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.

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.

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.

Local administration of monoclonal antibody-drug conjugate: a new strategy to reduce the local recurrence of colorectal cancer.

This report investigates the application of monoclonal antibody A7 and its drug conjugate in locally controlling colorectal cancer. The experimental protocol consisted of local retention, lymphatic delivery, normal organ distribution, systemic toxicity, and tumoricidal effects. When 125I-labeled monoclonal antibody (Mab) A7 was injected into the pelvis and the thigh of Balb/c mice, a high local retention unrelated to antigen-antibody interaction was observed at the injected site for 24 h after injection. An analysis of local retension properties related to antigen-antibody interaction, conducted by intratumorally or peritumorally injecting 125I-Mab A7 into the tumor-bearing athymic nude mice, revealed a significantly higher tumor localization of Mab A7 in comparison to i.v. injection. 125I-Mab A7 accumulated to a great extent in the ipsilateral regional lymph node but not in the contralateral regional lymph node. Normal organ accumulation of Mab A7 was lower in the locally injected group than in the i.v. injected group. Intratumoral injection of Mab A7-neocarzinostatin (A7-NCS) led to the complete remission of established tumor in 5 of 6 antigen-positive xenograft-bearing mice but exhibited a complete remission in only 1 of 6 antigen-negative xenograft-bearing mice. A single local injection of A7-NCS inhibited tumor development in 12 of 16 and 5 of 15 antigen-positive tumor-bearing mice and antigen-negative tumor-bearing mice, respectively, whereas neither a systemic injection of A7-NCS and NCS nor a local injection of NCS and saline had a notable inhibitory effect on tumor development. Systemic toxicity of NCS was markedly reduced when it was locally administered in the antibody-conjugated form. These findings indicate that local injection of immunoconjugate is a promising new field for controlling the local recurrence of colorectal cancer.

Chemical engineering of the monoclonal antibody A7 by polyethylene glycol for targeting cancer chemotherapy.

The murine monoclonal antibody A7 (Mab A7) against human colon cancer was chemically modified with methoxypolyethylene glycol (PEG) (Mr 5000). A high substitution of PEG molecules on Mab A7 produced a progressive reduction in antibody-binding activity. The pharmacokinetic and immunological properties of PEG-modified monoclonal antibody A7 (Mab A7) and the PEG-modified F(ab')2 fragment, which retained their antibody-binding activity, were assessed and compared with the parent Mab A7 and the parent F(ab')2 fragment. Blood clearance of PEG-modified antibodies appeared to be diminished by PEG modification and was fitted by a two-compartment model. Low PEG-substituted Mab A7 showed less organ uptake in the liver and spleen and similar uptake in the lung and kidney, compared with the parent Mab A7. PEG-F(ab')2 showed less uptake in the liver and kidney. Both preparations exhibited less tissue:blood ratios in all resected organs as compared with parent antibodies. Tumor localization was enhanced by PEG modification for the F(ab')2 fragment, but not by PEG modification for the whole Mab A7. Multiple i.v. administration of PEG-modified antibody to rabbit did not appear to elicit a measurable immune response to the antibody portion of the conjugate. In conclusion, PEG-modified antibodies are promising reagents as drug carriers to the target tumor.

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.

CD30/Ki-1-positive anaplastic large cell lymphoma preceded by Hodgkin's disease.

A 59-year-old man was initially diagnosed as having Hodgkin's disease, nodular sclerosis type, and complete remission was achieved after combination chemotherapy. One year later, he developed a high fever and recurrence of the Hodgkin's disease was diagnosed. Salvage chemotherapy was ineffective, and the patient died. Autopsy specimens showed infiltration of lymphoma cells into multiple organs. Lymph nodes showed characteristics of non-Hodgkin's lymphoma, with expansion of anaplastic large cells; this differed from the histological features at initial diagnosis. Immunohistochemical staining was positive for CD30/Ki-1, but negative for CD15 (LeuM1). These findings were compatible with Ki-1 lymphoma, suggesting that this may be a case of CD30/Ki-1 lymphoma preceded by Hodgkin's disease and that a certain proportion of Ki-1 lymphomas and Hodgkin's disease may share the same cellular origin.

