[Pre-Operative Factors Affecting Trifecta Achievement in the Initial Series of Robot-Assisted Partial Nephrectomy].

We investigated pre-operative factors affecting trifecta achievement in robot-assisted partial nephrectomy (RAPN). We retrospectively analyzed 81 patients who underwent RAPN from December 2016 to September 2021 with final malignant pathologies. Trifecta was defined as negative resection margin (RM),warm ischemic time (WIT) less than 25 minutes, and no severe perioperative complications (Clavien-Dindo＜III). Factors affecting trifecta achievement were analyzed using sex, age, body mass index, RENAL nephrometry score (low or moderate/high complexity), surgical approach (transabdominal or retroperitoneal), tumor diameter and surgical experiences of each surgeon. Negative RM, WIT less than 25 minutes, and no severe complications were obtained in 75 (93%), 65 (80%), and 79 patients (98%), respectively. The trifecta was achieved in 60 patients (74%). In multivariate regression analysis, surgical experience (OR:0.92, 95% CI : 0.86-0.99) was significantly associated with trifecta achievement. Receiver operating characteristic curve analysis identified 9 cases as the optimal cut-off values for the predication of trifecta achievement (AUC＝0.69,p ＝0.11). The achievement of WIT less than 25 minutes (65 vs 90%, p＜0.01) and trifecta (58 vs 84%,p ＜0.05) were significantly lower in surgical experiences less than 9 cases than in 9 or greater. We conclude that surgical experience in RAPN is an important factor affecting WIT and trifecta achievement in the initial series.

[Comparison of Perioperative Outcomes between Open and Robot-Assisted Laparoscopic Radical Cystectomy].

We compared the perioperative outcomes of open (ORC) and robot-assisted laparoscopic radical cystectomy (RARC) for patients with bladder cancer. We retrospectively investigated the intraoperative and 90-day postoperative complications of ORC and RARC performed from March 2014 to September 2021 based on the medical records. Perioperative complications were categorized according to the Clavien- Dindo classification. We used the propensity score matching to adjust for the inherent bias of the different patient characteristics at baseline including gender, age, preoperative chemotherapy, and pathological T classification. Surgery time of RARC was significantly shorter than that of ORC, and blood transfusion was significantly less frequent in RARC than in ORC (3% vs 81%, p＜0.01). The rate of overall complications of Grade III/IV was lower in RARC (8%) than in ORC (25%) (P＝0.09). The prevalence of perioperative urinary tract infection, ileus, and abscess/infectious cyst was similar in ORC and RARC. In patients who underwent RARC, the complication rate was similar in extracorporeal and intracorporeal urinary diversion. Compared to ORC, RARC is more beneficial to reduce blood loss and severe complications.

Deterioration of bladder compliance after botulinum toxin A injection and discontinuation of medication for overactive bladder.

Introduction: We report a case of deterioration of bladder compliance after botulinum toxin type A injection and discontinuation of medication for overactive bladder. Case presentation: A female patient with overactive bladder in her sixties had been visiting our outpatient clinic regularly for 4 years. She had received posterolateral spondylus fusion twice, which resulted in a compression fracture. She had been receiving a combination therapy of anticholinergics and ß3-adrenoceptor agonist for the management of overactive bladder. She received botulinum toxin type A injection for refractory overactive bladder and discontinued medical treatment for overactive bladder. Three months after botulinum toxin type A injection, cystometry revealed the deterioration of bladder compliance. Renal dysfunction, hydronephrosis, and vesicoureteral reflux were shown. Renal function and hydronephrosis were improved after restarting anticholinergics and ß3-adrenoceptor agonist therapy and inserting a temporary transurethral catheter. Conclusion: Deterioration of bladder compliance may occur after botulinum toxin type A injection and discontinuation of overactive bladder medication in some patients with underlying neurological disease.

[Treatment Outcome of Ureteral Reconstruction Surgery].

