Extent of lymph node dissection in patients with gallbladder cancer.

BACKGROUND: Definitions of regional lymph nodes for gallbladder cancer differ according to staging system. Hence, the appropriate extent of lymph node dissection has not yet been standardized. METHODS: Pathological stages and disease-specific survival (DSS) of patients who had undergone surgical resection of gallbladder cancer between 1990 and 2016 were reviewed. Patients with nodal metastases limited to the hepatoduodenal ligament or common hepatic artery, extending to the posterosuperior pancreatic head lymph nodes (PSPLNs), or in nodes along the coeliac axis or superior mesenteric vessels were grouped as having Na, Nb and Nc disease respectively. Metastases beyond these regions were defined as distant metastases (M1). Absence of distant metastasis was expressed as M0. RESULTS: A total of 259 patients were evaluated. There were 74, 31 and nine patients respectively in the Na, Nb and Nc groups. Twenty-five, nine and four patients in the respective groups had M1 disease (P = 0·682). The 5-year DSS rate was comparable between patients with Na M0 and those with Nb M0 disease (36 versus 34 per cent respectively; P = 0·950), whereas the rate in patients with Nc M0 status (0 per cent) was worse than that of patients with Nb M0 (P = 0·017) and comparable to that of patients with M1 disease (14 per cent; P = 0·590). Among 22 patients with Nb M0 disease, the 5-year DSS rate did not differ between those who had undergone pancreatoduodenectomy and those who had had dissection of PSPLNs without pancreatoduodenectomy (50 versus 30 per cent respectively; P = 0·499). CONCLUSION: PSPLNs and nodes along the hepatoduodenal ligament and hepatic artery should be considered regional nodes for gallbladder cancer, and should be resected.

Multidisciplinary management of locally recurrent rectal cancer with carbon ion radiotherapy followed by prophylactic removal of the irradiated bowel: a case report.

BACKGROUND: Locally recurrent rectal cancer (LRRC) involving the upper sacrum is typically incurable, and palliative treatment is the only option for most patients, resulting in a poor prognosis and reduced quality of life. Carbon ion radiotherapy (CIRT) has emerged as a promising modality for treating LRRC. This report presents a case of LRRC with sacral involvement that was managed via multidisciplinary therapy incorporating CIRT. CASE PRESENTATION: A 55-year-old male was diagnosed with an anastomotic recurrence of rectal cancer 15 months after undergoing anterior resection. Computed tomography (CT) suggested that the lesion was at an anastomosis site and broadly adherent to the upper sacrum, and colonoscopy confirmed the diagnosis of LRRC. Histopathological examination of the biopsy specimens revealed adenocarcinoma cells and that lesion was genetically RAS-wild. Induction chemotherapy with mFOLFOX6 and panitumumab was used as the first treatment. The recurrent lesion shrank and no signs of distant metastasis were observed after 11 cycles, although the range of the lesions attached to the sacrum remained unchanged. Therefore, we provided CIRT for this inoperable lesion and prophylactically removed the radiation-exposed bowel including the recurrent lesion, because radiation-induced ulcers can cause bleeding and perforation. Despite the presence of considerable fibrosis in the irradiated region, the operation was successful and the postoperative course had no untoward incidents. He is still recurrence-free 24 months following surgery, despite the lack of adjuvant chemotherapy. This is the first report of CIRT followed by CIRT-irradiated bowel removal for an unresectable anastomosis recurrent lesion. CONCLUSIONS: The clinical course of this case suggests that CIRT could be a potentially effective therapeutic option for LRRC involving the bowel, as long as the prophylactic removal of the irradiated bowel is performed at the optimal time. Further research involving larger sample sizes is warranted to validate the findings and conclusions of this case report.

Left hepatic trisectionectomy for advanced perihilar cholangiocarcinoma.