Lymphoid blast crisis during interferon-alpha therapy in a patient with chronic myelogenous leukemia in myeloid blast crisis.

A 47-year-old woman was admitted to the hospital on March 13, 1998, because of general malaise and fever. It was determined that she had chronic myelogenous leukemia (CML) in myeloid blast crisis. Hydroxyurea was started initially, and the blasts completely disappeared from peripheral blood on day 9 of therapy. Interferon (IFN)-alpha was subsequently started, but lymphoblasts newly appeared on day 13 of administration. Treatment with adriamycin, vincristine, and prednisolone (AdVP) was immediately started, which rapidly reduced the lymphoblasts. However, the myeloblasts again began to gradually increase. Subsequent examinations showed the combined presence of myeloblasts and lymphoblasts in the marrow and peripheral blood. The ratio between myeloblasts and lymphoblasts depended on the treatment (IFN-alpha or AdVP). The patient died from respiratory failure on November 16, 1998. This patient may have had an underlying bipotential blastic clone that evolved differently in response to IFN-alpha or AdVP. In some CML patients, IFN-alpha may induce lymphoid blast crisis.

Flow cytometric determination of active oxygen (hydroperoxide) produced by peripheral blood neutrophils in patients with hematological disorders.

We analyzed active oxygen (hydroperoxide; H2O2) production by peripheral neutrophils in various hematological diseases by flow cytometry. One hundred microliters of heparinized fresh blood was sequentially incubated at 37 degrees C with 2',7'-dichlorofluorescein diacetate and with or without phorbol myristate acetate (PMA). After hemolysis, the pelleted white blood cells were subjected to flow cytometry, and the neutrophil fraction was gated on the cytogram. Production of H2O2 by the fraction was estimated by determining the increase in the relative intensity of fluorescence emitted from the fraction in response to stimulation by PMA. In controlled chronic myelogenous leukemia (CML) (WBC < 1 x 10(10)/1), H2O2 production was normal, while in uncontrolled CML (WBC > or = 1 x 10(10)/1), it was reduced. In myelodysplastic syndrome (MDS), H2O2 production was also reduced, but no significant difference was observed among FAB classification disease types in MDS patients. In untreated acute non-lymphocytic leukemia (ANLL), H2O2 production was reduced, while in the complete remission stage of ANLL, its level was normal, suggesting recovery from normal clones. In aplastic anemia, the H2O2 production level was normal. Steroid therapy might be responsible for the reduction of H2O2 production in non-Hodgkin's lymphoma and multiple myeloma. The production of H2O2 is closely related to the oxygen-dependent bactericidal activity of neutrophils, and, hence, can be utilized as an index to indicate susceptibility to infection. This neutrophil function can be determined easily in ordinary clinical facilities by using flow cytometry, and care should be taken to prevent infection when H2O2 production is reduced.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Differentiation induction of human promyelocytic leukemia cells by acyclic retinoid (polyprenoic acid).

Acyclic retinoid (all-trans-3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoic acid) has a slightly different structure from all-trans retinoic acid (ATRA), while it binds cellular retinoic acid-binding protein with a similar binding affinity to that of ATRA. We studied the in vitro efficacy of acyclic retinoid for the differentiation induction of human promyelocyte-derived HL-60 cell line and primary cultured blast cells obtained from 8 patients with acute non-lymphocytic leukemia (ANLL) including 3 acute promyelocytic leukemia (APL) patients. HL-60 cells and ANLL cells were incubated with or without retinoids for 5 days. Acyclic retinoid induced the differentiation of HL-60 cells and APL cells at 10(-6) mol/l, while ATRA induced differentiation at 10(-7) mol/l. These concentrations were well below those that affected cell growth and viability. Although ATRA has an excellent capacity for differentiation induction of HL-60 and APL cells, it is also known to have severe, sometimes fatal, adverse effects, including retinoic acid syndrome. In contrast, acyclic retinoid is reported to have a much wider safety margin than that of ATRA. A clinical trial of acyclic retinoid for the differentiation induction therapy of APL may be worthwhile.

