Early enteral nutrition with arginine compensates for negative nitrogen balance in patients undergoing curative total gastrectomy.

The effects of early enteral arginine-rich nutrition (EAN) were analyzed among patients undergoing curative-intent total gastrectomy for gastric cancer. There were 19 patients in this prospective study, all randomly assigned to either a parenteral nutrition (PN) group or an EAN group for the first seven days after surgery. The EAN group received 1.8-fold greater arginine (10.1 g/day) compared with the PN group, which was administered through an enteral tube inserted into the jejunal loop. Both groups were provided almost identical amounts of total amino acids (54 g/day), and the total energy was set at 65% of the total requirement (25 kcal/kg/day). No significant differences were observed between the two groups in postoperative complications, length of hospital stay, oral intake, nutritional status, or body weight. The serum arginine profile was similar in the two groups, as it decreased significantly on postoperative day (POD) 1, and gradually returned to preoperative levels by POD 7. The nitrogen balance remained negative until POD 7 in the PN group, but turned neutral at POD 7 in the EAN group. While we could not confirm body weight loss improvement, these results suggested that early arginine-rich enteral nutrition could improve the nitrogen balance after total gastrectomy. J. Med. Invest. 70 : 325-333, August, 2023.

Malignant solitary fibrous tumor of the pancreas: a case report.

BACKGROUND: Solitary fibrous tumors (SFTs) are rare tumors, mostly derived from connective tissue mesenchymal cells that arise from the pleura. There are very few reports of primary pancreatic SFT. Preoperative diagnosis is difficult owing to the lack of distinctive radiological findings. We report a case of pancreatic SFT with particularly rare malignant findings. CASE PRESENTATION: A 60-year-old man was referred to the hospital because of a right upper quadrant mass and abnormal liver function test results. Contrast-enhanced computed tomography (CT) showed a well-defined enhanced tumor measuring approximately 8 cm in the pancreatic head. Magnetic resonance imaging (MRI) showed T1WI hypointensity, T2WI hyperintensity, and DWI hyperintensity. The main pancreatic duct and common bile duct were dilated owing to obstruction by the tumor. The following tumor markers were mildly elevated: carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), SPan-1, and DUPAN-2. The histological diagnosis obtained by endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) was negative for pancreatic ductal carcinoma, malignant lymphoma and neuroendocrine tumor, suggesting the possibility of mesenchymal tumor, but the diagnosis was not confirmed. The patient was judged suitable for surgery and underwent subtotal stomach-preserving pancreatoduodenectomy with D2 lymph node dissection. On histopathological examination of the resected specimen, infiltrating spindle-shaped cells had proliferated, containing numerous mitotic figures, with necrotic findings inside the tumor. Immunostaining was positive for cluster of differentiation-34 (CD34), B cell CLL/lymphoma-2 (Bcl-2), and signal transducer and activator of transcription (STAT6). On the basis of these findings, a diagnosis of malignant pancreatic SFT was made. The patient remains free of recurrent disease after 12 months of follow-up without adjuvant therapy and he is being carefully followed up as an outpatient. CONCLUSIONS: We experienced a case of malignant pancreatic head SFT. Immunohistochemical staining of the extracted specimens was useful for diagnosis.

[Postoperative Adjuvant Chemotherapy for Descending Colon Cancer Treated with Imatinib for Chronic Myeloid Leukemia].

A66 -year-old man was diagnosed with chronic myeloid leukemia(CML). Imatinib treatment had been initiated, and a major molecular response(MMR)was achieved. The patient had anemia and was diagnosed with descending colon cancer. The patient was surgically treated, and then received postoperative adjuvant chemotherapy with UFT/LV. However, imatinib was not administered during that period. The patient could undergo postoperative adjuvant chemotherapy for 6 months without acute exacerbation of the CML.

A novel S269C mutation in fibroblast growth factor receptor 3 in a Japanese child with hypochondroplasia.

Functionally activating mutations in fibroblast growth factor receptor 3 (FGFR3) can cause four types of autosomal dominant skeletal dysplasia with short-limbed dwarfism that include the mildest phenotype, hypochondroplasia (HCH). A novel mutation (c.805A>T, p.S269C) was identified in a Japanese infant with HCH through direct sequencing of all FGFR3 exons and exon/intron boundaries. This mutation creates an additional cysteine residue in the extracellular region of FGFR3 that results in the functional activation of FGFR3.

