Clinical features and treatment outcomes of resected large cell neuroendocrine carcinoma of the lung

Purpose@#Pulmonary large cell neuroendocrine carcinoma (LCNEC) is a high-grade lung neuroendocrine tumor with a poor prognosis, similar to small cell lung cancer (SCLC). However, it remains unclear whether to treat LCNEC as non-small-cell lung cancer (NSCLC) or as SCLC. We reviewed our experiences to suggest appropriate treatment strategy for resected pulmonary LCNEC. @*Materials and Methods@#Forty-four patients were treated for pathologically diagnosed pulmonary LCNEC during 2005‒2018. We considered curative surgery first in early-stage or some locally advanced tumors, unless medically inoperable. Adjuvant treatments were decided considering patient’s clinical and pathological features. After excluding two stage I tumors with radiotherapy alone and three stage III tumors with upfront chemotherapy, we analyzed 39 patients with stage I‒III pulmonary LCNEC, who underwent curative resection first. @*Results@#Adjuvant chemotherapy (NSCLC-based 91%, SCLC-based 9%) was performed in 62%, and adjuvant radiotherapy was done in three patients for pN2 or positive margin. None received prophylactic cranial irradiation (PCI). With a median follow-up of 30 months, the 2- and 5-year overall survival (OS) rates were 68% and 51%, and the 2- and 5-year recurrence-free survival (RFS) rates were 49% and 43%, respectively. Aged ≥67 years and SCLC-mixed pathology were significant poor prognostic factors for OS or RFS (p < 0.05). Among 17 recurrences, regional failures were most common (n = 6), and there were five brain metastases. @*Conclusions@#Surgery and adjuvant treatment (without PCI) could achieve favorable outcomes in pulmonary LCNEC, which was more similar to NSCLC, although some factors worsened the prognosis. The importance of intensified adjuvant therapies with multidisciplinary approach remains high.

Inter-alpha Inhibitor H4 as a Potential Biomarker Predicting the Treatment Outcomes in Patients with Hepatocellular Carcinoma / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: Early prediction of treatment outcomes represents an essential step towards increased treatment efficacy and survival in patients with hepatocellular carcinoma (HCC). In this study, we performed two-dimensional electrophoresis (2-DE) followed by protein profiling to identify biomarkers predictive of therapeutic outcomes in patients with HCC who received liver-directed therapy (LDTx) involving local radiotherapy (RT), and studied the underlying mechanisms of the identified proteins. MATERIALS AND METHODS: 2-DE analysis was conducted by pooling sera from patients with a good or poor prognosis; serum proteomic profiles of the two groups were compared and analyzed using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Identified proteins were confirmed via enzyme-linked immunosorbent assay. An invasion assay was performed after overexpression and knockdown of target protein in Huh7 cells. RESULTS: Levels of inter-alpha inhibitor H4 (ITIH4), fibrinogen gamma chain, keratin 9/1 complex, carbonic anhydrase I, and carbonmonoxyhemoglobin S were changed by more than 4-fold in response to LDTx. In particular, pre-LDTx ITIH4 expression was more than 5-fold higher in patients with a good prognosis, compared to patients with a poor prognosis. The migration ability of Huh7 cells was significantly suppressed and enhanced by ITIH4 overexpression and knockdown, respectively. The tumors of patients with HCC and a good prognosis expressed high levels of ITIH4, compared to those of patients with a poor prognosis. CONCLUSION: Taken together, ITIH4 may be a potential therapeutic target that could inhibit cancer metastasis, as well as a prognostic marker for patients with HCC who are receiving LDTx.

Neuropathic Pain Model of Peripheral Neuropathies Mediated by Mutations of Glycyl-tRNA Synthetase