We retrospectively reviewed the surgical outcome of ureteral reconstruction that was performed in Asahikawa Medical University Hospital between 2005 and 2021. A total of 14 patients (3 males, 11 females; 15 ureters) were included in this analysis. The median age was 57 years old. The reason for ureteral reconstruction was ureteral injury or stenosis due to pelvic surgery in 9 patients, transurethral lithotripsy for ureteral stone in 3, ureteral invasion of sigmoid colon cancer in one and ovarian cancer in one. The site of ureteral reconstruction was proximal ureter in 2, middle in 3 and distal in 10. The surgical procedure was ureteroneocystostomy with Boari flap in 8 patients (57%), ureteroureterostomy in 4 (21%), transureteroureterostomy in one (7%), and transureteroureterostomy combined with Boari flap for bilateral ureteral stenosis in the remaining patient (7%). Postoperatively, vesicoureteral reflux, ileus and surgical site infection were observed in 3, 2 and 1 patient, respectively. No patient required nephrostomy or ureteral catheter, or any additional procedure after the surgery. There was no episode of febrile urinary tract infection after the surgery. The mean estimated glomerular filtration rate was, respectivery 75.8 and 78.5 ml/min/1.73 m2 before surgery and at 1-101 months (median of 18) after the surgery. In conclusion, satisfactory outcome was achieved after ureteral reconstruction surgery. We emphasize the importance of selecting the most appropriate procedure for ureteral reconstruction in each patient to prevent renal function deterioration and urinary tract infection.

[Clinical Significance of Preoperative Image Classification Systems in Robot-Assisted Laparoscopic Partial Nephrectomy].

Robot-assisted laparoscopic partial nephrectomy (RAPN) is being used in Japan as a less invasive procedure. RENAL nephrometry (RN) score, Preoperative Aspects and Dimensions Used for an Anatomical (PADUA) Classification and Simplified PADUA Renal (SPARE) nephrometry system are tumor-specific morphometry scoring systems used for predicting the difficulty of partial nephrectomy. Adherent perinephric fat (APF) is one of the patient-specific factors related to the difficulty of partial nephrectomy. Mayo Adhesive Probability (MAP) score measures the difficulty of partial nephrectomy due to APF. Whether these scoring systems were associated with perioperative outcome of RAPN was retrospectively analyzed in 57 patients who underwent RAPN by two experienced surgeons at our hospital from December 2016 to March 2020. Forty-five patients were male and 12 were female. The right side was resected in 25 and the left side in 32 patients. The approach was transperitoneal in 42 and retroperitoneal in 15 patients. There were significant correlations among RN, PADUA and SPARE scores, while MAP score was independent from the other scores. Warm ischemic time was significantly correlated with RN (r＝0.46, p＜0.001), PADUA (r＝0.45, p＜0.001) and SPARE scores (r＝0.44, p＜0.001). Time for console was significantly correlated with MAP score (r＝0.28, p＝0.035). In conclusion, RN and MAP scores might be useful parameters to predict warm ischemic time and time for console during RAPN, respectively.

Dutasteride add-on treatment to tadalafil for patients with benign prostatic enlargement is similarly effective as dutasteride add-on treatment to alpha blocker: a propensity-score matching analysis.