Elevated Urinary Levels of 8-Hydroxy-2'-deoxyguanosine in a Japanese Child of Xeroderma Pigmentosum/Cockayne Syndrome Complex with Infantile Onset of Nephrotic Syndrome.

Nucleotide excision repair (NER) is an essential biological pathway protecting against ultraviolet light-induced DNA damage. Deficient NER causes a group of rare genetic disorders including two autosomal recessive diseases, xeroderma pigmentosum (XP) and Cockayne syndrome (CS). In addition to the cutaneous photosensitivity shared in XP and CS, CS is featured by growth failure, neurological deterioration, microcephaly, and deep sunken eyes. XP/CS complex is an extremely rare type of NER disorder with a distinct phenotype that is characterized by the skin and eye pathology of XP and the somatic and neurological abnormalities of CS. Some of CS cases have been reported to be complicated with renal failure, but the genetic background or the etiology of the renal failure has not been reported. We herein report a 1-year-old Japanese boy with XP/CS complex, complicated by nephrotic syndrome. Diagnosis was confirmed by the presence of compound heterozygous mutations, G47R (c.139G>A) and R616G (c.1846C>G), in the excision repair cross-complementation group 2 (ERCC2) gene. The kidney biopsies, performed at the age of 1 year and 2 months, revealed diffuse expansion of the mesangial matrix and segmental glomerulosclerosis under light microscopy, and diffused thin capillary walls with partially lamellated regions under electron microscopy. Notably, high levels of urinary 8-hydroxy-2'-deoxyguanosin, known as an oxidative stress marker, were observed during the clinical course. The patient died at the age of 1 year and 11 months because of renal failure. We suggest the involvement of oxidative stress in the pathogenesis of nephrotic syndrome in NER disorders.

Elevation of Serum Acid Sphingomyelinase Activity in Acute Kawasaki Disease.

Kawasaki disease (KD) is an acute systemic vasculitis that affects both small and medium-sized vessels including the coronary arteries in infants and children. Acid sphingomyelinase (ASM) is a lysosomal glycoprotein that hydrolyzes sphingomyelin to ceramide, a lipid, that functions as a second messenger in the regulation of cell functions. ASM activation has been implicated in numerous cellular stress responses and is associated with cellular ASM secretion, either through alternative trafficking of the ASM precursor protein or by means of an unidentified mechanism. Elevation of serum ASM activity has been described in several human diseases, suggesting that patients with diseases involving vascular endothelial cells may exhibit a preferential elevation of serum ASM activity. As acute KD is characterized by systemic vasculitis that could affect vascular endothelial cells, the elevation of serum ASM activity should be considered in these patients. In the present study, serum ASM activity in the sera of 15 patients with acute KD was determined both before and after treatment with infusion of high-dose intravenous immunoglobulin (IVIG), a first-line treatment for acute KD. Serum ASM activity before IVIG was significantly elevated in KD patients when compared to the control group (3.85 ± 1.46 nmol/0.1 ml/6 h vs. 1.15 ± 0.10 nmol/0.1 ml/6 h, p < 0.001), suggesting that ASM activation may be involved in the pathophysiology of this condition. Serum ASM activity before IVIG was significantly correlated with levels of C-reactive protein (p < 0.05). These results suggest the involvement of sphingolipid metabolism in the pathophysiology of KD.

Congenital hyperinsulinism in an infant with paternal uniparental disomy on chromosome 11p15: few clinical features suggestive of Beckwith-Wiedemann syndrome.

Beckwith-Wiedemann syndrome (BWS) is the most common congenital overgrowth syndrome involving tumor predisposition. BWS is caused by various epigenetic or genetic alterations that disrupt the imprinted genes on chromosome 11p15.5 and the clinical findings of BWS are highly variable. Hyperinsulinemic hypoglycemia is reported in about half of all babies with BWS. We identified an infant with diazoxide-unresponsive congenital hyperinsulinism (HI) without any apparent clinical features suggestive of BWS, but diagnosed BWS by molecular testing. The patient developed severe hyperinsulinemic hypoglycemia within a few hours after birth, with macrosomia and mild hydronephrosis. We excluded mutations in the K(ATP) channel genes on chromosome 11p15.1, but found a rare homozygous single nucleotide polymorphism (SNP) of ABCC8. Parental SNP pattern suggested paternal uniparetal disomy in this region. By microsatellite marker analysis on chromosome 11p15, we could diagnose BWS due to the mosaic of paternal uniparental disomy. Our case suggests that some HI of unknown genetic etiology could involve undiagnosed BWS with no apparent clinical features, which might be diagnosed only by molecular testing.

