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Background: Thrombotic microangiopathy is caused by various conditions, but few cases secondary to trauma have been reported. We present the rare case of a patient with thrombotic microangiopathy-induced high-impact trauma with hemorrhagic shock., Case Presentation: An 86-year-old Japanese woman was transferred to our hospital after a traffic accident. A whole-body computed tomography scan revealed pelvic fractures with massive extravasation. She received a blood transfusion and emergency angiographic embolization. On post-traumatic day 1, she showed unexplained severe hemolysis, thrombocytopenia, and renal failure despite her stable condition. Disseminated intravascular coagulation was excluded because her activated partial thromboplastin time and prothrombin time-international normalized ratio were normal. Her fragmented red blood cell concentration was 28.8%. We suspected clinical thrombotic thrombocytopenic purpura and started plasma exchange. She recovered fully after the plasma exchange and was discharged on day 31. We eventually diagnosed thrombotic microangiopathy because her ADAMTS13 activity was not reduced., Conclusions: It is important to recognize the possibility that thrombotic microangiopathy may occur after severe trauma. In the critical care setting, unexplained thrombocytopenia and hemolytic anemia should be investigated to eliminate the possibility of thrombotic microangiopathy. Early plasma exchange may help to prevent unfortunate outcomes in patients with thrombotic microangiopathy following trauma.

The patient-a Jehovah's Witness-was a woman in her 60s, with locally advanced sigmoid colon cancer. She had severe anemia, and a computed tomography scan of her abdomen showed a tumor with abscess formation and perforation that had invaded into the left urinary duct and the left ovary, without distant metastasis. It was difficult to perform curative resections without transfusion; therefore, CapeOX therapy was plannedas the neoadjuvant treatment. After 3 courses of CapeOX therapy, the patient's anemia improved, and the tumor and abscess had shrunk. Subsequently, a sigmoidectomy with D3 lymph node dissection, partial resection of the small intestine, and the left adnexectomy, as a radical surgery, were performed without blood transfusion. In cases of concomitant colon cancer with anemia that are treated with highly invasive surgery, it might be necessary to conduct systematic treatment in order to complete non-transfusion therapy.

Background: Bochdalek hernias are one of the most common types of diaphragmatic hernia, with most cases diagnosed during the neonatal period. In contrast, diagnosis of a Bochdalek hernia in an adult is rare and is typically observed on the left side of the diaphragm. Even more rare is the diagnosis of a right-sided Bochdalek hernia in an adult, where there is concurrent visceral malformation in most cases., Case Presentation: We describe a case of an 89-year-old female who presented with abdominal pain. An abdominal computed tomography (CT) scan showed decreased intravenous contrast uptake and thickening of the wall of herniated small intestine through the right side of the diaphragm, which led to the diagnosis of a strangulated diaphragmatic hernia. The patient underwent emergent laparotomy and required a partial resection of the necrotic ileum and a hernia repair with direct closure. Interestingly, in this case, organ malformation was not observed. The patient was discharged approximately 2 weeks after surgery without complication., Conclusions: Adult right-sided Bochdalek hernia with strangulation in the absence of hepatic atrophy is a rare entity. Considering the severity of this condition, accurate diagnosis and proper treatment are needed. A tailored operative approach is required on an individual case basis.

Multicentric Castleman disease (MCD) is a heterogeneous lymphoproliferative disorder. It is characterized by inflammatory symptoms, and interleukin (IL)-6 contributes to the disease pathogenesis. Human herpesvirus 8 (HHV-8) often drives hypercytokinemia in MCD, although the etiology of HHV-8-negative MCD is idiopathic (iMCD). A distinct subtype of iMCD that shares a constellation of clinical features including thrombocytopenia (T), anasarca (A), fever (F), reticulin fibrosis (R), and organomegaly (O) has been reported as TAFRO-iMCD, however the differences in cytokine profiles between TAFRO-iMCD and iMCD have not been established. We retrospectively compared levels of serum interferon γ-induced protein 10 kDa (IP-10), platelet-derived growth factor (PDGF)-AA, interleukin (IL)-10, and other cytokines between 11 cases of TAFRO-iMCD, 6 cases of plasma cell type iMCD, and 21 healthy controls. During flare-ups, patients with TAFRO-iMCD had significantly higher serum IP-10 and tended to have lower PDGF-AA levels than the other 2 groups. In addition, serum IL-10, IL-23, and vascular endothelial growth factor-A were elevated in both TAFRO-iMCD and iMCD. Elevated serum IP-10 is associated with inflammatory diseases including infectious diseases. There was a strong correlation between high serum IP-10 and the presence of TAFRO-iMCD, suggesting that IP-10 might be involved in the pathogenesis of TAFRO-iMCD.