BACKGROUND: Data on outcomes of left hepatic trisectionectomy (LT) for perihilar cholangiocarcinoma are limited. The aim of this study was to clarify short- and long-term outcomes of LT for perihilar cholangiocarcinoma. METHODS: Patients with perihilar cholangiocarcinoma who underwent LT between January 2000 and October 2011 were analysed. Surgical variables, mortality, morbidity (Clavien grade I-V), recurrence sites and survival were compared between subjects who underwent LT, right hemihepatectomy or left hemihepatectomy. RESULTS: A total 214 patients underwent resection for perihilar cholangiocarcinoma, 25 (11·7 per cent) of whom underwent LT, 88 (41·1 per cent) right hemihepatectomy and 94 (43·9 per cent) left hepatectomy. There were no deaths among those who had LT, but 20 patients developed complications. The incidence of grade IIIa complications was significantly higher among patients who underwent LT than in patients who had right or left hemihepatectomy (P = 0·001 and P < 0·001 respectively). Only one patient developed a grade IIIb or IV complication (liver failure) after LT. The overall 5-year survival rate after LT was 39 per cent and median survival was 45 months. There were no significant differences in survival between patients who underwent LT and those who had a right or left hemihepatectomy. CONCLUSION: LT may provide a good outcome for advanced perihilar cholangiocarcinoma.

Resection of segment VIII for hepatocellular carcinoma.

BACKGROUND: Anatomical resection of segment VIII (SVIII) is technically demanding. Only two small studies have published short-term outcomes. The aim of the present study was to evaluate short- and long-term outcomes after anatomical resection involving SVIII for hepatocellular carcinoma (HCC), and to compare long-term outcomes with those after non-anatomical resection of SVIII. METHODS: Outcomes after anatomical resection of SVIII or its subsegments for HCC were compared with those in patients who underwent primary non-anatomical resection of SVIII during the same period. RESULTS: A total of 154 patients underwent anatomical resection involving SVIII and 122 had non-anatomical resection. In patients undergoing anatomical resection, the preoperative indocyanine green retention rate at 15 min ranged from 2·9 to 32·2 (median 13·6) per cent, and was 10 per cent or more in 109 patients (70·8 per cent). Median duration of operation and blood loss were 378 min and 705 ml respectively. There were no postoperative deaths, but major adverse events occurred in ten patients (6·5 per cent). The cumulative 5-year recurrence-free and overall survival rates were 28·5 and 79·6 per cent, which were significantly better than rates of 19·4 and 64·8 per cent respectively after non-anatomical resection (P = 0·036 and P < 0·001). CONCLUSION: Complete resection of SVIII or its subsegments can be performed safely and the long-term outcomes seem acceptable. This can be a curative procedure for HCC, especially in patients with limited liver function reserve, in whom right hepatectomy or right paramedian sectorectomy might otherwise be needed.

Prognostic and predictive values of tumour budding in stage IV colorectal cancer.

BACKGROUND: Tumour budding is an important prognostic feature in early-stage colorectal cancer, but its prognostic significance in metastatic disease has not been fully investigated. METHODS: Patients with stage IV disease who had primary colorectal tumour resection without previous chemotherapy or radiotherapy from January 2000 to December 2018 were reviewed retrospectively. Budding was evaluated at the primary site and graded according to the criteria of the International Tumor Budding Consensus Conference (ITBCC) (BD1, low; BD2, intermediate; BD3, high). Patients were categorized by metastatic (M1a, M1b) and resectional (R0/R1, R2/unresected) status. Subgroups were compared for overall (OS) and recurrence-free (RFS) survival in R0/R1 subgroups; R2/unresected patients were evaluated for the rate of tumour progression, based on change in tumour size from baseline. RESULTS: Of 371 patients observed during the study, 362 were analysed. Patients with BD3 had a lower 5-year OS rate than those with BD1 + BD2 (18·4 versus 40·5 per cent; P < 0·001). Survival analyses according to metastatic and resection status also showed that BD3 was associated with shorter OS than BD1 + BD2. In multivariable analysis, BD3 (hazard ratio (HR) 1·51, 95 per cent c.i. 1·11 to 2·10; P = 0·009), T4 status (HR 1·39) and R2/unresected status (HR 3·50) were associated with decreased OS. In the R0/R1 subgroup, the 2-year RFS rate was similar for BD3 and BD1 + BD2 according to metastatic status. There was no significant difference between BD3 and BD1 + BD2 for change in tumour size in the R2/unresected subgroup (P = 0·094). Of 141 patients with initially unresectable metastases who had chemotherapy, 35 achieved conversion from unresectable to resectable status. The conversion rate was significantly higher for BD1 + BD2 than for BD3 (36 versus 18 per cent; P = 0·016). CONCLUSION: Stage IV colorectal cancer with high-grade tumour budding according to ITBCC criteria correlates with poor prognosis.