Metachronous double cancer after curative resection for pancreatic adenocarcinoma: report of four cases.

We experienced four cases of metachronous double cancer after curative resection for pancreatic adenocarcinoma without the background of intraductal papillary mucinous neoplasm. Case 1, a 67-year-old Japanese female developed tongue cancer 53 months after a pylorus-preserving Whipple resection for pancreatic head adenocarcinoma. Case 2, a 66-year-old female developed multiple breast cancers 52 months after a pylorus-preserving pancreaticoduodenectomy for pancreatic head adenocarcinoma. Case 3, a 59-year-old male developed an adenocarcinoma in the remnant pancreatic head 63 months after a distal pancreatectomy for pancreatic body cancer. Case 4, a 68-year-old male developed lung cancer 92 months after a Whipple procedure for pancreatic head adenocarcinoma. Gemcitabine was administered to three patients as adjuvant chemotherapy at an average administrated dose of 38,199 mg per body surface area. Since primary pancreatic ductal adenocarcinoma is aggressive and always associated with a devastating outcome, metachronous double cancer is scarcely seen. All four cases received curative-intent surgery for each metachronous cancer and were alive for at least 20 months.

[A case of locally advanced sigmoid colon cancer invading the bladder and seminal vesicle effectively treated with preoperative mFOLFOX6].

A 77-year-old male was admitted to our hospital complaining of dyschezia. Computed tomography (CT) and colonoscopy (CF) revealed a huge sigmoid colon cancer invading the bladder and seminal vesicle. Chemotherapy with mFOLFOX6 was initiated preoperatively, and the tumor shrunk markedly after seven courses of treatment. Pelvic exenteration with negative margins was carried out. The patient is still alive and disease-free 16 months after surgery. It was suggested that mFOLFOX6 may be useful for advanced colon cancer invading other organs when used as neoadjuvant chemotherapy.

Metachronous multiple adenocarcinomas of the pancreas.

We report a rare case of metachronous multiple adenocarcinoma of the pancreas. A 59-year-old Japanese man visited our institute for a routine workup as a hepatitis C virus carrier, resulting in detection of a 3-cm tumor in the pancreatic body by screening echogram. Results from several imaging modalities were consistent with pancreatic carcinoma. Distal pancreatectomy along with dissection of partial gastrectomy, transverse colectomy, and lymph node dissection were performed in November 2003. Histological examination confirmed a pancreatic ductal adenocarcinoma with a clear surgical margin and negative lymph node metastases. Gemcitabine was administered for 5 years, then suspended because no recurrent signs were found. The patient returned to our hospital in March 2009, with obstructive jaundice along with a 2-cm tumor in the head of the remnant pancreas. The condition of the patient was carefully investigated and extra-pancreatic metastatic lesions were not found; a pancreaticoduodenectomy was then carried out. Histological examination revealed a diagnosis of pancreatic adenocarcinoma arising from the remnant pancreas gland.

[A review for recent advances in AA amyloid research and therapeutic approach to AA amyloidosis complicating rheumatoid arthritis].

AA amyloidosis is a life threatening clinical complication of chronic inflammatory diseases such as rheumatoid arthritis. It has been demonstrated biochemically that amyloidosis resulted from abnormal folding of proteins, which are deposited as insoluble fibrils in extracellular tissue, leading to the disruption of their normal function. In this regard, amyloidosis has been recognized as a conformation disorder. Interestingly, genetic polymorphisms of amyloid precursor protein (SAA) have been reported to associate with increased risk for AA amyloidosis. Also recent biochemical research revealed that SAA is synthesized under the influence of the proinflammatory cytokines, such as IL-6, TNF-alpha, IL-1. Additionally, it was suggested that amyloid deposits in extracellular tissue could reflect to the serum level of SAA in the reversible fashion, leading to the hypothesis that the control of the SAA synthesis could be beneficial to the treatment of amyloidosis. In this context, anti-cytokine therapies may be most effective. Especially the inhibition of IL-6 is critical to suppression of SAA production, so treatment with a humanized monoclonal antibody against human IL-6 receptor may not only ameliorate RA disease activity but also pave the way for the treatment of AA amyloidosis.