Multicentric Castleman disease (MCD) describes a heterogeneous group of disorders involving systemic inflammation, characteristic lymph node histopathology, and multi-organ dysfunction because of pathologic hypercytokinemia. Whereas Human Herpes Virus-8 (HHV-8) drives the hypercytokinemia in a cohort of immunocompromised patients, the etiology of HHV-8-negative MCD is idiopathic (iMCD). Recently, a limited series of iMCD cases in Japan sharing a constellation of clinical features, including thrombocytopenia (T), anasarca (A), fever (F), reticulin fibrosis (R), and organomegaly (O) has been described as TAFRO syndrome. Herein, we report clinicopathological findings on 25 patients (14 males and 11 females; 23 Japanese-born and two US-born), the largest TAFRO syndrome case series, including the first report of cases from the USA. The median age of onset was 50 years old (range: 23-72). The frequency of each feature was as follows: thrombocytopenia (21/25), anasarca (24/25), fever (21/25), organomegaly (25/25), and reticulin fibrosis (13/16). These patients frequently demonstrated abdominal pain, elevated serum alkaline phosphatase levels, and acute kidney failure. Surprisingly, none of the cases demonstrated marked hypergammoglobulinemia, which is frequently reported in iMCD. Lymph node biopsies revealed atrophic germinal centers with enlarged nuclei of endothelial cells and proliferation of endothelial venules in interfollicular zone. 23 of 25 cases were treated initially with corticosteroids; 12 patients responded poorly and required further therapy. Three patients died during the observation period (median: 9 months) because of disease progression or infections. TAFRO syndrome is a unique subtype of iMCD that demonstrates characteristic clinicopathological findings. Further study to clarify prognosis, pathophysiology, and appropriate treatment is needed., (© 2015 Wiley Periodicals, Inc.)

Background: Natural orifice specimen extraction (NOSE) has been developed as a means of decreasing the incidence of surgical wound complications. However, NOSE performed using a conventional multiport technique has been reported previously. The current authors performed totally laparoscopic anterior resection with transvaginal specimen extraction (TVSE) using the reduced-port surgery (RPS) technique. The Alexis wound retractor (Applied Medical, Rancho Santa Margarita, CA, USA) and Free Access (Top Corporation, Tokyo, Japan) were attached to the transvaginal route for transvaginal assistance and smooth specimen extraction. The authors documented this simple and safe technique and its short-term results., Methods: Data were prospectively collected for five patients who underwent totally laparoscopic anterior resection with TVSE for colorectal cancer between June 2012 and December 2012. A multiport access device (GelPOINT advanced-access platform; Applied Medical) was inserted into the navel, and a 5-mm port was inserted into the right lower quadrant to be used as a drain site. Transverse transvaginal posterior colpotomy then was performed. One ring of an Alexis ring pair was inserted into the peritoneal cavity through the vagina. The other white ring was placed outside of the vagina and then covered with a Free Access to maintain the pneumoperitoneum for insertion of a 12-mm port. Lymph node dissection and transection of the distal colon were performed with transvaginal assistance. The specimen then was extracted transvaginally. After the Alexis had been removed, the vaginal incision was closed transvaginally. End-to-end colorectal anastomosis was performed using the double-stapling technique., Results: Transvaginal extraction was completed in all five cases. The median operation time was 235 min. One case was complicated by chyloperitoneum. The median hospital stay was 6 days. Only one patient required intravenous analgesics once on postoperative day 1. All the patients remained disease free., Conclusion: Totally laparoscopic anterior resection using TVSE with RPS appears to be feasible, safe, and oncologically acceptable for selected cases.

We report a case of hyperammonemic encephalopathy related to 5-FU in an aged patient with recurrent colon cancer treated with FOLFIRI therapy. An 80-year-old man underwent right hemicolectomy for cecal cancer. After 10 months, surgical resection was performed for its local recurrence. He was then treated with FOLFIRI therapy, and during the fifth course, he presented with a sudden onset of congestive disturbances. Through radiographic examination and laboratory data, only hyperammonemia was found; he was therefore diagnosed with hyperammonemic encephalopathy. By starting branchedamino acid solutions for its treatment, his consciousness and serum ammonia were promptly improved. Hyperammonemic encephalopathy related 5-FU is caused by increasing ammonia production and its metabolic inhibition, and is worsened by renal dysfunction, dehydration, constipation, infections, or body weight loss. On account of the potential decrease of metabolic function of liver and kidney, an aged person tends to have hyperammonnemia more than a youth. Clinicians should be aware of the adverse events associated with hyperammonemia when then administer a large amount of 5-FU to elderly patients.

Gastrointestinal stromal tumors (GISTs) developing in the colon are rare, accounting for <5 % of all GISTs. There are few data on the clinical efficacy of tyrosine kinase inhibitors in colonic GISTs. We report here on an 80-year-old male patient with advanced GIST of the transverse colon. The patient underwent palliative resection of the primary tumor because the disease was associated with multiple liver metastases and peritoneal dissemination. Immunohistochemical analysis of the surgical specimens showed KIT and CD34 expression. Sequence analysis revealed that the tumor harbored deletion mutation at codons 557-558 in exon 11 of the c-kit gene. A diagnosis of colonic GIST was made. The patient postoperatively underwent imatinib therapy for the remaining metastatic tumors. Imatinib therapy induced a cyst-like appearance of the liver metastases and stabilized the disease. In the present case, c-kit gene analysis was found to be clinically helpful for validating the diagnosis and therapeutic decision making for this rare disease.