ANTECEDENTES: La esofaguectomía por cáncer se asocia con un descenso de la calidad de vida relacionada con la salud (health-related quality of life, HRQoL) a largo plazo. El objetivo de este estudio fue evaluar el efecto de las comorbilidades sobre la HRQOL entre pacientes supervivientes de cánceres de esófago o de la unión gastroesofágicas después de 10 años o más. MÉTODOS: Este estudio incluye una cohorte de base poblacional recogida de forma prospectiva que incluía todos los pacientes operados de cáncer de esófago o de la unión gastroesofágica en Suecia en 2001-2005 con seguimiento hasta el 31 de diciembre de 2016. Todos los datos relacionados con las características de los pacientes y del tumor, detalles del tratamiento y HRQoL se recogieron en una base de datos prospectiva. Se utilizaron modelos de regresión multivariable ANCOVA, ajustados por edad, sexo, histología del tumor, estadio, y técnica quirúrgica, para calcular las puntuaciones medias ajustadas con los i.c. del 95% para todas las variables de la HRQoL. RESULTADOS: Un total de 92 (88%) supervivientes respondieron a los cuestionarios. En función del impacto de las comorbilidades en la salud en general, se clasificaron a los pacientes en los grupos de bajo versus alto impacto. Los resultados muestran que los pacientes en el grupo de alto impacto presentaban un descenso clínicamente significativo de la HRQoL y un aumento en el nivel de síntomas, pero las diferencias entre estos dos grupos no fueron estadísticamente significativas. CONCLUSIÓN: A los 10 años de la esofaguectomía por cáncer, las comorbilidades con un alto impacto sobre la salud general siguen contribuyendo en el deterioro de la HRQoL.

Discovery of a potent, metabolically stabilized resorcylic lactone as an anti-inflammatory lead.

With bioactivity-guided phenotype screenings, a potent anti-inflammatory compound f152A1 has been isolated, characterized and identified as the known natural product LL-Z1640-2. Metabolic instability precluded its use for the study on animal disease models. Via total synthesis, a potent, metabolically stabilized analog ER-803064 has been created; addition of the (S)-Me group at C4 onto f152A1 has resulted in a dramatic improvement on its metabolic stability, while preserving the anti-inflammatory activities.

Feasibility of resecting the portal vein only when necessary during pancreatoduodenectomy for pancreatic cancer.

Background: Whether the portal/superior mesenteric vein (PV) should be resected during pancreatoduodenectomy for pancreatic ductal adenocarcinoma (PDAC) based on preoperative CT or intraoperative findings is controversial. Methods: This was a retrospective study with data of patients who had undergone pancreatoduodenectomy for PDAC between 2002 and 2016 in a tertiary referral centre. Based on the extent of contact between the PV and tumour on CT, patients were categorized into: group 1, no contact; group 2, contact 180° or less; group 3, contact greater than 180°. Extent of pathological PV invasion (pPV) (no invasion, pv0; invasion to tunica adventitia, pv1; invasion to media, pv2; invasion to intima, pv3) was compared with patient survival. To assess the feasibility of performing PV resection (PVR) based on intraoperative findings, the prognosis of patients in groups 1 and 2 with pv0 and no PVR (PVR(-)pv0) was compared with that of patients who had PVR (PVR(+)pv0), selected using propensity score matching. Results: Groups 1, 2 and 3 comprised 230, 232 and 38 patients respectively, and PVR was performed in 10·9, 73·3 and 95 per cent of them (P < 0·001). Extent of pPV differed significantly (P < 0·001). The positive predictive value of radiological tumour contact with PV in predicting positive pPV was 42·6 per cent. In 64 patients with PVR(-)pv0 and 64 matched patients with PVR(+)pv0, the R0 resection rate (66 versus 73 per cent respectively; P = 0·337) and survival (median 32·4 versus 32·1 months; P = 0·780) were not significantly different. Conclusion: PVR is needed only when the tumour is in clear contact with the PV and cannot be detached during surgery.