Intercalation of poly(oxyethylene) alkyl ether into a layered silicate kanemite.

Poly(oxyethylene) alkyl ether (CnEOm) is intercalated into the interlayer space of a layered silicate kanemite by using layered hexadecyltrimethylammonium (C16TMA) intercalated kanemite (C16TMA-kanemite) as the intermediate. C16TMA-kanemite was treated with an aqueous solution of C16EO10, and the intercalation of C16EO10 was confirmed by the slight increase in the basal spacing (from 2.92 to 3.34 nm) with the increase in the carbon content, yielding C16EO10-C16TMA-kanemite. The product was dispersed again in a C16EO10 aqueous solution, and then 1.0 M HCl was added to the suspension to remove C16TMA ions completely. The basal spacing was further increased (from 3.34 to 5.52 nm) and the content of nitrogen was virtually zero, indicating further intercalation of C16EO10 molecules and complete elimination of C16TMA ions simultaneously. Though C16EO10 molecules are not directly intercalated into kanemite, the mutual interactions among C16TMA ions, C16EO10 molecules, and the interlayer silicate surfaces effectively induce the intercalation of C16EO10. C16EO10-kanemite shows a reversible adsorption of n-decane and water owing to the hydrophobicity and hydrophilicity of C16EO10, respectively, in the interlayer space. Layered CnEO10-kanemites (n = 12 and 18) were also synthesized in a manner similar to layered C16EO10-kanemite.

Niemann-Pick type C disease: novel NPC1 mutations and characterization of the concomitant acid sphingomyelinase deficiency.

Niemann-Pick type C (NPC) disease is an inherited lipid storage disorder characterized by the lysosomal accumulation of free cholesterol in affected cells. Three novel mutations in the NPC1 gene (c.3615delA, c.2000C > T, and c.2240delT) were detected in two unrelated patients with the severe phenotype of NPC. The analyses showed that the c.2240delT mutation, which causes a premature stop at codon 748, resulted in nonsense-mediated decay of the mutant transcripts. Immunoblotting analyses for the NPC1 protein did not detect the mutant proteins in COS-1 cells transiently transfected with the two mutant NPC1 cDNA constructs (c.3615delA and c.2000C > T). In NPC cells, sphingomyelin accumulates with cholesterol, leading to an identical subcellular distribution of both lipids. Acid sphingomyelinase (ASM), which is responsible for the lysosomal hydrolysis of sphingomyelin, is partially reduced in NPC fibroblasts. Therefore, NPC fibroblasts were studied to determine if ASM activity was perturbed due to the accumulation of cholesterol. However, these studies demonstrated that the subcellular localization of ASM was preserved, suggesting that the high content of lysosomal cholesterol was not responsible for the decreased ASM activity.

Bax cleavage implicates caspase-dependent H2O2-induced apoptosis of hepatocytes.

Oxidative stress plays an important role in the development of ischemia/reperfusion (I/R)-induced apoptosis of hepatocytes. We aimed to examine the involvement of caspases and calpains in H2O2-induced hepatic cell apoptosis. TUNEL-positive apoptotic cells appeared in parallel with poly(ADP-ribose) polymerase (PARP) cleavage and procaspase-3 proteolysis by H2O2 treatment in a dose-dependent manner (250-1,000 micro M). Bcl-xL and intact Bax expression levels decreased when H2O2 was >250 micro M. The cleaved form of Bax appeared prior to caspase-3 activation, increasing in a dose-dependent manner. A pan-caspase inhibitor, Z-VAD-fmk, completely blocked H2O2-induced procaspase-3 proteolysis and PARP cleavage without changing Bax cleavage, but partially attenuated H2O2-induced apoptosis. Calpeptin, a calpain inhibitor, did not inhibit caspase-3 activation, Bax cleavage or apoptosis. Our results indicate that Bax cleavage is upstream signal of caspase-dependent apoptosis in hepatocytes exposed to H2O2, but not independent upon calpain. Molecular targeting of Bax cleavage may allow the development of strategies to prevent hepatic I/R injury.