We report five cases that presented with high fever, anasarca, hepatosplenomegaly and severe thrombocytopenia with reticulin fibrosis of the bone marrow. The constellation of symptoms is not compatible with any known disease, and we had difficulty in diagnosis and treatment. The age distribution was from 47 to 56 years, and two men and three women were affected. Two patients needed hemodialysis because of renal dysfunction and oliguria with massive pleural effusion. Laboratory examinations showed normal immunoglobulin levels and no monoclonal protein. None of them showed diagnostic autoantibodies for any autoimmune diseases. Histological examination of the liver in three patients and spleen in two showed non-specific findings. Lymphadenopathy was tiny and lymph node biopsy was carried out in only one case. Histologically, paracortical hyperplasia with vascular proliferation and atrophic germinal centers resembling hyaline-vascular-type Castleman's disease or POEMS syndrome were detected. Without a definitive diagnosis, treatment was started with cyclophosphamide, hydroxydaunorubicin, vincristine and prednisolone (CHOP) regimen in one patient, semi-pulse therapy with methyl-predonisolone in three and cyclosporin A in three. Two patients achieved complete remission, two were steroid-dependent and the remaining one died of multiple organ failure. These findings suggest that this disease may be a novel clinical entity belonging to systemic inflammatory disorder with a background of immunological abnormality or a unique variant of multicentric Castleman's disease. [J Clin Exp Hematop 53(1): 63-68, 2013].

The patient was a 62-year-old man with bowel obstruction in a locally advanced rectal cancer. Computed tomography (CT) scan of the abdomen showed tumor enlargement(11.4 × 9.0 cm)that invaded the urinary bladder, but no distant metastasis. XELOX therapy was planned in order to shrink or eliminate the tumor after a sigmoid colostomy. Four courses of XELOX therapy were perfomed. Consequently, the level of the tumor marker had been restored to a normal range. CT scan revealed marked shrinkage of the tumor (6.1 × 5.2 cm) and a sharply-defined border between the tumor and the urinary bladder. Three weeks after chemotherapy, a low anterior resection as a radical surgery, and a temporary ileostomy were performed. The post-operative course was good. The histological effect was judged to be grade 3. There were no viable cancer cells in the rectal tumor and lymph nodes. The patient is alive and has been disease-free for 10 months after the operation. XELOX therapy as pre-operative chemotherapy might be safe and effective for patients with locally advanced rectal cancer.

A 35-year-old man admitted to the hospital for oral hemorrhage was diagnosed with acute promyelocytic leukemia (APL). Remission from APL was achieved by induction therapy with all-trans retinoic acid (ATRA); the PML/RARA fusion gene was not detected on PCR analysis. Despite complete molecular remission, severe persistent pancytopenia, massive ascites, and renal failure were observed. The liver surface appeared rough and irregular on computed tomographic images. On the basis of the liver biopsy results, we diagnosed his condition as portal hypertension due to autoimmune hepatitis. Indocyanine green test showed good residual function of the liver, and therefore, 2 courses of consolidation therapy were administered; chemotherapy was stopped because of severe pancytopenia due to portal hypertension. Instead of continuing the consolidation therapy, maintenance therapy involving 8 rounds of ATRA monotherapy (45 mg/m(2), days1∼14) was initiated. Portal hypertension did not progress further with this maintenance therapy and therefore it was continued. The patient has been in remission from APL ever since, and no relapses have occurred since the past 5 years. These results suggest that ATRA can be used for long-term therapy in such cases.

A 61-year-old man admitted for pancytopenia was diagnosed with acute myeloid leukemia. On day 26 of induction therapy, the patient suddenly developed cardiogenic shock. The ultrasound cardiogram showed imaging features typical of takotsubo cardiomyopathy. Cardiogenic shock caused by takotsubo cardiomyopathy is rare in patients with hematological malignancies but is a severe complication during chemotherapy.

Background: Conventional techniques for laparoscopic-assisted colectomy (LAC) require abdominal minilaparotomy for extraction of the specimen. Abdominal wound complications often increase the invasiveness of LAC. To decrease the incidence of wound complications, natural orifice specimen extraction (NOSE) has been reported. However, only a few devices that allow smooth extraction and reduced intracorporeal contamination have been reported previously. We performed totally laparoscopic sigmoid colectomy using transanal specimen extraction (TASE) and the Alexis(®) wound retractor (Applied Medical, Rancho Santa Margarita, CA, USA). We document this simple and safe technique and its short-term results., Methods: We prospectively collected data on 18 patients who underwent totally laparoscopic sigmoid colectomy with TASE from April 2009 to July 2010. Lymph node dissection and transection of proximal and distal colon were performed in conventional manner. The transected rectal stump was opened transversely, and a long Babcock grasper was inserted transanally through the opened rectal stump. One of a pair of Alexis rings was held and pulled out of the anus. The other ring was placed in the opened rectal stump. The specimen was then extracted transanally through the Alexis. After the Alexis had been removed, the rectal opening was reclosed with a linear stapler. End-to-end colorectal anastomosis was then performed using the double-stapling technique., Results: Transanal extraction was achieved in 17 cases. We switched to conventional LAC in a case involving a bulky specimen. In 16 cases not including the combined cholecystectomy case, mean operation time was 241 min. One case was complicated by anastomotic leakage and wound infection, while another had enterocolitis. Median hospital stay was 6 days. All patients remained disease free. Mean Wexner score at 12 months after operation was 2.3., Conclusion: Totally laparoscopic sigmoid colectomy using TASE and the Alexis appears to be feasible, safe, and oncologically acceptable for selected cases.