PURPOSE: To investigate the efficacy of dutasteride add-on treatment to tadalafil in patients with lower urinary tract symptoms (LUTS) suggestive of benign prostatic enlargement (BPE). METHODS: A prospective study was conducted in patients with BPE who had not been satisfied with tadalafil monotherapy for more than 3 months. Inclusion criteria were prostate volume (PV) ≥ 30 ml and IPSS ≥ 8 or QOL index ≥ 3 under administration of tadalafil without anticholinergic agent. Before and 24 weeks after dutasteride add-on treatment to tadalafil, we assessed IPSS, overactive bladder symptom score (OABSS), serum PSA and testosterone, and uroflowmetry (UFM) to compare these parameters before and after dutasteride add-on treatment. Using a propensity-score matching analysis, the efficacy of dutasteride add-on treatment to tadalafil was compared with the previous study of dutasteride add-on treatment to alpha blocker. RESULTS: Of 52 patients who were enrolled in this study, 48 patients completed the study (mean age: 72 ± 5 years old). Dutasteride add-on treatment to tadalafil significantly improved IPSS (from 16.4 ± 5.2 to 13.3 ± 6.4) and IPSS-QOL (from 4.0 ± 1.2 to 3.3 ± 1.1), and reduced PV from 55 ± 26 to 39 ± 22 ml. Propensity-score matching identified 42 matched pairs of patients. The improvement rate of IPSS and reduction rate of PV were similar between patients treated with dutasteride add-on treatment to tadalafil and dutasteride add-on treatment to alpha blocker. The logistic regression analysis showed that PV at baseline and reduction rate of PV after treatment were associated with the effective symptomatic outcome. CONCLUSIONS: The dutasteride add-on is a reasonable treatment option for male patients with LUTS who are not satisfied with tadalafil monotherapy.

Risk factors for failure of long-term dutasteride add-on treatment to alpha-adrenergic antagonist for patients with lower urinary tract symptoms and benign prostatic enlargement.

PURPOSE: To identify the clinical factors resulting in the failure of dutasteride add-on treatment to alpha-adrenergic antagonist for patients with lower urinary tract symptoms and benign prostatic enlargement (BPE). METHODS: We retrospectively surveyed the patient cohort who had been enrolled in the study of dutasteride add-on treatment to alpha-adrenergic antagonist from December 2009 to November 2011. Treatment failure was defined as receiving surgery for BPE or requiring intermittent catheterization or permanent bladder catheter for urinary retention or huge postvoid residual urine. Clinical parameters before dutasteride treatment were compared between the successful and failed group. RESULTS: Of 92 patients, 23 (25%) were defined as treatment failure at 7-109 months (mean: 38 months) after dutasteride add-on treatment. In the failed group, the patient' age was younger (71.6 ± 6.8 vs 75.4 ± 8.4, p = 0.033), prostatic volume (PV) was larger (76 ± 41 vs 49 ± 26 ml, p = 0.005), voiding efficiency was lower (54 ± 27 vs 68 ± 24%, p = 0.045) and bladder outlet obstruction index was higher (73 ± 30 vs 48 ± 30, p = 0.015). The cox proportional-hazards model indicated that only intravesical prostatic protrusion (IPP) was associated with treatment failure. Non-failure rate at 3 years after dutasteride add-on treatment was 89% with patients of IPP < 13 mm versus 51% with those of IPP ≥ 13 mm (p < 0.001). CONCLUSION: IPP ≥ 13 mm is the risk factor resulting in the failure of dutasteride add-on treatment to alpha-adrenergic antagonist. This kind of information should be provided to the patients early in the clinical practice so that they could consider the necessity of BPE surgery in the long run.

Uroflowmetry pattern in detrusor underactivity and bladder outlet obstruction in male patients with lower urinary tract symptoms.

OBJECTIVES: To investigate if uroflowmetry (UFM) curve patterns could differentiate between detrusor underactivity (DU) and bladder outlet obstruction (BOO). METHODS: A hundred consecutive data sets of male patients who were evaluated using UFM and invasive urodynamics (pressure flow study) were retrospectively collected. DU and BOO were diagnosed according to the bladder contractility index and BOO index. The UFM curve with two or more notches was defined as sawtooth pattern, and the interrupted pattern was defined if several curves with interruptions reducing to zero were noted. We also compared other UFM parameters including maximum and average flow rates (Qmax and Qave), voiding time, time to Qmax, the slope to first peak flow, the number of notches on the curve (sawtooth pattern), the number of curves (interrupted pattern), and the maximum drop on the sawtooth pattern. RESULTS: Twenty-five and forty-nine patients were categorized in the BOO group and the DU group, respectively. The incidence of sawtooth pattern was significantly higher in the DU group (57%) than in the BOO group (32%), while the incidence of interrupted pattern was not different between the two groups (36% in the BOO group and 49% in the DU group). There were significant differences in age (area under the curve = 0.75), prostatic volume (0.67), the slope to first peak flow (0.58), the number of notches on the curve (0.61), and the maximum drop (0.76) between the two groups. CONCLUSIONS: The sawtooth UFM pattern is more common in patients with DU than in those with BOO. New parameters on UFM curve patterns could be helpful to evaluate DU and BOO without invasive urodynamics.

