Prognostic impact of six versus eight cycles of standard regimen in patients with diffuse large B-cell lymphoma: propensity score-matching analysis.

BACKGROUND: R-CHOP-21 has been the standard treatment for diffuse large B-cell lymphoma (DLBCL), but there is a paucity of evidence focusing on the number of cycles of regimens. PATIENTS AND METHODS: We conducted a retrospective study to compare the effectiveness of six cycles of standard regimens versus eight cycles for overall survival (OS) in DLBCL patients using propensity score matching, in consideration of relative dose intensity (RDI). RESULTS: A total of 685 patients with newly diagnosed DLBCL were identified in three institutions from 2007 to 2017. Patients treated using six cycles of standard regimens were matched by propensity scores with those treated using eight cycles. A 1 : 1 propensity score matching yielded 138 patient pairs. Eight cycles did not significantly improve OS in the conventional Cox proportional hazards model (hazard ratio 0.849, 95% confidence interval 0.453-1.588, P = 0.608). Restricted cubic spline Cox models for OS confirmed that the effect of the number of cycles was not modified by total average RDI, the International Prognostic Index, and age. Occurrence of adverse events did not differ between six and eight cycles. CONCLUSION: Even considering the impact of RDI, six cycles of the initial standard regimen for DLBCL is not inferior to eight cycles.

Combined endobronchial and endoscopic ultrasound-guided fine needle aspiration for mediastinal nodal staging of lung cancer.

BACKGROUND: Recently, transesophageal endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) has been evaluated for mediastinal nodal staging (N staging) of lung cancer, as this technique is less invasive than mediastinoscopy and possibly more accurate than 18F-fluorodeoxyglucose positron emission tomography with computed tomography (PET-CT). However, EUS-FNA does not provide access to pretracheal and hilar lymph nodes. More recently, endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has been introduced as a novel technique for accessing pretracheal and hilar lymph nodes. Although the combined endoscopic approach of EUS-FNA and EBUS-TBNA is presumably more accurate than PET-CT, only a few reports have quantitatively evaluated its diagnostic ability. Therefore, we prospectively assessed the diagnostic yield of this combined endoscopic approach for mediastinal N staging of lung cancer. METHODS: A consecutive series of 120 patients with suspected resectable lung cancer on CT findings underwent PET-CT and combined EUS-FNA/EBUS-TBNA. The accuracy and other diagnostic indices of the combined approach in mediastinal N staging were compared with those of PET-CT. RESULTS: Among the enrolled patients, a final pathological N stage was established in 110 patients. The accuracy of the combined approach using EUS-FNA and EBUS-TBNA was significantly higher than that of PET-CT (90.0 % vs. 73.6 %; P < 0.0001). The sensitivity, specificity, and positive and negative predictive values were respectively 71.8 %, 100 %, 100 %, and 86.6 % for the combined approach vs. 47.4 %, 87.5 %, 66.7 %, and 75.9 % for PET-CT. CONCLUSIONS: The combined endoscopic approach using EUS-FNA and EBUS-TBNA provided excellent diagnostic performance. Therefore, this approach is strongly recommended before surgery or mediastinoscopy to avoid futile thoracotomy and surgical intervention.

Endoscopic ultrasound-guided fine needle aspiration biopsy for splenic tumor: a case series.

Splenic tumors are occasionally found in clinical practice but the diagnosis is often difficult if only serologic and imaging tests are used. Therefore, pathologic sampling is required in such cases. Endoscopic ultrasonography (EUS) provides a good image of the spleen through the gastric wall, and a transgastric EUS-guided fine needle aspiration (EUS-FNA) biopsy may be easier than the percutaneous approach. Furthermore, a large-gauge needle may raise the capability of EUS-FNA for the histopathologic diagnosis. The aim of this study was to evaluate the yield of EUS-FNA using a large-gauge needle for a splenic tumor. Five patients with splenic tumor were subjected to EUS-FNA with a 19-gauge needle to obtain histopathologic materials. A pathologic sample was obtained in all cases, and the diagnoses were lymphoma (n = 2), sarcoidosis (n = 2), and inflammatory pseudotumor (n = 1). EUS-FNA using a 19-gauge needle is safe and useful for the diagnosis of splenic tumors.