This retrospective analysis investigated the prognostic value of monitoring the response to imatinib using peripheral blood (PB) samples and the impact of the response on outcome in 133 patients with chronic myeloid leukemia (CML). We divided the response into 3 categories according to the results of neutrophil (N)-FISH and BCR-ABL transcript levels in PB; more than a 3-log reduction [major molecular response (MMR)], between a 2-log and 3-log reduction or negative with N-FISH [complete cytogenetic response equivalent (CCyRe)], N-FISH positive or less than a 2-log reduction (non-CCyRe). The median follow-up was 5.46 years. At 5 years, the overall survival (OS) rate and progression-free survival (PFS) rate were 94.4 and 92.0%, respectively. The estimated rate of the CCyRe and MMR were 81.7 and 67.1%, respectively. 106 patients achieving the CCyRe had significantly better OS and PFS than 27 patients without achieving the CCyRe. Patients with MMR had significantly better survival free from death, progression, imatinib withdrawal and a loss of the CCyRe, than patients whose response level remained in the CCyRe without achieving MMR until 18 months. Our observation suggests that the response level of the CCyRe on PB serve as a prognostic indicator, and achieving MMR provides stable long-term survival.

A 52-year-old woman presented with isolated thrombocytosis in 2003. After 5 years of observation under a tentative diagnosis of essential thrombocythemia (ET), she was referred to our hospital because of anemia and leukopenia. Bone marrow biopsy demonstrated increases of megakaryocytes and myelofibrosis, but splenomegaly was absent. A karyotype study of bone marrow detected t(9;22) (q34;q11.2) in 6 of the 20 metaphases studied. Peripheral blood neutrophil BCA-ABL fusion signals (FISH) were not detected. Because RT-PCR assay of bone marrow detected major-BCR-ABL mRNA (b3a2), treatment with imatinib (400 mg/day) was started. After transient thrombocytopenia, normalization of blood cell counts and improvement of myelofibrosis were achieved. JAK2 V617F mutation and M-BCR-ABL mRNA was negative in peripheral blood. Clinical and laboratory data suggest that this case represents a rare and atypical myeloproliferative neoplasm with BCR-ABL translocation restricted mainly to the megakaryocyte lineage.

A 46-year-old woman with Graves' disease was admitted for anemia and thrombocytopenia. She had previously been treated with methimazole but she self-discontinued the treatment 6 months prior to admission. She was diagnosed with Evans syndrome associated with Graves' disease and treated with propylthiouracil without corticosteroids, which normalized her thyroglobulin level. Surprisingly, while Evans syndrome is characterized by frequent relapses, this patient has been in remission of Evans syndrome for approximately 4 years. The remission of Evans syndrome associated with Graves' disease in the absence of immunosuppressive therapy suggests that these 2 diseases have a common pathogenetic mechanism.

We report three patients who presented with high fever, anasarca, hepatosplenomegaly, lymphadenopathy and severe thrombocytopenia accompanied by reticulin fibrosis of the bone marrow. This constellation of symptoms is not compatible with any known disease entity, and we had difficulty in diagnosis and treatment. A 47-year-old woman was suspected of having splenic lymphoma and received one course of CHOP regimen followed by continued steroid therapy. Her condition was improved but repeatedly became exacerbated with tapering of steroid. A 56-year-old man was treated with steroid pulse therapy and splenectomy without improvement. Histology of the liver and spleen did not show any specific findings. Immunosuppressive therapy with cyclosporin A was successful. Another 49-year-old man showed histological findings of paracortical hyperplasia with vascular proliferation and atrophic germinal centers on inguinal lymph node biopsy. These findings were similar to those of the hyaline-vascular type of Castleman disease or POEMS syndrome, but non-specific. Although he received steroid pulse therapy, he died of multiple organ failure. Autopsy demonstrated cytomegalovirus infection and hemophagocytic histiocytosis without malignant lymphoma. We suggest that this constellation represents a new clinical entity belonging to systemic inflammatory disorders with a background of immunological abnormality, requiring prompt and vigorous immunosuppressive therapy.

Purpose: We aimed to examine the safety and antitumor effects of a combination of S-1 and paclitaxel in patients with unresectable or recurrent gastric cancer in a phase I/II setting., Patients and Methods: The study was designed as a phase I/II clinical trial. In phase I portion, the dose of paclitaxel was escalated to estimate the maximum-tolerated dose (MTD) and recommended dose (RD) of paclitaxel with fixed dose of S-1. S-1 (daily dose, 80 mg/m(2)) was given orally on days 1-21 every 35-day cycle (rest on days 22-35). Paclitaxel was administered intravenously on days 1, 8 and 15, at an initial dose of 40 mg/m(2), stepping up to 70 mg/m(2) in 10-mg/m(2) increment. Dose-limiting toxicity (DLT) was defined as grade 4 hematological toxicity, grade 3 or higher nonhematological toxicity, and treatment discontinuation due to adverse reactions during the first course of treatment. In phase II portion, the efficacy and toxicity at the RD of paclitaxel with S-1 were assessed., Results: The MTD of paclitaxel was estimated to be 60 mg/m(2), because >33.3% of patients (2/3) developed DLTs. DLT included postponement of treatment due to grade 2 neutropenia, and grade 3 stomatitis, anorexia, and nausea. Therefore, the RD of paclitaxel was estimated to be 50 mg/m(2). In the phase II portion, 22 patients were evaluated with 50 mg/m(2) paclitaxel and 80 mg/m(2) S-1 in a 35-day cycle. The response rate was 54.5% (95% CI, 32.2-75.6%). The median survival time was 283 days (95% CI, 218-508 days). The median number of treatment courses was 4 (range 1-10), indicating that this regimen could be given repeatedly., Conclusions: This phase I/II trial of combination therapy with S-1 and paclitaxel in patients with unresectable or recurrent gastric cancer showed that this regimen has substantial antitumor activity and can be given safely.