Growth Hormone Stops Excessive Inflammation After Partial Hepatectomy, Allowing Liver Regeneration and Survival Through Induction of H2-Bl/HLA-G.

BACKGROUND AND AIMS: Growth hormone (GH) is important for liver regeneration after partial hepatectomy (PHx). We investigated this process in C57BL/6 mice that express different forms of the GH receptor (GHR) with deletions in key signaling domains. APPROACH AND RESULTS: PHx was performed on C57BL/6 mice lacking GHR (Ghr-/- ), disabled for all GH-dependent Janus kinase 2 signaling (Box1-/- ), or lacking only GH-dependent signal transducer and activator of transcription 5 (STAT5) signaling (Ghr391-/- ), and wild-type littermates. C57BL/6 Ghr-/- mice showed striking mortality within 48 hours after PHx, whereas Box1-/- or Ghr391-/- mice survived with normal liver regeneration. Ghr-/- mortality was associated with increased apoptosis and elevated natural killer/natural killer T cell and macrophage cell markers. We identified H2-Bl, a key immunotolerance protein, which is up-regulated by PHx through a GH-mediated, Janus kinase 2-independent, SRC family kinase-dependent pathway. GH treatment was confirmed to up-regulate expression of the human homolog of H2-Bl (human leukocyte antigen G [HLA-G]) in primary human hepatocytes and in the serum of GH-deficient patients. We find that injury-associated innate immune attack by natural killer/natural killer T cell and macrophage cells are instrumental in the failure of liver regeneration, and this can be overcome in Ghr-/- mice by adenoviral delivery of H2-Bl or by infusion of HLA-G protein. Further, H2-Bl knockdown in wild-type C57BL/6 mice showed elevated markers of inflammation after PHx, whereas Ghr-/- backcrossed on a strain with high endogenous H2-Bl expression showed a high rate of survival following PHx. CONCLUSIONS: GH induction of H2-Bl expression is crucial for reducing innate immune-mediated apoptosis and promoting survival after PHx in C57BL/6 mice. Treatment with HLA-G may lead to improved clinical outcomes following liver surgery or transplantation.

Role of growth hormone signaling pathways in the development of atherosclerosis.

OBJECTIVE: The direct actions of growth hormone (GH) in the development of atherosclerosis are unclear. The goal of this study was to characterize GH-induced changes in expression of signaling pathway elements and other proteins that may be related to atherosclerosis. METHODS: Human umbilical vein endothelial cells (HUVEC) and THP-1, a human acute monocytic leukemia cell line, were stimulated by exposure to 10-9 M or 10-8 M human GH with or without pretreatment with a mitogen-activated protein kinase kinase (MEK) 1 inhibitor. Levels of transcripts encoding vascular cell adhesion molecule (VCAM) -1, E-selectin, monocyte chemotactic protein (MCP-1), interleukin (IL) -6, and IL-8 were investigated by reverse transcription (RT) -PCR. For the quantitative adhesion assay, THP-1 cells or human primary monocytes were fluorescently labeled with 3'-O-acetyl-2',7'-bis(carboxyethyl) -4 diacetoxymethyl ester (BCECF/AM). HUVEC treated with human GH were co-incubated with BCECF-labeled THP-1 cells. One hour later, the number of BCECF-labeled THP-1 cells was assessed. An equivalent experiment was performed using BCECF-labeled primary monocytes, and the number of monocytes adhering to HUVEC was counted. RESULTS: Treatment with hGH increased the levels of E-selectin- and VCAM-1-encoding mRNAs in HUVEC. This effect was attenuated by pretreatment with a MEK1 inhibitor. Furthermore, hGH treatment increased adhesion of BCECF-labeled THP-1 cells or primary monocytes to HUVEC, and this effect was attenuated by pretreatment with a MEK1 inhibitor. CONCLUSIONS: VCAM-1 and E-selectin expression was stimulated by GH via the mitogen-activated protein kinase pathway, resulting in augmented adhesion of THP-1 cells and monocytes to HUVEC. These data suggested that GH directly stimulates the development of atherosclerosis.