Blood eosinophilia after living donor liver transplantation for hepatitis C virus-related cirrhosis.

BACKGROUND: Differentiating between acute cellular rejection (ACR) and recurrent hepatitis C virus after liver transplantation in hepatitis C virus-positive patients is difficult, but vital for preventing graft loss. METHODS: The blood eosinophil counts 3 days before or on the day of biopsy were retrospectively reviewed to evaluate their value for predicting ACR in 91 biopsy samples from 45 patients. RESULTS: Eosinophil counts on the day of biopsy were significantly higher in the ACR group (n = 20) than in the non-ACR (n = 71) group, although the difference was negligible 3 days before the biopsy. A relative eosinophil count of 2% or an absolute eosinophil count of 200 cells/mm(3) predicted ACR with a specificity of 94% or 96%, respectively. CONCLUSIONS: Blood eosinophil count on the day of biopsy can be helpful in the diagnosis of ACR in patients who underwent living donor liver transplantation for hepatitis C virus-related cirrhosis.

Three-dimensional computed tomography for planning donor hepatectomy.

BACKGROUND: An accurate estimation of preoperative volumetric measurements of the donor liver is essential in living donor liver transplantation. METHODS: Three-dimensional (3-D) computed tomography (CT) was applied to 56 living donors. 3-D images of the liver were constructed using the region-growing method and the volume of each sector was measured. RESULTS: The median volume ratios of the left liver, caudate lobe, right paramedian, and lateral sectors were 34%, 4%, 38%, and 25% of the total liver volume, respectively. The shape of the congestive area in the right paramedian sector was properly demonstrated by 3-D CT. The volume of the region corresponded to 32% of the right liver. The actual volume of the graft correlated well with the estimated graft volume (n = .86). CONCLUSIONS: The region-growing method was useful for graft selection and for determining the indication of middle hepatic vein reconstruction in right liver grafts.

Salvage hepatectomy for local recurrence of hepatocellular carcinomas offers survival comparable to that of matched patients who undergo primary hepatectomies.

BACKGROUND: The feasibility of salvage hepatectomy for locally recurrent hepatocellular carcinomas (HCCs) is unclear, especially for patients with viable parts of previously multinodular tumors. METHODS: We reviewed charts of patients who underwent initial hepatectomies between 2000 and 2014 to select those with local recurrences (LR) after non-surgical treatments. Their postoperative outcomes, including morbidity, recurrence-free survival (RFS), and overall survival (OS) were compared with matched patients who underwent initial hepatectomies for primary HCCs (PR). Their local recurrence patterns were divided into recurrent solitary tumors (Subgroup A); and recurrent parts of multinodular tumors (Subgroup B). RESULTS: Among 664 patients, hepatectomy for LR was performed in 62 patients. Matched 59 patients were selected as PR. Clinicopathologic profiles at initial surgery were comparable between the LR and PR groups. Incidence of major morbidity (LR vs. PR, 7% vs. 5%, P = 1.00), 5-year RFS (21% vs. 37%, P = 0.28), and 5-year OS (69% vs. 69%, P = 0.62) were comparable. In the LR group, Subgroup B showed worse 5-year RFS (A vs. B, 29% vs. 0%, P < 0.01) and 5-year-OS (80% vs. 53%, P = 0.01). Postoperative recurrence occurred in 46 patients, but local and extrahepatic recurrence was seen only in 2 patients and 2 patients, respectively. CONCLUSION: Salvage hepatectomy for locally recurrent HCCs is feasible, and results in prognosis comparable with hepatectomy for primary HCCs. Although the risk of postoperative recurrence was high in Subgroup B, rare local recurrence suggests the usefulness of salvaging uncontrolled tumor by nonsurgical treatment.