Alkylating agents are often used to treat patients with multiple myeloma (MM). However, it is not common for high-dose cyclophosphamide (CPM) therapy to be used as a treatment for MM. Herein, we report a case of refractory MM associated with hypercalcemia. We decided to give her high-dose CPM. After this treatment, the serum calcium level decreased and the tumor mass in the iliac bone was reduced. This therapy is potentially useful for patients with refractory MM.

We have experienced successful treatment of a multiple hepatic metastasis of rectal cancer with combination chemotherapy. The patient is a 57-year-old male with bowel obstruction accompanied by rectal cancer (SE, N3, P1, H3, M (-) stage IV) who underwent a Hartmann operation with D3 lymph node dissection on July 6, 2000. The histopathological findings revealed a well-differentiated adenocarcinoma (se, INFbeta, n3, ly2, v2, p1). From the 11th postoperative day, combination chemotherapy using 5-FU 750 mg/day and LV 300 mg/day was performed once a week. When he underwent 5 combination chemotherapy treatments, adverse effects of grade 3 occurred, and the serum CEA level rose rapidly. We changed his regimen at that time. He underwent 2 courses of combination chemotherapy with 5-FU 500 mg/day and CDDP 10 mg/day for 5 days. Additional courses of combination chemotherapy with 5-FU 500 mg/day, LV 25 mg/day and CDDP 10 mg/day were performed weekly in the outpatient department. The treatment was effective, and a complete response (CR) was noted 4 months after the chemotherapy. The same combination chemotherapy was performed biweekly for one year after CR. The patient has been receiving a subsequent single administration of UFT and has remained in remission for 3 years and 7 months after surgery.

A 72-year-old woman was admitted with left cervical lymphadenopathy, high fever, pancytopenia and liver dysfunction. Bone marrow aspiration showed infiltration of large atypical lymphoid cells and hemophagocytic histiocytes, thus suggesting a diagnosis of lymphoma associated hemophagocytic syndrome (LAHS). An abdominal CT scan revealed multiple low-density areas in the liver, and the patient's liver function rapidly deteriorated. Histologically, the cervical biopsy showed lymphoma cell infiltration with prominent necrosis and karyorrhectic debris. The lymphoma cells expressed CD3+, CD4-, CD8+, CD20-, CD56+/-, TIA-1+, granzyme B+, and EBER was positive using in situ hybridization. DNA analysis of the TCR beta and gamma chain gene with the Southern blot showed rearranged bands. These findings were compatible with those of EB-virus associated peripheral T-cell lymphoma. After chemotherapy with the THP-COP regimen, the patient's liver dysfunction improved rapidly, but she died from bacterial peritonitis due to perforation of a recurrent duodenal ulcer. Post-mortem examination of the liver showed multiple irregular massive necroses of the hepatocytes, where no lymphoma cell infiltration was present. Hemophagocytic histiocytosis was remarkable in the bone marrow, spleen, lymph nodes, and liver. Marked elevation of serum levels of cytokines such as TNF-alpha or IFN-gamma suggests that these cytokines played an important role in the pathogenesis of the hepatic cell necrosis.

Chronic myelogenous leukemia is caused by the acquisition of the reciprocal (9;22)(q34;q11) chromosomal translocation in hematopoietic stem cells. The fusion protein showed higher and aberrant tyrosine kinase activity. The inhibition of the tyrosine kinase activity of the protein represents a specific therapeutic strategy for bcr/abl-expressing leukemias. STI571 is a compound of the 2-phenylaminopyrimidine class that selectively inhibits the tyrosine kinase activity of the Abl protein tyrosine kinase. In this study, we evaluated the effects of STI571 on antigen presentation of dendritic cells generated from the patients with CML. The data showed that by the addition of STI571 the dendritic cells derived from CML clone showed an increased expression of CD1a, CD83, CD80 and CD86 by flow cytometry analysis and showed more intense abilities of allogeneic antigen presentation by mixed leukocyte culture, compared with the control cells without STI571. Our results suggested that STI571 not only has a direct cytotoxic effect on bcr-abl gene rearranged cells but also an indirect effect associated with increased anti-leukemic immunological function due to an intensified antigen presentation., (Copyright 2003 John Wiley & Sons, Ltd.)

We treated a case of advanced gastric cancer with paclitaxel and TS-1. A 64-year-old man underwent total gastrectomy, splenectomy, and D2 + No. 16 a 2, b 1 lymph node (LN) dissection for gastric cancer. Computed tomography (CT) revealed metastases of supraclavicular and para-aortic LNs in the 4th postoperative month. Paclitaxel 90 mg was infused once a week, and TS-1 100 mg was administered daily. One course consisted of infusion of paclitaxel for 3 weeks followed by 2 weeks rest and administration of TS-1 for 4 weeks followed by 2 weeks rest. At the end of 4 courses of paclitaxel and 3 courses of TS-1, a partial response of the supraclavicular LN metastasis and a complete response of the para-aortic LN metastasis were achieved. There were no remarkable side effects for 2 years after the operation. This chemotherapy might be suitable to treat patients with LN metastases of advanced gastric cancer.