Thyroid-related hormones as potential markers of hypoxia/ischemia.

This study aimed to investigate the usefulness of the thyroid-related hormones as markers of acute systemic hypoxia/ischemia to identify deaths caused by asphyxiation due to neck compression in human autopsy cases. The following deaths from pathophysiological conditions were examined: mechanical asphyxia and acute/subacute blunt head injury; acute/subacute non-head blunt injury; sharp instrument injury as the hemorrhagic shock condition; drowning as alveolar injury; burn; and death due to cardiac dysfunction. Blood samples were collected from the left and right cardiac chambers and iliac veins, and serum triiodothyronine (T3), thyroxine (T4), thyroglobulin (Tg), and thyroid-stimulating hormone (TSH) levels were measured using electrochemiluminescence immunoassays. Two types of thyroid cell lines were used to confirm independent thyroid function under the condition of hypoxia (3% O2). The human thyroid carcinoma cell line (HOTHC) cell line derived from human anaplastic thyroid carcinoma and the UD-PTC (sample of the second resection papillary thyroid carcinoma) cell line derived from human thyroid papillary adenoma, which forms Tg retention follicles, were used to examine the secretion levels of T3, T4, and Tg hormones. The results showed a strong correlation between T3 and T4 levels in all blood sampling sites, while the TSH and Tg levels were not correlated with the other markers. Serum T3 and T4 levels were higher in cases of mechanical asphyxia and acute/subacute blunt head injury, representing hypoxic and ischemic conditions of the brain as compared to those in other causes of death. In the thyroid gland cell line, T4, T3, and Tg levels were stimulated after exposure to hypoxia for 10-30 min. These findings suggest that systemic advanced hypoxia/ischemia may cause a rapid and TSH-independent release of T3 and T4 thyroid hormones in autopsy cases. These findings demonstrate that increased thyroid-related hormone (T3 and T4) levels in the pathophysiological field may indicate systemic hypoxia/ischemia.

Postmarketing surveillance on clinical use of edoxaban in patients with nonvalvular atrial fibrillation (ETNA-AF-Japan): Three-month interim analysis results.

BACKGROUND: Direct oral anticoagulants are the first-line drugs for anticoagulation therapy in nonvalvular atrial fibrillation (NVAF). However, a real-world, large-scale, clinical study on edoxaban has not been performed. Our ongoing postmarketing surveillance, ETNA-AF-Japan (Edoxaban Treatment in routiNe clinical prActice in patients with non-valvular Atrial Fibrillation; UMIN000017011), was designed to collect such data. METHODS: Enrollment started on 13 April 2015 and ended on 30 September 2017. Eligible patients were those diagnosed with NVAF who were to receive edoxaban for the first time and provided written consent for study participation. Baseline patient characteristics and adverse events (AEs) were collected. RESULTS: A total of 11 569 patients were enrolled. Data for 8157 patients in the first 3 months were analyzed. Mean age, body weight, creatinine clearance (CLcr), and CHADS 2 score were 74.2 ± 10.0 years, 60.0 ± 12.6 kg, 64.0 ± 25.6 mL/min, and 2.2 ± 1.3, respectively. Female patients, and patients with age ≥75 years, body weight ≤60 kg, and CLcr <30 mL/min constituted 40.7%, 52.4%, 54.6%, and 4.7%, respectively. Patients with paroxysmal, persistent, and permanent AF constituted 46.1%, 38.7%, and 15.1%, respectively. Most patients (85.3%) received dosages according to the prescribing information, and 90.8% continued the medication for 3 months. Bleeding AEs occurred in 3.29%, including major bleeding in 0.29%. CONCLUSIONS: The majority (90.8%) of patients continued medication and no significant safety concerns related to edoxaban were reported during the first 3 months of treatment. Clearer safety and efficacy profiles of edoxaban await data analyses after the 2-year follow-up period.

