carboxyfluorescein. Tro at 50 microM in the bath significantly depolarized both transepithelial voltage and V(B). To examine whether the basolateral rheogenic Na+/HCO3- cotransport activity is affected by Tro, we observed V(B) deflection upon abrupt 10-fold decrease in bath HCO3- in the absence and presence of Tro. The apparent transference number of HCO3- (tHCO3), as calculated from the V(B) deflection, was significantly greater in the presence of Tro (50 microM) than that seen in its absence. Tro caused cell acidification and increased the intracellular acidification rates (dpH(i)/dt) upon abrupt 10-fold decreases in bath HCO3- and Na+ concentrations. The stimulatory effects of Tro on tHCO3 and dpH(i)/dt were dose dependent between 5 and 50 miccroM, but they were unaffected at 0.5 microM. From these results, we conclude that Tro acts on the proximal straight tubule and stimulates the basolateral rheogenic Na+/HCO3- cotransport activity. The stimulatory action of Tro may partly account for edema formation., (Copyright 2001 S. Karger AG, Basel)

Protamine is known to inhibit cation selectivity of the paracellular shunt pathway in several leaky nephron segments. Ion permeability of the superficial (SF) proximal straight tubules (PST) is selective to Cl(-), whereas that of the juxtamedullary (JM) PST is selective to Na(+). Protamine was used to estimate the contribution of the paracellular shunt pathway to ion selectivity in these segments. PSTs were isolated from the kidneys of Japanese white rabbit and microperfused in vitro. The ratio of Na(+) to Cl(-) permeability (P(Na)/P(Cl)) was estimated from the diffusion potential (dV(T)) generated by NaCl gradients. When 300 microg/ml protamine was added to the lumen, P(Na)/P(Cl) was decreased from 0.33 to 0.26 in SF-PST and from 1.80 to 1.29 in JM-PST, respectively, as the results of inhibition of cation selectivity. Addition of 30 U/ml heparin to the lumen, which neutralizes protamine, returned the ratios toward the control levels. Protamine exhibited similar effect on P(Na)/P(Cl) in the presence or the absence of ouabain in the bath, indicating that the observed voltage deflections were independent of the transcellular active transport process. Although P(Na)/P(Cl) was different between SF- and JM-PST, protamine inhibits Na(+) permeability in both segments. Preferential Cl(-) permeability in the SF-PST may be intrinsic to the paracellular route of this segment. The mechanism of this anion selectivity remains to be established.

To further characterize the alpha- and beta-intercalated cells (alpha-IC, beta-IC) in the isolated and perfused connecting tubule (CNT), cortical collecting duct (CCD) and outer medullary collecting duct in the inner stripe (OMCDi) of rabbit kidneys, we studied the effects of various transport inhibitors on electrical parameters. They included inhibitors of Cl-/HCO3- exchanger (4-acetamino-4'-isothiocyanostilbene-2,2'-disulfonic acid, SITS), carbonic anhydrase (acetazolamide) and Na(+)-K(+)-ATPase (ouabain). Upon addition of 10(-3) M SITS to the bath, the basolateral membrane voltage (VB) of alpha-IC in the OMCDi and CCD was significantly hyperpolarized by 20.8 +/- 4.6 (n = 5) and 29.8 +/- 5.6 mV (n = 11), respectively. On the other hand, luminal addition of SITS had no effects on VB of alpha-IC in the OMCDi and CCD. Neither bath nor lumen SITS affected VB of beta-IC in the CCD and CNT. When 10(-4) M acetazolamide was added to the bath, VB of alpha-IC in the OMCDi and CCD was significantly hyperpolarized by 20.0 +/- 4.1 (n = 4) and 18.6 +/- 1.7 mV (n = 3), respectively. Similarly, 10(-4) M acetazolamide in the bath caused the basolateral membrane of beta-IC in the CCD and CNT to hyperpolarize significantly by 34.3 +/- 7.9 (n = 6) and 21.6 +/- 2.9 mV (n = 3), respectively. Luminal addition of acetazolamide had no effect on VB of alpha-IC in the CCD and OMCDi and beta-IC in the CCD and CNT.(ABSTRACT TRUNCATED AT 250 WORDS)

A 51-year-old Japanese woman with hypokalemia due to distal renal tubular acidosis associated with Sjögren's syndrome exhibited a decreased plasma aldosterone level despite elevated plasma renin activity. Our studies revealed selective hypoaldosteronism with normal adrenoglucocorticoid function. In the presence of a low level of serum potassium (3.6 mEq/l), plasma levels of deoxycorticosterone and corticosterone were normal, while plasma aldosterone was very low. The levels of these three mineralocorticoids showed only minor changes during infusion of angiotensin II. Furosemide administration under almost the same level of serum potassium (3.7 mEq/l) resulted in only a slight increase of plasma aldosterone. Since hypokalemia might possibly suppress the synthesis of aldosterone in the zona glomerulosa, angiotensin II was also infused under a normal level of potassium (4.3 mEq/l). However, angiotensin II also failed to stimulate any secretion of aldosterone, despite a progressive rise in blood pressure and sufficient suppression of plasma renin activity. On the other hand, rapid ACTH administration in the presence of 4.4 mEq/l of serum potassium increased both plasma aldosterone and cortisol. These results suggest that adrenal insensitivity to angiotensin II was the cause of the selective hypoaldosteronism in our patient, possibly due to a dysfunction of adrenal angiotensin II receptors, a disorder of postreceptors or both.