Three cases of malignant lymphoma (ML) accompanied by renal cell carcinoma (RCC) are reported. From September 1997 through August 2000, we treated 85 patients with ML. Among these patients, three had accompanying RCC (clear cell type): case 1, a 57-yr-old man with gamma/delta-T cell lymphoma; case 2, a 25-yr-old man with Grade 3 follicular lymphoma; case 3, a 64-yr-old man with MALToma of the right orbit. Renal cell carcinoma is a relatively rare disease, but several reports have indicated that, for some reason, the incidence of concurrent RCC and ML is higher than expected. It is possible that the two malignancies share some common background factors, such as genetic mutation, immunological abnormality, or an immunomodulatory effect of the first tumor. The patient in case 2 was thought to have an abnormal immunological background from his medical history, which included bronchial asthma, idiopathic thrombocytopenic purpura, and mesangial proliferative glomerulonephritis (non-IgA type). Therefore the combination of ML and RCC in this patient may have been due to immunological impairment.

Dendritic cells are potent antigen-presenting cells derived from CD34+ haemopoietic stem cells. Dendritic cells have been reported to be generated from cells in granulocytic lineage as well as monocytes, blood dendritic cell precursors and lymphoid progenitors. In order to explore the differentiation pathway of dendritic cells from granulocytic cells and the applicability of leukaemia-derived dendritic cells for anti-leukaemic immunotherapy in acute leukaemia of granulocytic origin, we tried to generate dendritic cells from leukaemia cells of a patient with acute promyelocytic leukaemia (APL). Leukaemia cells were cultured with GM-CSF, IL-4 and TNF-alpha for 10 days. Azurophilic granule-containing cells with marked cytoplasmic projections were generated in the culture. FACS analysis of these cultured cells revealed the generation of CD1a+, CD83+, CD80+, CD86+, CD40+ and HLA-DR+ cells. The leukaemic origin of these dendritic-like cells was demonstrated by in situ hybridization of magnetic-bead-sorted CD1a+ dendritic cells using the DNA probes of t(15;17). Cells generated by culturing leukaemia cells were demonstrated to have a potent antigen-presenting function in allogeneic mixed leucocyte cultures. These findings show the plausibility of the previously reported pathway of dendritic cell maturation through granulocytic cells and suggest the possibility of anti-leukaemic immunotherapy using leukaemia-derived dendritic cells even in patients with acute promyelocytic leukaemia., (Copyright 2001 S. Karger AG, Basel)

Homologous recombination (gene targeting) has many desirable features for gene therapy, because it can precisely correct mutant genes and restore their normal expression, and random nonhomologous integration of DNA is infrequent in cells in which homologous recombination has occurred. There are, however, no reports of attempts to use homologous recombination to correct mutant genes in normal hematopoietic stem cells (HSCs), which are prime cells for therapy of a variety of hematological and other conditions, presumably because of their low abundance and uncertainty that homologous recombination can occur at a usable frequency in these cells. The experiments reported here encourage optimism in this respect by demonstrating targeted correction of a defective hypoxanthine phosphoribosyltransferase gene in hematopoietic progenitor cells that can form colonies in methylcellulose culture. These clonogenic cells are in the same lineage as HSCs but are more abundant and more mature and so less pluripotent. Corrected colonies were identified by their survival in selective medium after electroporation of correcting DNA into unfractionated mouse bone marrow cells and were confirmed by reverse transcription-PCR and sequencing. The observed frequency (4.4 +/- 3.3 x 10(-5) per treated clonogenic cell) is the same as in embryonic stem cells (2.3 +/- 0.4 x 10(-5)) with the same DNA and mutation. These data suggest that gene targeting to correct mutant genes eventually will prove feasible in HSCs capable of long-term bone marrow reconstitution.

A seventy-eight year-old man with esophageal small cell carcinoma was reported. He was treated with chemotherapy of 5-FU and Cisplatin combined with radiotherapy. After 3 Courses of chemotherapy, the tumor almost disappeared. A biopsy specimen revealed moderate dysplasia but did not show residue of small cell carcinoma. The patient had lived with no evidence of cancer recurrence for 1.5 years. He died of lung metastasis and pleuritis carcinomatosa about two years after the first treatment with chemotherapy. Chemotherapy of 5-FU and Cisplatin (combined with radiotherapy) is one of the useful treatments for patients with small cell carcinoma of the esophagus.