An Excess of CYP24A1, Lack of CaSR, and a Novel lncRNA Near the PTH Gene Characterize an Ectopic PTH-Producing Tumor.

Thus far, only 23 cases of the ectopic production of parathyroid hormone (PTH) have been reported. We have characterized the genome-wide transcription profile of an ectopic PTH-producing tumor originating from a retroperitoneal histiocytoma. We found that the calcium-sensing receptor (CaSR) was barely expressed in the tumor. Lack of CaSR, a crucial braking apparatus in the presence of both intraparathyroid and, probably, serendipitous PTH expression, might contribute strongly to the establishment and maintenance of the ectopic transcriptional activation of the PTH gene in nonparathyroid cells. Along with candidate drivers with a crucial frameshift mutation or copy number variation at specific chromosomal areas obtained from whole exome sequencing, we identified robust tumor-specific cytochrome P450 family 24 subfamily A member 1 (CYP24A1) overproduction, which was not observed in other non-PTH-expressing retroperitoneal histiocytoma and parathyroid adenoma samples. We then found a 2.5-kb noncoding RNA in the PTH 3'-downstream region that was exclusively present in the parathyroid adenoma and our tumor. Such a co-occurrence might act as another driver of ectopic PTH-producing tumorigenesis; both might release the control of PTH gene expression by shutting down the other branches of the safety system (e.g., CaSR and the vitamin D3-vitamin D receptor axis).

Adipsic hypernatremia without hypothalamic lesions accompanied by autoantibodies to subfornical organ.

Adipsic (or essential) hypernatremia is a rare hypernatremia caused by a deficiency in thirst regulation and vasopressin release. In 2010, we reported a case in which autoantibodies targeting the sensory circumventricular organs (sCVOs) caused adipsic hypernatremia without hypothalamic structural lesions demonstrable by magnetic resonance imaging (MRI); sCVOs include the subfornical organ (SFO) and organum vasculosum of the lamina terminalis (OVLT), which are centers for the monitoring of body-fluid conditions and the control of water and salt intakes, and harbor neurons innervating hypothalamic nuclei for vasopressin release. We herein report three newly identified patients (3- to 8-year-old girls on the first visit) with similar symptoms. The common features of the patients were extensive hypernatremia without any sensation of thirst and defects in vasopressin response to serum hypertonicity. Despite these features, we could not detect any hypothalamic structural lesions by MRI. Immunohistochemical analyses using the sera of the three patients revealed that antibodies specifically reactive to the mouse SFO were present in the sera of all cases; in one case, the antibodies also reacted with the mouse OVLT. The immunoglobulin (Ig) fraction of serum obtained from one patient was intravenously injected into wild-type mice to determine whether the mice developed similar symptoms. Mice injected with a patient's Ig showed abnormalities in water/salt intake, vasopressin release, and diuresis, which resultantly developed hypernatremia. Prominent cell death and infiltration of reactive microglia was observed in the SFO of these mice. Thus, autoimmune destruction of the SFO may be the cause of the adipsic hypernatremia. This study provides a possible explanation for the pathogenesis of adipsic hypernatremia without demonstrable hypothalamus-pituitary lesions.

Trivalent inactivated influenza vaccine effective against influenza A(H3N2) variant viruses in children during the 2014/15 season, Japan.