Endoscopic ultrasound-guided fine-needle aspiration biopsy for lymphadenopathy of unknown origin.

BACKGROUND AND STUDY AIMS: The diagnosis of mediastinal and intra-abdominal lymphadenopathy is sometimes difficult, especially in patients who have no other primary lesions. Lymphoma is one of the main causes of this condition. Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) is a safe and accurate diagnostic procedure for lesions surrounding the gastrointestinal tract. However, diagnosing lymphoma using the EUS-FNA technique remains a diagnostic challenge, due to limitations in the amount of material sampled. The aim of the present study was to evaluate the yield of EUS-FNA biopsy (EUS-FNAB) using a large-gauge needle in patients with mediastinal and intra-abdominal lymphadenopathy of unknown origin, especially in relation to subclassification of the lymphomas. PATIENTS AND METHODS: Consecutive patients with mediastinal and intra-abdominal lymphadenopathy of unknown origin who were referred between October 2003 and March 2005 were enrolled in the study. EUS-FNAB was carried out using a 19-gauge needle, passing through the esophageal, gastric, and duodenal walls. Pathological diagnoses were made on the basis of histological findings, including immunopathological staining. RESULTS: A total of 104 patients were included in the study. The locations of the lymph nodes were mediastinal in 50 patients, intra-abdominal in 48 patients, and both mediastinal and intra-abdominal in six patients. The diagnoses made using EUS-FNAB were lymphoma (n = 48), metastasis (n = 16), and benign/reactive (n = 40). The overall accuracy of EUS-FNAB for unknown lymphadenopathy was 98 %, and it was possible to classify the lymphomas in accordance with the World Health Organization classifications in 88 % of cases. No serious complications occurred with the procedure. CONCLUSIONS: Open thoracic surgery, laparotomy, and other invasive diagnostic procedures such as mediastinoscopy and laparoscopy can now be avoided, as EUS-FNAB is potentially a safe and accurate tool for diagnosing unknown lymphadenopathy, including lymphoma.

Expansion of genetically corrected neutrophils in chronic granulomatous disease mice by cotransferring a therapeutic gene and a selective amplifier gene.

Hematopoietic stem cell gene therapy has not provided clinical success in disorders such as chronic granulomatous disease (CGD), where genetically corrected cells do not show a selective advantage in vivo. To facilitate selective expansion of transduced cells, we have developed a fusion receptor system that confers drug-induced proliferation. Here, a 'selective amplifier gene (SAG)' encodes a chimeric receptor (GcRER) that generates a mitotic signal in response to estrogen. We evaluated the in vivo efficacy of SAG-mediated cell expansion in a mouse disease model of X-linked CGD (X-CGD) that is deficient in the NADPH oxidase gp91phox subunit. Bone marrow cells from X-CGD mice were transduced with a bicistronic retrovirus encoding GcRER and gp91phox, and transplanted to lethally irradiated X-CGD recipients. Estrogen was administered to a cohort of the transplants, and neutrophil superoxide production was monitored. A significant increase in oxidase-positive cells was observed in the estrogen-treated mice, and repeated estrogen administration maintained the elevation of transduced cells for 20 weeks. In addition, oxidase-positive neutrophils were increased in the X-CGD transplants given the first estrogen even at 9 months post-transplantation. These results showed that the SAG system would enhance the therapeutic effects by boosting genetically modified, functionally corrected cells in vivo.

Lymphoid blast crisis of chronic myelogenous leukemia occurring more than 11 years after receiving an allogeneic bone marrow transplant for chronic myelogenous leukemia in myeloid blast crisis at onset.

A 25-year-old male developed lymphoid blast crisis (BC) of chronic myelogenous leukemia (CML) more than 11 years after receiving an allogeneic bone marrow transplant (alloBMT) for CML with myeloid BC at presentation from his HLA-identical brother. The lymphoid BC of CML probably occurred without a preceding chronic phase of CML. This case illustrates the difficulties involved in determining the appropriate length of follow-up after alloBMT.

A variant form of acute promyelocytic leukemia with marked myelofibrosis.