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.

Idiopathic myelofibrosis developing isolated granulocytic sarcoma with der (1;7)(q10; p10) after splenectomy and finally transforming to acute myelogenous leukemia.

A 47-year-old female with idiopathic myelofibrosis developed isolated granulocytic sarcoma with der (1; 7)(q10; p10) after splenectomy, followed by acute myelogenous leukemia. The patient had myelofibrosis since 22 years of age, received splenectomy at 47 years, and developed isolated submandibular granulocytic sarcoma, 8 months later. Although the initial tumor disappeared after irradiation, recurrent tumors selectively appeared in the areas of operative scars. She subsequently developed blastic transformation with der (1; 7)(q10; p10), and the blasts were refractory to different chemotherapy. This case is very rare in the following aspects: the onset of myelofibrosis occurred at a relatively young age; isolated granulocytic sarcoma after splenectomy preceded the transformation to acute leukemia; and the subcutaneous tumors developed in areas of operative scars.

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.

The combined effects of all-trans retinoic acid and granulocyte colony-stimulating factor as a differentiation induction therapy for acute promyelocytic leukemia.

A 61-year-old male with acute promyelocytic leukemia (APL) had been in complete remission for the previous 15 months, but his APL relapsed with neutropenia. Although promyelocytes in bone marrow were reduced after administration of 60 mg all-trans retinoic acid (ATRA) daily, myelocytes were predominant on the myelogram and neutropenia did not recover. By adding 75 micrograms of granulocyte colony-stimulating factor (G-CSF) daily, neutrophils accounted for 35.0-55.5% of the myelogram, and the peripheral neutrophil count rose dramatically. Such morphological differentiation of myeloid series was also ascertained in terms of their functions of both neutrophil alkaline phosphatase activity and active oxygen producing capacity. This case supports the concept that G-CSF accelerates ATRA-induced neutrophilic differentiation of blast cells in APL.

[Flow cytometric determination of active oxygen produced by neutrophils in patients with inflammatory diseases].

We investigated active oxygen (H2O2) production by neutrophils in patients with inflammatory diseases such as connective tissue disease and respiratory tract infection. The analysis was done by flow cytometry using as small volume of whole-blood as 100 microliters. H2O2 production as well as C-reactive protein (CRP) were increased in connective tissue diseases, and was decreased after steroid therapy. In a case of neuro-Behçet's disease, changes in H2O2 production was observed in agreement with those in clinical symptoms such as gait disturbance. H2O2 production as well as CRP and neutrophil count were increased in acute respiratory tract infection, but in chronic patients H2O2 production alone was rather reduced. In stages of enhanced H2O2 production, tissue damage or inflammation may exist, the degree of which seems to be well reflected by H2O2 production. During stages of impaired H2O2 production, care should be taken to prevent infections. Using flow cytometry, H2O2 production can be easily determined as one of functions of neutrophils.

[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.

[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.

[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.

[Multiple myeloma presenting as massive ascites].

Ascites is a rare complication of multiple myeloma. We report a case of multiple myeloma with peritoneal involvement. An 80-year-old woman was admitted to our hospital because of massive ascites. Laboratory findings included an Hb of 7.8 g/dl, IgA of 2,160 mg/dl, and CA125 of 942 IU/ml. Immunoelectropheresis analysis detected a monoclonal component of IgA lambda in serum, and of BJP lambda in urine. Bone marrow aspirtion revealed normal cellularity with 32.7% atypical plasma cells. The ascites was characterized by an exudate with numerous atypical plasma cells and elevated IgA and CA125 levels. The IL-6 level was 22 pg/ml and 79 pg/ml in serum and ascites, respectively. A diagnosis of IgA lambda multiple myeloma with peritoneal involvement was made. Chemotherapy consisting of melphalan and prednisolone reduced the serum IgA and CA125 levels markedly, and alleviated the patient's ascites.