In order to elucidate the possibility of costimulatory molecules-mediated immuno or immuno-gene therapy for human hematological malignancies, we analyzed 30 hematopoietic cell lines and cells obtained from 48 patients with hematological malignancies for the expression of costimulatory molecules such as CD80 and CD86. The 30 hematopoietic cell lines were composed of 4 cell lines derived from the patients with T-cell acute lymphoblastic leukemia (T-ALL), 3 from Philadelphia chromosome positive ALL (Ph1+ALL), 8 from acute myeloblastic leukemia (AML), 3 from acute promyelocytic leukemia (APL), 8 from chronic myeloid leukemia at blast crisis (CML-BC), 3 from Burkitt's lymphoma and one from follicular cell lymphoma. The expression of CD80 or CD86 was frequent on cell lines derived from the patients with CML-BC or Burkitt's lymphoma, while it was rare on cell lines from T-ALL. Subsequently we analyzed the cells obtained from 48 patients with hematological malignancies, which consisted of 6 samples from patients with ALL, 30 from AML, 2 from CML-BC, 3 from B-cell lymphoma and one from each acute mixed leukemia (AMixL), adult T cell leukemia (ATL), T-cell large granular lymphocytic leukemia (T-LGL leukemia), chronic lymphocytic leukemia (CLL), myelodysplastic syndrome (MDS)-RAEB in T, multiple myeloma (MM) or T-cell lymphoma. Among all the 48 cases, all cases except one case with CLL and two with B cell lymphoma were demonstrated to be negative for CD80 on the neoplastic cells. CD86 and HLA-DR were shown to be expressed in 50% and 88% of total 48 cases respectively. In 30 AML samples, CD86 was positive in 15 cases (50%), which was sharply in contrast with the finding that CD80 was not detected in any AML samples. HLA-DR was expressed in 25 AML samples (83%). We also treated seven human hematopoietic cell lines with IFN-gamma, IL-12 or IL-15 and observed whether these cytokines could induce or enhance the expression of CD40, CD54, CD58 and HLA-DR as well as CD80 and CD86. The present study demonstrated that the expression of CD86 could be upregulated not only by IFN-gamma, but also by IL-12 or IL-15 in some cell lines. These findings suggested the possibility that the absence of CD80 on neoplastic cells may be associated with the lack of efficient anti-tumor immunity in most patients with hematological malignancies and that the immuno or immuno-gene therapy manipulating the expression of costimulatory molecules such as CD80 may be a useful treatment modality for hematological malignancies.

To clarify the efficacy of allogeneic bone marrow transplantation (BMT) for adult ALL in first remission we retrospectively studied long-term outcomes of adult ALL patients of age between 15 and 44 years who were treated in our institute from 1980 to 1990. In this period thirteen patients with HLA compatible donors were offered allogeneic BMT during the first remission, while 16 patients without HLA-compatible donor were treated with maintenance chemotherapy (Cancer Chemoth Pharmacology 33:359-365, 1994). Patient and disease characteristics (age, leukocyte count at presentation, immunophenotype, Ph1 chromosome, and duration to first remission) in the two groups were not significantly different (chi-square test p > 0.1). As causes of treatment failure, relapse was 90% for chemotherapy while relapse and therapy-related death were 67% and 33%, respectively, for transplantation. The leukemia-free survival (LFS) rates at 10 years were 52 +/- 13% for transplantation and 30 +/- 11% for chemotherapy (P > 0.2, g-Wilcoxon, Logrank). The 10-year-LFS rates of Ph1-negative patients of 15 to 29 year-old were 67 +/- 15% for transplantation (n = 9) and 62 +/- 15% for chemotherapy (n = 8) (P > 0.9). Although the present data are derived from a non randomized retrospective study and a relatively small number of patients, this study revealed no superiority of BMT over chemotherapy for the prolongation of first remission in adult ALL, especially, in a standard risk group such as young patients without Ph1 chromosome.

A case of early gastric cancer, limited to submucosal layer, which was manifested as cerebral metastasis is presented herein. A 47-year-old man was admitted to Nagaoka Chuo General Hospital with convulsions and a disturbance in consciousness, where a computed tomography (CT) scan revealed a cerebral tumor in the left temporal lobe. The resected tumor was identified as a metastatic adenocarcinoma. Further investigation revealed gastric cancer involving the posterior wall of the cardia. At laparotomy, multiple and small metastases of the liver and a jejunal metastasis were found and a palliative total gastrectomy was performed. The surgical specimen revealed a protruding, poorly differentiated medullary adenocarcinoma, with invasion of the submucosal layer. The patient died 4 months after undergoing the laparotomy. This case report is presented to make clinicians aware of the possibility that early gastric cancers may present as brain metastasis.

Spontaneous perforation of the extrahepatic bile duct is rare. We herein report the case of an 80-year-old woman who underwent emergency laparotomy for bile peritonitis due to a spontaneous perforation of the common bile duct. A 2-mm perforation was found in the posterior wall of the choledochus, and its wall was paper-thin. Three stones, 2mm in diameter, were removed from the common bile duct. She underwent T-tube decompression with intraoperative cholangiography demonstrating a swollen papilla of Vater. The swelling of the papilla disappeared 4 weeks after the operation. Her postoperative course was uneventful. It seems likely that the elevated intraductal pressure due to the swollen papilla following stone impaction caused the perforation in this patient. Furthermore, the excessive friability of the common bile duct of unknown etiology may also have contributed to the perforation. This experience along with a review of the literature indicate that biliary decompression is the treatment of choice for this condition.