The 2014/15 influenza season in Japan was characterised by predominant influenza A(H3N2) activity; 99% of influenza A viruses detected were A(H3N2). Subclade 3C.2a viruses were the major epidemic A(H3N2) viruses, and were genetically distinct from A/New York/39/2012(H3N2) of 2014/15 vaccine strain in Japan, which was classified as clade 3C.1. We assessed vaccine effectiveness (VE) of inactivated influenza vaccine (IIV) in children aged 6 months to 15 years by test-negative case-control design based on influenza rapid diagnostic test. Between November 2014 and March 2015, a total of 3,752 children were enrolled: 1,633 tested positive for influenza A and 42 for influenza B, and 2,077 tested negative. Adjusted VE was 38% (95% confidence intervals (CI): 28 to 46) against influenza virus infection overall, 37% (95% CI: 27 to 45) against influenza A, and 47% (95% CI: -2 to 73) against influenza B. However, IIV was not statistically significantly effective against influenza A in infants aged 6 to 11 months or adolescents aged 13 to 15 years. VE in preventing hospitalisation for influenza A infection was 55% (95% CI: 42 to 64). Trivalent IIV that included A/New York/39/2012(H3N2) was effective against drifted influenza A(H3N2) virus, although vaccine mismatch resulted in low VE.

Functional analysis of three novel cell lines derived from human papillary thyroid carcinomas with three different clinical courses.

Papillary thyroid carcinoma (PTC) is the most frequent thyroid carcinoma. PTC cell lines have been of considerable value in studying aspects of thyroid cancer, such as gene expression, cell proliferation, and differentiation. Here we report three novel PTC lines established from three patients with different backgrounds. Case 1 was a 38-year-old woman with PTC in the right thyroid lobe, with no metastasis. The cell line was established from the resection sample and named D-PTC. The cell line consisted of epithelial cells with few lysosomes and showed a pavement structure and follicular formation at confluency. There was a little pilling up. The secretion of free thyroxin (fT4) and thyroglobulin (Tg) was increased by TSH, or GH and IGF-I treatment. Case 2 was a 22-year-old woman with PTC initially in the right thyroid lobe, but 4 years after the right lobe resection, PTC metastasis was observed in left lobe. The cell line was established from a sample of the second resection and named UD-PTC. This cell line consisted of small epithelial cells with evident lysosomes and exhibited floating cell clusters. The secretion of fT4 and Tg was slightly increased by TSH, or GH and IGF-I treatment. Case 3 was an 85-year-old man with PTC and with acromegaly. Metastasis was observed at cervical lymph nodes. The cell line was derived from the metastasis region and named A-PTC. This cell line consisted of small epithelial cells and many lysosomes. The cells frequently showed pilling up. The secretion of fT4 and Tg was significantly increased by GH and IGF-I treatment. We have established three PTC cell lines with substantial variation in their phenotype. The cell lines may be useful for thyroid cancer research.

GH-dependent STAT5 signaling plays an important role in hepatic lipid metabolism.

GH deficiency is known to be clinically associated with a high incidence of nonalcoholic fatty liver disease, and this can be reversed by GH administration. Here we investigated the mechanistic basis for this phenomenon using engineered male mice lacking different signaling elements of the GH receptor, hepatic stat5a/b(-/-) mice and a mouse hepatoma line. We found deficient GH-dependent signal transducer and activator of transcription (STAT)-5 signaling correlates with steatosis, and through microarray analysis, quantitative PCR, and chromatin immunoprecipitation, identified putative targets of STAT5 signaling responsible for the steatosis seen on a normal diet. These targets were verified with liver-specific stat5a/b deletion in vivo, and in vitro we show that dominant-negative (DN) STAT5 increases lipid uptake in a mouse hepatoma line. Because loss of STAT5 signaling results in elevated STAT1 and STAT3 activity and intracellular lipid accumulation, we have used DN-STAT5a/b, DN-STAT1, constitutively active (CA)-STAT3, or addition of oleate/palmitate in the hepatoma line to assign which of these apply to individual targets in STAT5 signaling deficiency. These findings and published mouse models of steatosis enable us to propose elevated cd36, pparγ, and pgc1α/ß expression as primary instigators of the steatosis along with elevated fatty acid synthase, lipoprotein lipase, and very low-density lipoprotein receptor expression. Decreased fgf21 and insig2 expression may also contribute. In conclusion, despite normal plasma free fatty acids and minimal obesity, absent GH activation leads to steatosis because activated STAT5 prevents hepatic steatosis. These results raise the possibility of low-dose GH treatment for nonalcoholic fatty liver disease.