Charcot-Marie-Tooth disease (CMT) is the most common inherited motor and sensory neuropathy. Previous studies have found that, according to CMT patients, neuropathic pain is an occasional symptom of CMT. However, neuropathic pain is not considered to be a significant symptom associated with CMT and, as a result, no studies have investigated the pathophysiology underlying neuropathic pain in this disorder. Thus, the first animal model of neuropathic pain was developed by our laboratory using an adenovirus vector system to study neuropathic pain in CMT. To this end, glycyl-tRNA synthetase (GARS) fusion proteins with a FLAG-tag (wild type [WT], L129P and G240R mutants) were expressed in spinal cord and dorsal root ganglion (DRG) neurons using adenovirus vectors. It is known that GARS mutants induce GARS axonopathies, including CMT type 2D (CMT2D) and distal spinal muscular atrophy type V (dSMA-V). Additionally, the morphological phenotypes of neuropathic pain in this animal model of GARS-induced pain were assessed using several possible markers of pain (Iba1, pERK1/2) or a marker of injured neurons (ATF3). These results suggest that this animal model of CMT using an adenovirus may provide information regarding CMT as well as a useful strategy for the treatment of neuropathic pain.

Neuropathic Pain Model of Peripheral Neuropathies Mediated by Mutations of Glycyl-tRNA Synthetase

Charcot-Marie-Tooth disease (CMT) is the most common inherited motor and sensory neuropathy. Previous studies have found that, according to CMT patients, neuropathic pain is an occasional symptom of CMT. However, neuropathic pain is not considered to be a significant symptom associated with CMT and, as a result, no studies have investigated the pathophysiology underlying neuropathic pain in this disorder. Thus, the first animal model of neuropathic pain was developed by our laboratory using an adenovirus vector system to study neuropathic pain in CMT. To this end, glycyl-tRNA synthetase (GARS) fusion proteins with a FLAG-tag (wild type [WT], L129P and G240R mutants) were expressed in spinal cord and dorsal root ganglion (DRG) neurons using adenovirus vectors. It is known that GARS mutants induce GARS axonopathies, including CMT type 2D (CMT2D) and distal spinal muscular atrophy type V (dSMA-V). Additionally, the morphological phenotypes of neuropathic pain in this animal model of GARS-induced pain were assessed using several possible markers of pain (Iba1, pERK1/2) or a marker of injured neurons (ATF3). These results suggest that this animal model of CMT using an adenovirus may provide information regarding CMT as well as a useful strategy for the treatment of neuropathic pain.

Souvenir made of tiger part revealed to be Banteng (Bos javanicus): species identification using DNA sequence analysis / 대한수의학회지

Tigers are one of the most endangered species over the world and protected internationally or locally. However, they are still traded illegally for the Traditional East Asia Medicine or souvenirs / mementos as well as fake products. In the present study, to identify the species of the specimen known as the tiger's genitalia that was sold for mementos in China, two approaches of genetic tools and morphological comparisons were applied. On the basis of the entire sequences of mitochondrial cytochrome b gene (1,140 bp), the result of nucleotide comparisons showed that the specimen examined here is matched with banteng, Bos javanicus (Identities = 1,138/1,140; 99%). In addition, the examination of external morphological characters revealed that the genitalia of the specimen is much more similar to the one of cows, not to tigers. The outcomes highlighted that there are still some fake products of tigers traded in market and molecular genetic tools could help identifying species of wildlife products.

Restless Legs Syndrome in Patients on Hemodialysis: Symptom Severity and Risk Factors

BACKGROUND AND PURPOSE: Restless legs syndrome (RLS) is a sleep disorder that frequently occurs in dialysis patients, which disturbs the sleep and reduces the quality of life. The aim of this study was to determine the risk factors for RLS in dialysis patients. METHODS: Patients who visited any of four outpatient dialysis clinics between September 2005 and May 2006 were included in this study. The diagnosis of RLS and the severity assessment were made using the criteria described by the International Restless Legs Syndrome Study Group. We collected basic demographic data, clinical information, and laboratory findings, and then analyzed their association with various aspects of RLS using univariate and multivariate analyses. RESULTS: RLS was present in 46 (28.0%) of 164 dialysis patients. We found no significant risk factor for inducing RLS. The predialysis serum blood urea nitrogen (BUN) level in the dialysis patients with RLS was significantly correlated with RLS symptom severity. CONCLUSIONS: Predialysis BUN is related to RLS symptom severity. Further studies on the underlying mechanism are needed.