Isotopically enriched polymorphs of dysprosium single molecule magnets.

A triclinic polymorph Dy(t) and a monoclinic polymorph Dy(m) of [Dy(tta)3(L)] with L = 4-[6-(1,3-benzothiazol-2-yl)pyridin-3-yl]-4',5'-bis(methylthio)tetrathiafulvene behave as Single-Molecule Magnets with hysteresis loops opened at zero field. Magnetic properties were enhanced through magnetic dilution and 164Dy isotopic enrichment which definitively support the importance of isotopes for the control of quantum magnets.

Comprehensive isolation of meiosis-specific genes identifies novel proteins and unusual non-coding transcripts in Schizosaccharomyces pombe.

In order to isolate meiosis-specific genes in Schizosaccharomyces pombe, we have constructed a subtracted cDNA library enriched in clones whose expression is enhanced during meiosis induced by nitrogen starvation. Using northern blot analysis, we isolated 31 kinds of clones whose expression was induced in a meiosis/sporulation-specific manner. We comprehensively named them meu after meiotic expression upregulated. The transcription of 20 meu genes was found to be dependent on the mei4(+) gene, which encodes a transcription factor required for the progression of meiosis. DNA sequencing indicated that most of the meu genes encode novel proteins. Notably, five of the meu genes harbor no apparent protein coding sequences, and the transcripts form stable hairpin structures, suggesting that they may generate non-coding RNAs or antisense RNAS: The results presented here imply that RNAs are also important for the comprehensive characterization of genomic expression.

New-onset diabetes mellitus after living donor liver transplantation: possible association with hepatitis C.

BACKGROUND: The relationship between hepatitis C virus (HCV) infection and new-onset diabetes mellitus (NODM) after liver transplantation is a controversial issue. METHODS: A total of 223 adult living donor liver transplantation (LDLT) recipients followed for more than 6 months were analyzed for the prevalence of NODM. The prevalence was compared between 62 HCV-positive and 161 HCV-negative patients. All the HCV-positive patients underwent preemptive antiviral treatment with interferon alpha2b and ribavirin. RESULTS: Preoperative diabetes mellitus was more frequently observed in HCV-positive patients (18% vs 4%, P = .001). NODM occurred more frequently in HCV-positive patients (41% vs 22%, P = .003). Multivariate analysis, however, revealed that HCV was not a predictor for NODM. A comparison of 14 HCV-positive patients with persistent NODM and 48 patients without persistent NODM indicated that there was no significant difference in the frequency of the viral response to antiviral therapy nor in HCV-RNA levels. Impaired glucose tolerance did not impact postoperative survival after LDLT. CONCLUSIONS: HCV was not associated with the prevalence of NODM after LDLT. NODM did not influence patient survival.

Preoperative estimation of right lateral sector graft by three-dimensional computed tomography.

The right lateral sector is an alternative graft for living donor liver transplantation. Three-dimensional image reconstruction of right lateral sector grafts was performed to reveal vascular anatomy and volume using three-dimensional computed tomography software in three donors. There was a correlation between actual and estimated volume (r=.93), although actual graft volume tended to be larger than the preoperative estimated volume. In one donor, a portal branch of the right lateral sector was independently ramified. The branch was sacrificed in the operation because its territory volume was only 44 cm3. Three-dimensional images matched the shape of the right lateral sector graft. Three-dimensional computed tomography might be useful before donor hepatectomy, providing important information for decisions regarding the operative procedure.

In vitro and in vivo anticancer activities of synthetic macrocyclic ketone analogues of halichondrin B.