Leukemic transformation in essential thrombocythemia (ET) is rare. We describe a patient with ET which transformed to megakaryoblastic leukemia with myelofibrosis after treatment with melphalan for 8 years. His course after transformation smouldered for 20 months without antileukemic chemotherapy. A 61-year-old man was referred by a local doctor to Niigata University Hospital due to nasal bleeding in June 1984. Complete blood count (CBC) was as follows; hemoglobin 12.4 g/dl, platelets 268.8 x 10(4)/microliters, and white blood cells 11,900/microliters, with differentials of 39% PMN, 1% basophils, 2% eosinophils, 4% monocytes, and 13% lymphocytes. Bone marrow examination revealed hyperplasia of megakaryocytes without increase of reticulin fibers. Neutrophil alkaline phosphatase activity and karyotype of marrow cells were normal. ET was diagnosed. He was followed up by local doctor. The platelet count was controlled at a level of approximately 40 x 10(4)/microliters with melphalan for eight years. In January 1992 he developed pain in his lower extremities. He was admitted to our hospital on May 29, 1992. CBC was as follows; hemoglobin 8.9 g/dl, platelets 14.3 x 10(4)/microliters, and white blood cells 3,500/microliters, with differentials of 25% PMN, 5% monocytes, 28% lymphocytes, and 24% blasts. Bone marrow aspiration was unsuccessful and bone marrow biopsy revealed increases in fibroblasts and collagen fibers. Circulating blasts were positive for CD4, CD7, CD25, CD13, CD33, CD34, and HLA-DR and partly positive for CD41 and CD36. In ultrastructural cytochemistry blasts were positive for platelet peroxidase but negative for myeloperoxidase. Cytogenetic study revealed 46, XY, +der (1) t(1:7) (p11;q11) in all of five metaphases. He was diagnosed with megakaryoblastic leukemia accompanied by myelofibrosis.(ABSTRACT TRUNCATED AT 250 WORDS)

In order to clarify the function of P210 bcr/abl oncogene in leukemogenesis, IL-3 dependent murine hematopietic cell line, FDC-P2, was transfected with the plasmid containing cDNA of P210 bcr/abl oncogene (pGD'210) or murine IL-3 (pcDmIL3) by electroporation. Four out of five pGDH210 transfected clones as well as FDC-P2 transfected with pcDmIL3, acquired autonomous proliferation (i.e. lost the requirement for IL-3 supplementation). The expression of bcr/abl oncogene was weak in one clone, which remained dependent on IL-3. Unlike pcDmIL3 transfectants, which secrete IL-3 into the supernatant, IL-3 was not demonstrated in the culture supernatant of pGD'210 transfected FDC-P2. These finding suggest that P210 bcr/abl oncogene is directly associated with autonomous proliferation, which is the first process of leukemogenesis.

To develop new purging regimens for ABMT the ability to predict potential for purging of tumor cells from BM is important. Since the sensitivity of human B cell lymphoma to hyperthermia is not known, we examined its effect on the growth of B cell lymphoma cell lines (Raji and Daudi) in vitro to evaluate potential for purging clonogenic tumor cells from normal marrow by heat, using a limiting dilution assay to measure log depletion of tumor cells in a 20-fold excess of normal BM. When exposed to heat (42-43 degrees C) for 120 min, both clonogenic Raji and Daudi cells were dramatically reduced (a 4-to-6 log reduction) with time, whereas at 42 degrees C over half and at 43 degrees C 10% of normal granulocyte-macrophage progenitor cells survived for the same time period. This high level of lymphoma cell depletion by heat correlated with that of immunologic and pharmacologic studies. In addition, these survival curves during heating were found to correlate with the Gompertz-Makeham formula--a law of human mortality. This formula may be useful in predicting the purging effect of heat. These results suggest that in vitro hyperthermia could be applied effectively for the elimination of residual, clonogenic lymphoma cells in autologous marrow grafts before ABMT.

Because GM-CSF possesses burst-promoting activity (BPA) and megakaryocyte colony-stimulating activity (Meg-CSF) as well as stimulating activity on granulocyte-macrophage progenitors, and erythropoietin (Epo) has thrombopoietin-like activity, the combination therapy of GM-CSF and Epo seems to be more effective for stimulating erythropoiesis and thrombocytopoiesis in patients with pancytopenia. For this reason, the combination therapy of recombinant human GM-CSF (rhGM-CSF) and rhEpo was performed in two patients with refractory anemia (RA) and aplastic anemia (AA). Epo-unresponsive anemia was remarkably improved by adding rhGM-CSF to Epo and the effect lasted for 1 1/2 months in a patient with RA, but severe anemia occurred again immediately after the discontinuation of Epo. The neutralizing antibodies against GM-CSF were not demonstrated at the phase when anemia re-progressed in this patient. In a patient with AA, anemia and thrombocytopenia, which were refractory to previous administration of rhGM-CSF, responded to the combined administration of GM-CSF and Epo. Although the effects were maintained for 3 1/2 months, the anemia and thrombocytopenia became worse again after the administration of rhGM-CSF was changed from daily to every other day. These findings suggest the usefulness of combination therapy of GM-CSF and Epo for patients with pancytopenia.

Our previous study demonstrated the positive relationship between the gene introduction rate into hematopoietic cell lines by electroporation and the percentage of cells in S-phase. In the present study, granulocyte-macrophage progenitor cells (CFU-C) rich marrow cell fraction were cultured in suspension with IL-3, GM-CSF and G-CSF for 4 days. The number of CFU-C were increased three times after the culture, and 3H-thymidine suicide tests of cultured cells demonstrated that the proportion of CFU-C in S-phase was increased by two to four times. The efficiency of gene transfer into CFU-C with the plasmid pMoZtk (containing the beta-galactosidase gene) by electroporation was nearly doubled by culturing marrow cells with these growth factors. These findings confirm that the introduction rate of the gene into CFU-C by electroporation is more efficient in cell populations with a higher percentage of CFU-C in S-phase.