Novel functional hepatocyte cell line derived from spontaneous dwarf rat: model of growth hormone function in vitro.

Currently there is no good hepatocyte model for studying growth hormone (GH) function that reflects its normal physiological roles. Here we report the establishment of a functional hepatocyte cell line, SDRL-1, from the liver of young male spontaneous dwarf rats (SDR), with isolated GH deficiency. This line has been maintained in Dulbecco's Modified Eagle Medium (DMEM)/F12 medium supplemented with 10% fetal bovine serum (FBS) with retention of a near diploid karyotype for extended periods of time. When grown as a monolayer sheet, it displayed a pavement-like appearance and contact inhibition. These cells have a poorly developed rough endoplasmic reticulum (r-ER), few mitochondria and glycogen granules, and produce a small amount of albumin and α-fetoprotein, that is enhanced when grown on a collagen gel sponge. Human recombinant GH stimulated JAK2 and STAT5b tyrosine phosphorylation and IGF-I production in a concentration-dependent manner. When the cells were cultured with GH-supplemented medium, the number of mitochondria and glycogen granules increased together with the r-ER and Golgi apparatus. A number of microvilli were observed on the surface of the cultured cells, further suggesting that this cell line is composed of normally functioning hepatocytes. In summary, we established a novel hepatocyte cell line (SDRL-1), that appears to display normal function, which we propose can serve as a good in vitro model for studying GH-target organ interactions.

A case of juvenile acromegaly that was initially diagnosed as severe congestive heart failure from acromegaly-induced dilated cardiomyopathy.

Acromegaly is characterized by chronic hypersecretion of growth hormone (GH) and is associated with increased mortality rate because of the potential complications such as cardiovascular disease, respiratory disease, or malignancy, which are probably caused by the long-term exposure of tissues to excess GH, for at least 10 years, before diagnosis and treatment. A 22-year-old man with a 2-month history of fatigue was admitted to our hospital because of chest discomfort, dyspnea, and pitting edema of the lower limbs experienced over a 1-month period. On admission, his height and body weight were 186 cm and 138.5 kg, respectively, with a BMI of 39.8 kg/m(2). He showed acromegalic features and elevated serum GH and IGF-1 levels, which were 11.5 ng/mL and 960 ng/mL, respectively. There was no GH suppression in the 75-g oral glucose tolerance test. Pituitary magnetic resonance imaging (MRI) revealed microadenoma. Chest X-ray revealed cardiomegaly, and echocardiogram showed dilated left ventricular (LV) cavity and diffuse hypokinesis with extremely decreased ejection fraction (EF). He was diagnosed as having acromegaly with congestive heart failure from diastolic cardiomyopathy. After the successful transsphenoidal resection of the pituitary adenoma, the level of GH was normalized. However, the cardiac dysfunction did not show any improvement even after the administration of ß-blockers, angiotensin-converting enzyme inhibitor (ACE-I), or diuretics. The patient was re-hospitalized, and he died of cardiac failure at the age of 25 years. Patients with acromegaly have been reported to have about 30% higher mortality rate, and cardiovascular disease accounts for 60% of the deaths. We report a case of a patient with juvenile acromegaly who was diagnosed with severe cardiac failure at the time of diagnosis and failed to recover cardiac function even after the successful resection of the pituitary adenoma. Immediate diagnosis and treatment are required for better control of acromegalic cardiomyopathy.