Halichondrin B is a highly potent anticancer agent originally found in marine sponges. Although scarcity of the natural product has hampered efforts to develop halichondrin B as a new anticancer drug, the existence of a complete synthetic route has allowed synthesis of structurally simpler analogues that retain the remarkable potency of the parent compound. In this study, we show that two macrocyclic ketone analogues of halichondrir B, ER-076349 and ER-086526, have sub-nM growth inhibitory activities in vitro against numerous human cancer cell lines as well as marked in vivo activities at 0.1-1 mg/kg against four human xenografts: MDA-MB-435 breast cancer, COLO 205 colon cancer, LOX melanoma, and NIH: OVCAR-3 ovarian cancer. ER-076349 and ER-086526 induce G2-M cell cycle arrest and disruption of mitotic spindles, consistent with the tubulin-based antimitotic mechanism of halichondrin B. This is supported further by direct binding of the biotinylated analogue ER-040798 to tubulin and inhibition of tubulin polymerization in vitro by ER-076349 and ER-086526. Retention of the extraordinary in vitro and in vivo activity off halichondrin B in structurally simplified, fully synthetic analogues establishes the feasibility of developing halichondrin B-based agents as highly effective, novel anticancer drugs.

Alpha-lipoic acid: effect on glucose uptake, sorbitol pathway, and energy metabolism in experimental diabetic neuropathy.

The peripheral nerve of experimental diabetic neuropathy (EDN) is reported to be ischemic and hypoxic, with an increased dependence on anaerobic metabolism, requiring increased energy substrate stores. When glucose stores become reduced, fiber degeneration has been reported. We evaluated glucose uptake, nerve energy metabolism, the polyol pathway, and protein kinase C (PKC) activity in EDN induced by streptozotocin. Control and diabetic rats received lipoic acid (0, 10, 25, 50, 100 mg/kg). Duration of diabetes was 1 month, and alpha-lipoic acid was administered intraperitoneally 5 times per week for the final week of the experiment. Nerve glucose uptake was reduced to 60, s 37, and 30% of control values in the sciatic nerve, L5 dorsal root ganglion, and superior cervical ganglion (SCG), respectively, in rats with EDN. Alpha-lipoic acid supplementation had no effect on glucose uptake in normal nerves at any dose, but reversed the deficit in EDN, with a threshold between 10 and 25 mg/kg. Endoneurial glucose, fructose, sorbitol, and myo-inositol were measured in sciatic nerve. Alpha-lipoic acid had no significant effect on either energy metabolism or polyol pathway of normal nerves. In EDN, endoneurial glucose, fructose, and sorbitol were significantly increased, while myo-inositol was significantly reduced. Alpha-lipoic acid had a biphasic effect: it dose-dependently increased fructose, glucose, and sorbitol, peaking at 25 mg/kg, and then fell beyond that dose, and it dose-dependently increased myo-inositol. Sciatic nerve cytosolic PKC was increased in EDN. ATP, creatine phosphate, and lactate were measured in sciatic nerve and SCG. Alpha-lipoic acid prevented the reduction in SCG creatine phosphate. We conclude that glucose uptake is reduced in EDN and that this deficit is dose-dependently reversed by alpha-lipoic acid, a change associated with an improvement in peripheral nerve function.

Palytoxin induces an increase in the cation conductance of red cells.