A Case of Adult-Onset Minimal Change Nephrotic Syndrome Relapsed after 15-year of Complete Remission / 대한신장학회잡지

We report an unusual case of adult minimal change nephrotic syndrome relapsed after 15-year of complete remission. In this case, the disease had occurred to the patient for the first time when he was 52 years old; relatively high age, and had been remitted with steroid therapy. After 15 years of complete remission, he visited our hospital with the symptoms of the generalized edema and the pitting edema of both lower extremities that occurred 15 days ago. Massive proteinuria(15, 865 mg/day) and hypoalbuminemia(1.7 g/dL) were detected. The pathologic evaluation of the biopsied specimen of the kidney showed the global sclerosis in 19% of glomeruli in light microscopic finding and the fusion of epithelial foot processes in electron microscopic finding. He was treated with pulse steroid therapy (methylprednisolone 500 mg/day iv for 3 days) and then, with oral prednisolone (60 mg/day). Generalized edema and proteinuria disappeared after 14 days of treatment, and there has been no relapse ever since. Adult-onset minimal change nephrotic syndrome relapses within 4 years after complete remission in 90 % of relapsed patients. The relapse after more than 5 years of complete remission, like this case, is very rare, especially in the case of late-onset disease. However, the possibility of relapse of the minimal change nephrotic syndrome after several years of its remission should be considered constantly and the long-term follow-up more than 10 years may be needed.

Polypeptides Inhibiting Angiogenesis / 대한내분비학회지

No abstract available.

Effect of Mineralocorticoid on Serum Potassium Regulation and Urine Ammonium Excretion in Chronic Renal Patients / 대한신장학회잡지

Mineralocorticoids influences on acid-base homeostasis by the regulation of urine acidification. But its mechanism of acion is not well known in human. This study compared the acid-base status and the indices of urine acidification before and after mineralocorticoid administration in human, and analyzed the effect of mineralocorticoids on human acid-base homeostasis. We administered 9a-fludrocortisone in 6 chronic renal failure patients and 6 normal controls 0.5mg daily for 7 days. The results were as following: 1) After administration of 9a-fludrocortisone in patients group, serum aldosterone level changed from 120.2+/-71.0pg/mL to 44.8+/-32.2pg/mL(mean+/-SD, p< 0.05). Serum HCO- level was not changed. Urine ammonium excretion was incresed from 24.6+/-12.3 mmol/day to 43.7+/-19.0 (p<0.05), but there were no change in urine pH and urine anion gap, Serum potassium level decreased from 5.5+/-0.7mBq/L to 4.1+/-0.5mEq/L (p<0.05), and TTKG increased from 3.9 to 8.9(p<0.05). 2) After administration of 9a-fludrocortisone in control group, serum aldosterone level changed from 99.7+/-44.5pg/mL to 25.1+/-3 mL(p<0.05). Serum HCO- level was not changed. Urine ammonium excretion was incresed from 44.3+/-21.6mmoVday to 76.3+/-19.6(p<0.05), but there were no change in urine pH and urine anion gap. Serum potassium level decreased from 4.8+/-0.5mEq/L to 3.9+/-0.2mHq/L(p< 0.05), but there was no change in TTKG. 3) No patient or control showed any discomfort after 9-fludrocortisone administration, and there was no elevation in diastolic blood pressure, increase in body weight, electrolyte abnormality. In summary, after 9alpha-fludrocortisane administration, urinary ammonium excretion increased in both patients and control group, and this phenomenon occured with correction of hyperkalemia without urine pH change. This result implies urinary ammonium excretion increase by mineralocorticoid. In human increase in renal distal acidification by mineralocorticoid is due to increase in renal ammoniagenesis rather than stimulation on proton excretion.

Cerebrovascular complications in autosomal dominant polycystic kidney disease(ADPKD) / 대한내과학회지