We describe a variant form, French-American-British (FAB) M3v, of acute promyelocytic leukemia (APL; FAB M3) with atypical morphocytochemical features, immature antigens (CD34 and HLA-DR) and marked myelofibrosis (MF). Usual APL cells do not express CD34 or HLA-DR antigens. MF may be more frequently observed in patients with M3v expressing CD34 and HLA-DR antigens than in patients with M3 lacking these antigens. Despite marked MF, recovery from the hypoplastic phase in the case we described was not delayed after remission induction chemotherapy consisting of enocitabine, 200 mg/mi2 intravenously; 6-mercaptopurine, 70 mg/m2 orally for 10 days; daunorubicin 40 mg/m2 intravenously for 4 days; and all-trans retinoic acid 45 mg/M2 orally between days 20 and 33. The promyelocytic leukemia-retinoic-acid receptor (PML-RAR) alpha fusion transcript, according to reverse transcriptase-polymerase chain reaction (RT-PCR), became negative in the bone marrow after the first course of consolidation chemotherapy. Autologous peripheral blood stem cell transplantation (autoPBSCT) was carried out after 3 courses of consolidation chemotherapy. There were no specific complications based on MF throughout the clinical course, including engraftment in autoPBSCT. The patient has been without MF and in molecular remission, defined as disappearance of the PML-RAR alpha fusion transcript according to RT-PCR, for 21 months. Longer follow-up will clarify the effects of autoPBSCT on prognosis in APL with MF.

[Diffuse large B-cell lymphoma expressing cytoplasmic IgM and kappa in a patient with lambda-type primary macroglobulinemia].

A 69-year-old woman who had had lambda-type primary macroglobulinemia (PMG) since December 1993 was admitted in October 1997 because of obstructive jaundice due to compression of the common bile duct by a retroperitoneal tumor. A biopsy sample was obtained by exploratory laparotomy, and from this a diagnosis of diffuse large cell lymphoma (DLCL) expressing cytoplasmic IgM/kappa was made. Partial remission was obtained after 6 courses of combination chemotherapy consisting of pirarubicin, cyclophosphamide, vincristine and prednisolone. However, the DLCL was generally progressive, and the patient died in August 1998 due to multiple organ failure. There was no difference in the plasma monoclonal IgM/lambda level before and during the course of DLCL. The clone of the DLCL may have been different from that of the PMG.

[Multiple myeloma complicated by bilateral abducens nerve palsy due to a tumor in the clivus].

A 62-year-old woman was admitted to our hospital because of double vision. Bone marrow aspiration revealed normal cellularity with 21.6% atypical plasma cells. Immunoelectrophoresis revealed a monoclonal component of IgG kappa in the patient's serum. Coronal and sagittal cranial MRI images showed a tumor in the clivus behind the sella turcica. The patient was diagnosed as having multiple myeloma complicated by double vision due to compression of the bilateral abducens nerve by a plasmacytoma. VAD therapy consisting of vincristine, doxorubicin and dexamethasone, followed by irradiation of the clivus tumor achieved only a transient therapeutic effect, and the double vision and bone disease worsened. Cranial nerve palsy may be a significant complication of multiple myeloma.

Graft failure due to hemophagocytic syndrome after autologous peripheral blood stem cell transplantation.

Hemophagocytic syndrome (HPS) after hematopoietic stem cell transplantation can occasionally cause graft failure. We describe a female patient with B-cell non-Hodgkin's lymphoma (NHL) with graft failure due to HPS 12 days after autologous peripheral blood stem cell transplantation (PBSCT). Autologous PBSCT was carried out during unconfirmed/uncertain complete remission according to the Cotswolds classification after 6 cycles of biweekly (cyclophosphamide, doxorubicin, vincristine, and prednisolone) therapy and 3 courses of salvage chemotherapy including etoposide. The patient developed a high fever on day 2 post-PBSCT. Her white blood cell count rose to 0.9 x 10(9)/L on day 10 post-PBSCT, but then began to decrease. A bone marrow aspirate on day 12 post-PBSCT revealed an increase in the number of benign histiocytes with hemophagocytosis, and the patient was diagnosed with HPS. Although high-dose methylprednisolone therapy was continued, her white blood cell count further decreased to 0.3 x 10(9)/L, and the patient died of multiple organ failure on day 29 post-PBSCT. A computed tomography scan did not identify recurrent NHL, and necropsy specimens from the bone marrow, liver, and kidney revealed no neoplastic infiltration. Bone marrow necropsy showed marked hypocellularity with active histiocytic hemophagocytosis. HPS may have been induced by infection with methicillin-resistant Staphylococcus aureus rather than by lymphoma-associated HPS.