In 68 patients with chronic renal failure (CRF), 15 patients with duodenal ulcer and 15 normal subjects, basal plasma gastrin levels and basal and stimulated gastric acid secretion were measured. Two antisera were used: antiserum R2702 with specificity for human G34 and its N-terminal fragments [G34] and antiserum 2604 with specificity for the four main components of gastrin (total gastrin). Basal gastrin concentrations of both total gastrin and G34-like immunoreactivity (G34LI) were significantly higher in the CRF patients than in the other two groups, irrespective of dialysis. Total gastrin levels were not correlated with serum creatinine levels. Total gastrin levels were significantly decreased during hemodialysis, but G34LI levels showed no significant change. A small amount of total gastrin was detected in the dialysate by antiserum 2604. As to the postprandial gastrin release, in the first 30 min, the pattern of response in the patients with CRF was similar to that of the normal subjects, but the peak value was attained later, and the response was more rather prolonged. Gastric analysis showed a low basal acid out put and impaired acid secretion in response to secretagogue. It is concluded that (1) one of the predominant circulating forms of gastrin in CRF is G34LI, and (2) the hypergastrinemia in the CRF patients is probably due to reduced removal of gastrin by kidneys, increased gastrin production by impairment of the negative acid feedback mechanism induced by parietal cell dysfunction or reduced parietal cell sensitivity to gastrin by atrophic gastritis.

This report describes the case of a 50-year-old male with end-stage renal failure accompanied with congenital heart disease and polycythemia. After he had received continuous ambulatory peritoneal dialysis for 1 year, he still remained polycythemic and his serum erythropoietin titer, assayed using fetal mouse liver cells, was markedly increased. An inhibitory effect on erythropoiesis was not detected by this method. Bone marrow examination showed erythroid hyperplasia. These phenomena could be explained by an overproduction of erythropoietin by the remnant kidneys or extrarenal organs, such as the liver, in response to persisting hypoxia. The patient's bone marrow was still responsive to erythropoietin.

In 40 young patients with chronic renal failure (CRF) on maintenance hemodialysis and 22 control subjects, (1) basal and test meal-stimulated gastrin concentrations, (2) basal and pentagastrin-stimulated gastric acid outputs, and (3) endoscopic examinations were studied. Age-matched CRF patients with control subjects had higher circulating gastrin levels both in the fasting and the test meal-stimulated state and they also had hypochlorhydria. After a test meal, the peak increment of serum gastrin in the CRF patients was more prolonged and greater than in controls. Endoscopic findings showed that the most predominant lesion in the CRF patients was hemorrhagic gastritis. Nine (64.2%) out of 14 patients were hyposecretors and none were hypersecretors. Patients with hyposecretion had higher gastrin levels as well as the same incidence of abnormal endoscopic findings as patients with normosecretion. It is concluded that hypergastrinemia in young CRF patients might be due to a combined effect of impaired renal clearance capacity and overproduction of gastrin associated with hypochlorhydria and also that the cause of gastritis in the young CRF patients might partly be due to a relative impairment of the mucosal defensive mechanism to acid. Our data suggest that the parietal cell response to gastrin in CRF patient may be impaired.

In 15 undialyzed (UD) patients and 26 hemodialyzed (HD) patients, (1) basal and test meal-stimulated gastrin concentrations, (2) basal and pentagastrin-stimulated gastric acid outputs, and (3) endoscopic examinations were studied. Also studied were the morphological and functional differences of the gastrointestinal tract between UD and HD patients. HD patients had lower gastric acid outputs and higher circulating gastrin levels in the fasting state. After a test meal, the peak increment of serum gastrin in UD and HD patients occurred 30 and 60 min later, respectively, and the response was prolonged in each group. Endoscopic findings showed that the incidence of abnormalities in each group was very similar, that is, the most predominant lesions in each group were hemorrhagic and atrophic gastritis. The data suggested that the response to gastrin of parietal cell and the defensive mechanism of gastrointestinal mucosa in HD patients may be impaired.

Adhesion variants can be isolated from suspension growing highly metastatic murine ESb tumor cells under reproducible conditions from uncloned as well as from cloned ESb tumor cells. One such variant, ESb-MP, has been analyzed in detail. In vitro it had similar growth properties and high invasive capacity as the parental ESb cells. In vivo, ESb-MP cells showed a reduced growth capacity as compared to ESb cells. This was seen at the site of tumor cell transplantation (increased latency period) as well as at the site of secondary tumor growth in internal organs. ESb-MP tumor cells disseminated much later than ESb cells from the primary tumor into the blood stream. Both tumor lines metastasized to the liver but they affected liver functions in a different way: ESb cells infiltrated the liver diffusely and exerted toxic effects on liver parenchyma very quickly. This resulted in early increase of liver enzyme activity in the blood. In contrast, liver infiltrated by ESb-MP cells showed a more focal type of colonization and the organs seemed to be functioning for much longer periods. In fact, animals inoculated with ESb-MP cells subcutaneously or intravenously had an increased life expectancy compared to ESb-tumor-bearing animals of about 300%. The organotropism of both tumor lines remained similar although there were kinetic and quantitative differences, especially with regard to the kidney. In late stages of tumor growth, ESb-MP-tumor-bearing animals developed a high percentage of metastases in the kidney and around and within the spinal cord, thereby causing a syndrome of hind-leg paralysis. This syndrome was remarkable in its reproducibility, especially after intravenous tumor cell inoculation. The changed adhesiveness thus seemed to have affected the tumor latency period, the speed of dissemination into blood and internal organs, the mode of organ infiltration (focal vs. diffuse) and of metastatic growth, parameters which all might contribute to the greatly reduced overall malignancy.