BACKGROUND: ADPKD is one of the most common hereditary renal disease in adult and is a systemic disorder with a variety of cardiovascular manifestations. To elucidate the clinical characteristics of cerebrovascular complications in Korean ADPKD patients, we reviewed the medical records of ADPKD patients who was registered in ADPKD clinic of Seoul National University Hospital. METHODS: A total of 18 adult patients were included and their sex ratio was 8:10. The median age of ADPKD diagnosis was 45.5 year (range 19-85), and age at cerebrovascular accident(CVA) was 52 years(22-82). The median duration from hypertension to CVA was 8 years(0-30). RESULTS: There were 5 cases of infarction, 4 cases of intracerebral hemorrhage, 4 cases of subarachnoid hemorrhage, and 4 cases of transient ischemic attack. Other clinical parameters of ADPKD were not different from patients who were not complicated with CVA. Intracranial aneurysms were detected in 6 patients and their median age at diagnosis was 47.5 years(33-66). Four cases were manifested as subarachnoid hemorrhage. Five cases were diagnosed through TFCA, and two of them were revealed as multiple aneurysms. Five cases received surgical treatment and five of six cases improved without any neurologic sequeale. MR angiography(MRA) were taken in 16 asymptomatic patients, and multiple aneurysms were newly detected in one of them. CONCLUSION: Cerebrovascular complications in Korean ADPKD patients were not significantly different from western patients. Intracranial aneurysms must be included in differential diagnosis in ADPKD patients who manifest an acute neurologic symptoms, and high-risk group need to be screened selectively with MRA.

A Case of Renal Oncocytomatosis with Chronic Renal Failure / 대한신장학회잡지

Renal oncocytomas account for approximately 5% of renal parenchymal tumors. Usually it has unilateral solitary oncocytic nodule, but bilateral multifocal renal oncocytomasis is rare. The term renal oncocytoma should be used to characterize a well-differentiated renal epithelial tumor with eosinophilic granular cytoplasm that has benign behavior and favourable progress. Also, multiple oncocytoma distributed diffusely in both kidneys is termed renal oncocytomatosis Because of the benign nature, multicentricity, possible bilaterality and absence of pathognomonic radiographic features, renal oncocytomas should be considered in differential diagnosis of solid masses, especially renal cell carcinoma. We report a patient with bilaleral multifocal renal oncocytomatosis, who had progressive renal failure. Renal oncocytomatosis was diagnosed pathologically after bilateral nephrectomy.

Defect of Acid-base Transporters in Distal Renal Tubular Acidosis / 대한신장학회잡지

The purpose of this study was to elucidate whether the molecular defect of acid-base transporters in renal tubules is related to the functional defect of urinary acidification in distal renal tubular acidosis(RTA). We performed NH4Cl, furosemide, or bicarbonate loading test to evaluate renal acidification function, and immunohistochemistry using antibodies to H+- ATPase, Cl-/HCO3- exchanger(band-3 protein), and Na+/K+-ATPase in kidney tissue in 6 patients with RTA and renal cell carcinoma patients as normal controls. Kidney tissue was obtained either by percutaneous needle biopsy(RTA) or nephrectomy(NC). The results were as follows; 1) In all six RTA patients, proton secretory defect of distal acidification was shown by a failure to lower the urine pH after NH4Cl loading or furosemide test or abnormally low urine-blood pCO2 difference during bicarbonate loading. In two patients with RTA, proximal acidification defect was combined, which was demonstrated by increased fractional excretion of bicarbonate. 2) In normal control, intense H+-ATPase and band-3 protein staining was observed in collecting ducts. 3) In distal RTA patients, H+-ATPase and band- 3 protein staining was not demonstrable or markedly decreased in the intercalated cells of distal nephron. 4) In two patients who had both proximal and distal RTA, H+-ATPase staining was markedly decreased in the brush border of proximal tubules as well as the distal nephron. In conclusion, the defect of acid-base transporters in renal tubule was related with the functional defect of urinary acidification in distal RTA.

Diagnostic Significance of Fractional Excretion of Unmeasured Anion(FEua)in Metabolic Acidosis / 대한신장학회잡지