[Hypereosinophilic syndrome with DIC treated successfully with a combination of high-dose methylprednisolone and cyclosporin A].

A 47-year-old man was admitted to our hospital with subcutaneous nodules on the bilateral lower legs and disseminated intravascular coagulation (DIC). Peripheral blood examination revealed leukocytosis with an increase of mature eosinophils, thrombocytopenia and abnormal coagulation. Bone marrow aspiration revealed an increased eosinophil count, and a diagnosis of hypereosinophilic syndrome (HES) was made. Prednisolone (PSL) therapy was not effective. Subsequent methylPSL pulse therapy followed by PSL brought about a transient improvement of the HES and DIC, but after reduction of the PSL, the HES worsened. After addition of cyclosporin A to the PSL, however, the HES improved and did not worsen.

Detection of acute promyelocytic leukemia (APL) cells intermediately differentiated by all-trans retinoic acid in the cerebrospinal fluid: central nervous system involvement in APL.

We report a patient with acute promyelocytic leukemia (APL) involving the central nervous system. A 55-year-old male was admitted to our hospital with dysarthria and incomplete right hemiplegia. A CT scan of the brain revealed a low density area in the left cerebrum. APL was diagnosed by bone marrow aspiration and chromosomal analysis. The patient received all-trans retinoic acid (ATRA) in combination with chemotherapy. Complete hematological remission (CR) was obtained, and the patient's neurological symptoms improved. However, a cytospin smear of the cerebrospinal fluid after CR showed immature myelocytes ("intermediate cells") that had possibly been derived from leukemic promyelocytes. Comprehensive intrathecal treatment as well as cranial irradiation, caused a further reduction in dysarthria and a complete disappearance of hemiplegia with no atypical cells in the cerebrospinal fluid. The patient has undergone maintenance chemotherapy as an out-patient.

[Complete remission of plasmablastic IgD lambda multiple myeloma induced by continuous infusion of low-dose cytarabine and etoposide].

A 67-year-old man was admitted because of thrombocytopenia in May 1998. His white blood cell count was 4,900/microliter with 3.5% blasts. Laboratory findings were as follows: hemoglobin level, 10.1 g/dl; platelet count, 1.8 x 10(4)/microliter; ALT, 56 IU/l; LDH, 3,570 IU/l; IgG, 653 mg/dl; IgA, 64 mg/dl; IgM, 49 mg/dl; IgD, 674 mg/dl. Serum immunoelectrophoresis confirmed IgD lambda M-component. Bone marrow aspiration showed 79.2% myeloma cells expressing a mostly plasmablastic morphology. No mature plasma cells were found in the bone marrow. The patient received a continuous drip infusion of 20 mg/body cytarabine (Ara-C) and 50 mg/body etoposide (VP-16) for 7 days. No plasmablastic myeloma cells were detected, but 2.1% mature plasma cells were found in his bone marrow on day 20. On day 18 his platelet count exceeded 10.8 x 10(4)/microliter, and the serum IgD level fell to 210 mg/dl. Therapy consisting of melphalan, methylprednisolone and vincristine was started from day 23. No IgD lambda M-component was detectable by serum immunoelectrophoresis seven months after the diagnosis of multiple myeloma. The patient has been in complete remission as of April 2000.

Serum-soluble fas level determines clinical symptoms and outcome of patients with aggressive non-Hodgkin's lymphoma.