Palytoxin (PTX), isolated from the marine soft coral Palythoa tuberculosa, increases the cation conductance of human red cell membranes. In the presence of 10(-10) M PTX and 10(-5) M DIDS, the membrane potential approximates the equilibrium potential for Na+ or K+ rather than Cl-. Even in the absence of DIDS, the Na+ and K+ conductances were greater than the Cl- conductance. The selectivity of the PTX-induced cation conductance is K+ greater than Rb+ greater than Cs+ greater than Na+ greater than Li+ much greater than choline+ greater than TEA+ much greater than Mg2+. Measurements of K+ efflux revealed two apparent sites for activation by PTX, one with a Kal of 0.05 nM and a maximum flux, nu max1, of 1.4 mol/liter of cells per h and another with a Ka2 of 98 nM and a nu max2 of 24 mol/liter of cells per h. These effects of PTX are completely blocked by external ouabain (300 microM) and prevented by internal vanadate (100 microM). When the PTX channels are open, the Na,K pumps do not catalyze ATP hydrolysis. Upon thorough washout of cells exposed to about five molecules of PTX/pump, the Na,K pump of these cells operates normally. Blockage of the positively charged NH2 terminus of PTX with a p-bromobenzoyl group reduces the potency of the compound to induce Na and K fluxes by at least a factor of 100, and to compete with the binding of [3H]ouabain by at least a factor of 10. These data are consistent with the conclusion that PTX binds reversibly to the Na,K pumps in the red cell membrane and opens a (10-pS) channel equally permeable to Na and K at or near each pump site.

Optimal initial dose of oral cyclosporine in relation to its toxicities for graft-versus-host disease prophylaxis following reduced-intensity stem cell transplantation in Japanese patients.

Since the introduction of reduced-intensity stem-cell transplantation (RIST), allogeneic stem-cell transplantation has become available for elderly patients. While pharmacokinetics of cyclosporine might differ according to age or other factors, cyclosporine is uniformly started at an oral dose of 6 mg/kg/day. We retrospectively reviewed medical records of 35 patients aged between 32 and 65 (median 52) years who had undergone RIST. Doses of cyclosporine were adjusted to the target blood trough level of 150-250 ng/ml. Cyclosporine dosages were changed in 33 patients (94%). Dose reduction was required in 32 patients because of high blood levels (n=25), renal dysfunction (n=3), hepatic dysfunction (n=2), and hypertension (n=2). Cyclosporine doses were increased in one because of the suboptimal level. The median of the achieved stable doses was 3.1 mg/kg/day (range, 1.0-7.4). Five patients sustained Grade III toxicities according to NCI-CTC version 2.0: renal dysfunction (n=4), hyperbilirubinemia (n=2), and hypertension (n=2). No patients developed grade IV toxicity. There was no statistically significant difference in the frequency and severity of cyclosporine toxicities between patients aged 50 years and above and those below 50 years. The initial oral cyclosporine dose of 6 mg/kg/day was unnecessarily high irrespective of age. The possible overdose of cyclosporine might have aggravated regimen-related toxicities.

Intestinal thrombotic microangiopathy following reduced-intensity umbilical cord blood transplantation.

Thrombotic microangiopathy (TMA) is a significant complication after hematopoietic stem-cell transplantation (HSCT); however, there is little information on it following reduced-intensity cord blood transplantation (RI-CBT). We reviewed the medical records of 123 adult patients who received RI-CBT at Toranomon Hospital between January 2002 and August 2004. TMA was diagnosed in seven patients based on intestinal biopsy (n = 6) or autopsy results (n = 1). While these patients showed some clinical symptoms such as diarrhea and/or abdominal pain, mental status alterations or neurological disorders were not observed in any of them. Laboratory results were mostly normal at the onset of TMA; >2% fragmented erythrocytes (n = 1), <10 mg/dl haptoglobin (n = 1), and >200 IU/dl lactic dehydrogenase (LD) (n = 4). On endoscopic examination, TMA lesions, consisting of ulcers, erosions, and diffuse exfoliation, were distributed spottily from terminal ileum to rectum. Intestinal graft-versus-host disease (GVHD) and cytomegalovirus (CMV) colitis were confirmed in five and four patients, respectively. With therapeutic measures including supportive care (n = 4), fresh frozen plasma (n = 1), and a reduction of immunosuppressive agents (n = 1), TMA improved in four patients. The present study demonstrates that intestinal TMA is a significant complication after RI-CBT. Since conventional diagnostic criteria can overlook TMA, its diagnosis requires careful examination of the gastrointestinal tract using endoscopy with biopsy.