Alcohol can cause rhabdomyolysis by either direct toxicity or associated metabolic abnormality such as hypophosphatemia and hypokalemia. It can also predispose to or cause trauma, seizures, or coma- induced ischemic pressure necrosis. In order to investigate the clinical features of acute renal failure caused by alcohol induced rhabdomyolysis, we reviewed the medical records of the 12 patients. All patients had been drinking much amounts of alcohol for several years. All patients showed elevation of muscle enzyme such as creatine phosphokinase, lactic dehydrogenase, aspartate transaminase and blood urea nitrogen and serum creatinine. Predisposing factors of rhabdomyolysis were ischemic compression due to unconsciousness and dehydration(2 cases), and hypophosphatemia and dehydration(1 case), seizure and dehydration(1 case), and only severe dehydration(3 cases). Initial symptoms were painful swelling at lesion site(5 cases), abdominal pain(2 cases), general ache(2 cases), leg pain without swelling(1 case), dyspnea(1case), and lethargy(1 case). Seven patients developed delirium tremens during recovery stage. Eight patients showed oliguric acute renal failure and 8 patients were treated with hemodialysis. Complications were disseminated intravascular coagulation(DIC)(3 cases), compartment syndrome(2 cases), capillary leak syndrome and DIC(1 case). One of 12 patients died of disseminated intravascular coagulation and other patients showed complete recovery of renal function.

Clinical Characteristics of Hypernatremia / 대한신장학회잡지

Hypematremia is a rare but important medical condition and is associated with mortality rate of 40 to 70%. However, little has been known about its prognostic factors or treatment guidlines. To evaluate the prognostic factors and the outcome following treatment, we reviewed 22 available medical records among twenty five hypernatremic patients (0.2%) in 12841 admissions at medical ward from January to December 1995. We defined hypernatremia as serum sodium concentration more than or equal to 150 mEq/L. Of these patients, two had hypematrernia at admission and the remaining patients became hypernatremic during admission. Mean peak serum sodium concentration was 158 (150-178) mEq/L and mean total body water deficit was 11.4 (6.7-21.3)%. Factors correlated with the development of hypernatremia were diverse and multiple, and the most frequent factor was diminished access to water. Mortality rate was 59%, but mortality was not correlated with age, correction rate of hyper-natremia, primary route of fluid loss, and the severity of hypernatremia or total body water deficit. Mortality rate was higher in patients whose serum sodium concentrations were below 130 mEq/L at admission (P<0.05). In our study, development of hypernatremia from initial hyponatremic state was significantly associated with poor outcome, and age, rapidity of correction, route of fluid loss, and the severity of hypernatremia or total body water deficit were not.

The Role of Oxytocin and Vasopressin in Abnormal Water Retention in Generalized Edematous Patients / 대한신장학회잡지

Antidiuretic action of oxytocin is confirmed by in vitro study using with rat IMCD. Vasopressin is elevated in edematous disorders and may play a pathogenetic role in the formation of edema. If oxytocin plays a sirnilar role to vasopressin in water disturbances in human, oxytocin may change as the same way as vasopressin. To verify a role of oxytocin in the regulation of water balance in human, we measured plasma and urine oxytocin with vasopressin by radioimmunoassay in thirteen patients with generalized edema (8 nephrotic syndrome, 3 liver cirrhosis, 2 acute renal failure) before and after control of edema. And they were compared them with those of seven normal controls. Plasma oxytocin level correlated with plasma vasopressin level (r=0.543: P<0.05) and urinary oxytocin level correlated linearly with urinary vaso-pressin (r=0.983, P<0.01). After control of edema, body weight of patients decreased from 65+/- 2 to 58+/-2kg and fractional excretion of sodium decreased from 3.3+/-1.1 to 1.2+/-0.696 (P<0.05). There were no significant changes in serum and urine Na, osmolality, free water clearance, plasma renin activity, aldosterone and norepinephrine. In conclusion, oxytocin was elevated in edematous disorders, and may participate in formation of edema similar to vasopressin.

Hemolytic Uremic Syndrome In Adults / 대한신장학회잡지

Hemolytic uremic syndrome (HUS) occurs rarely in adults and its clinical manifestations are not well studied in Korea. We analyzed data from 14 adult patients admitted from 1987 to 1996 who fulfilled three criteria (Coombs negative microangiopathic hemolytic anemia, no artificial heart valve, and creatinine level>1.4mg/dL). No patient died, 3 patients needed dialysis for ESRD at first episode, 2 patients developed CRF, 1 patient had recurrence and progressed to ESRD at the second episode. 7 patients completely recovered their renal function without proteinuria nor hypertension. HUS secondary to other disease had the worst renal survival and patients with colitis had better renal survival. Patient age, sex, platelet counts, white blood cell counts, hemoglobin level, treatment modalities were not significantly associated with renal survival.