Soluble Fas (sFas) blocks apoptosis induced by Fas ligand in vitro. The serum concentration of sFas is elevated in lympho-proliferative diseases. We hypothesized that higher levels of sFas worsen the clinical symptoms and outcome of patients with aggressive non-Hodgkin's lymphoma (NHL). We prospectively measured the serum concentrations of sFas in 67 consecutive patients with aggressive NHL (59 with diffuse large cell lymphoma and 8 with diffuse small cleaved cell lymphoma). sFas was significantly elevated in patients with aggressive NHL compared to healthy controls (N = 36, P< 0.005), while sFas in patients with B symptoms (4.20 +/- 2.12 microg/l) was significantly higher than in those without B symptoms (2.66 +/- 1.08 microg/l, P < 0.005). No significant difference was observed between B-cell lymphoma and T-cell lymphoma or between patients with clinical stage I or II and those with clinical stage III or IV. Significant correlations were found between sFas concentration and both soluble interleukin-2 receptor (R = 0.400, P < 0.001) and C-reactive protein (R = 0.340, P < 0.01) levels in patients with aggressive NHL. No correlation was observed between sFas and either white blood cell count or lactate dehydrogenase. Generalized Wilcoxon analysis revealed that NHL patients with sFas less than 4 microg/l had better overall survival than those with sFas above 4 microg/l (P < 0.001). The serum concentration of sFas might be associated with clinical symptoms and the prognosis of patients with aggressive NHL.

[An elderly patient with myelodysplastic syndrome successfully treated with combination of granulocyte-colony stimulating factor and continuous-drip infusion of low-dose cytarabine and etoposide].

A 73-year-old man was given a diagnosis of myelodysplastic syndrome in October 1997. He was treated with red blood cell transfusion and granulocyte-colony stimulating factor (G-CSF). In February 1998, he was admitted due to progression of pancytopenia. Bone marrow aspiration revealed refractory anemia with excess of blasts in transformation. The patient was treated with continuous-drip infusion of low-dose cytarabine and etoposide with G-CSF (AVG therapy). Complete remission (CR) was obtained after 2 courses of AVG therapy. Non-hematologic adverse effects were mild enough to be tolerated. CR has been maintained for 16 months with 1 course of consolidation therapy and 3 courses of intensification therapy using the AVG regimen.

[Two cases of orbital non-Hodgkin's lymphoma presenting with hemophagocytic syndrome].

We report 2 cases of orbital non-Hodgkin's lymphoma (NHL) with hemophagocytic syndrome (HPS). Patient 1 was a 64-year-old man with a diagnosis of peripheral T-cell lymphoma originating in the right orbita (clinical stage: IV B). Epstein-Barr virus DNA was demonstrated in tissue specimens by polymerase chain reaction. Laboratory findings on admission were WBC: 4,700/microliter, Hb: 12.1 g/dl, Plt: 14.6 x 10(4)/microliter, LDH: 951 IU/l, sIL-2R: 2,553 IU/ml, and ferritin: 5998.1 ng/ml. Patient 2 was a 73-year-old man with a diagnosis of diffuse large B-cell lymphoma originating in the right orbita (Clinical stage: IV B). Laboratory findings on admission were WBC: 9,100/microliter, Hb: 7.7 g/dl, Plt: 15.4 x 10(4)/microliter, LDH: 1,043 IU/l, sIL-2R: 10,090 IU/ml, and ferritin: 2079.3 ng/ml. Both patients had high-grade fever and extremely high serum cytokine levels. Bone marrow aspiration disclosed many histiocytes with hemophagocytosis. In both cases, combined chemotherapy was transiently effective, but patient 1 died of relapse of HPS and patient 2 of cerebral bleeding. Orbital non-Hodgkin's lymphoma with HPS is rare. These cases were interesting in terms of the relationship between HPS and the primary site of lymphoma.

Graft failure of autologous peripheral blood stem cell transplantation due to acute metabolic acidosis associated with total parenteral nutrition in a patient with relapsed breast cancer.

A 32-year-old female had been diagnosed as having relapsed breast cancer and liver metastasis. She underwent high-dose chemotherapy followed by autologous peripheral blood stem cell transplantation (PBSCT) with 5.8 x 10(6)/kg CD34+ cells. She was supported by total parenteral nutrition (TPN) without vitamins throughout these therapies. Hematopoietic recovery was not observed by day 28 after PBSCT, necessitating a second PBSCT on day 29 using the back-up material of 4.4 x 10(6)/kg CD34+ cells. On the next day, she suddenly developed severe metabolic acidosis, heart failure and deep coma. After immediate infusion of thiamine, heart failure and coma rapidly improved. The neutrophil count reached 0.5 x 10(9)/l on day 9 and the platelet count 50 x 10(9)/l on day 15 after the second PBSCT. This is a rare graft failure due to acute metabolic acidosis or thiamine deficiency associated with TPN.