Clinical analysis of 33 patients with adult T-cell leukemia (ATL)-diagnostic criteria and significance of high- and low-risk ATL

The clinical characteristics of 33 patients with adult T-cell leukemia (ATL) are described. All patients were born and have lived in Miyazaki Prefecture (southwest of Japan). Because of a wide range of clinical presentations and courses, they were subdivided into 2 groups. In the high-risk group, patients presented with high white-cell counts (WBC greater than or equal to 20,000/microliter) and over 30% of abnormal lymphoid cells (18 patients) and hypercalcemia with a low percentage of leukemic cells (5 patients). In this group the median survival time was only 3 months despite various modes of treatment. In contrast, patients of the second group exhibited a low percentage of abnormal lymphoid cells (WBC less than 20,000/microliter and/or leukemic cells less than 30%) and had no hypercalcemia (8 patients). Their clinical course was chronic with a median survival of 8 months, regardless of modalities of treatment. Two patients went through a period when the number of circulating leukemic cells was low (less than or equal to 5%) before overt leukemia appeared. Other clinical features, signs, symptoms, routine laboratory data, serum anti-ATL-associated antibody, cell membrane markers and cytogenetic studies were similar to those observed in other districts of Kyushu island.     

A case of fulminant Mycoplasma pneumoniae pneumonia successfully treated by steroid therapy]

A 35-year-old previously healthy woman was admitted because of pulmonary infiltrates in both lungs and respiratory failure associated with Mycoplasma pneumoniae infection. Although she initially required temporary mechanical ventilatory assistance, her clinical condition improved dramatically in response to steroid therapy. In this report, we discussed the effectiveness of steroid therapy in treating a case of severe M. pneumoniae pneumonia.     

Recovery of respiratory motion and deformation of the liver using laparoscopic freehand 3D ultrasound system

The present paper describes a method for intraoperative recovery of respiratory motion and deformation of the liver by using a laparoscopic freehand 3D ultrasound (US) system. The proposed method can extend 3D US data of the liver to 4D by acquiring additional several sequences of time-varying 2D US images during a couple of respiration cycles. 2D US images are acquired on several sagittal image planes and their time-varying 3D positions and orientations are measured using a miniature magnetic 3D position sensor attached to a laparoscopic US (LUS) probe. During the acquisition, the LUS probe is assumed to move together with hepatic surface. Respiratory phases and in-plane 2D deformation fields are estimated from time-varying 2D US images, and then time-varying 3D deformation fields on sagittal image planes are obtained by combining 3D positions and orientations of the image planes. Time-varying 3D deformation field of the volume, that is, 4D deformation field, is obtained by interpolating the 3D deformation fields estimated on several planes. In vivo experiments using a pig liver showed that the proposed method could perform accurate estimation of respiratory cycle and in-plane 2D deformation fields. Furthermore, evaluation for the effects of sagittal plane interval indicated that 4D deformation fields could be stably recovered.     

Dynamic sealing of lung air leaks by the transplantation of tissue engineered cell sheets

Current methods including the use of various biological and synthetic sealants are ineffective in the closure of intraoperative air leaks that often occur during cardiothoracic surgeries, resulting in a decreased quality of life for patients. We present the development of a novel lung air leak sealant using tissue engineered cell sheets. In contrast to previous materials such as fibrin glue, these bioengineered cell sheets immediately and permanently seal air leaks in a dynamic fashion that allows for the extensive tissue contraction and expansion involved in respiration, without any postoperative recurrences. Additionally, we demonstrate that mesothelial cells migrate to cover the transplanted cells sheets, thereby confirming excellent biocompatibility and integration with the host tissues. Finally, we present the use of skin fibroblasts as an effective and readily available autologous cell source that can be easily applied. This study shows for the first time, the development of an immediate and permanent lung air leak sealant, suitable for future clinical applications.     

Dok-1 and Dok-2 are negative regulators of T cell receptor signaling

Interaction of the TCR complex with self- or foreign peptides is a central event in the immune responses. Upon TCR stimulation, a protein-tyrosine kinase (PTK), ZAP-70, is recruited to signaling units of the TCR complex, such as TCRzeta, to play an essential role in T cell activation. Here, we find that mice lacking adaptor proteins Dok-1 and Dok-2 show augmented responses to thymus-dependent, but not thymus-independent, antigens, and that their T cells show elevated responses to TCR stimulation, including the activation of ZAP-70 and subsequent proliferation and cytokine production. Furthermore, the forced expression of Dok-1 or Dok-2 in a CD3(+)CD4(+) T cell clone inhibited the activation of ZAP-70 upon TCR stimulation. Interestingly, the Dok-1 and Dok-2 COOH-terminal moieties bearing the src homology 2 target motifs were dispensable for this negative regulation, even though they are crucial for the known adaptor function of Dok-family proteins. Thus, by an as yet unidentified mechanism, Dok-1 and Dok-2 play an essential role in the negative regulation of TCR signaling. Consistently, all mice lacking these proteins exhibited elevated titers of antibodies to double-stranded DNA and developed lupus-like renal disease.     

Iron-dependent formation of homocysteine from methionine and other thioethers

OBJECTIVE: We tested whether homocysteine is formed from methionine and other thioethers in vitro and in vivo, because methionine can be chemically demethylated to homocysteine. DESIGN: In in vitro studies, chemical conversions of thioethers (methionine, S-adenosylhomocysteine and cystathionine) into homocysteine were measured under various aerobic conditions. In humans, oral methionine (0.17 mmol/kg body weight) loading tests with and without an oral iron dose (ferrous sulfate, 13 mumol/kg) were performed. SETTING: A university setting in Birmingham, AL, USA. SUBJECTS: A total of five healthy adult subjects volunteered. RESULTS: The in vitro incubation of methionine, S-adenosylhomocysteine or cystathionine with chelated iron resulted in the formation of homocysteine. These conversions were iron- and pH-dependent (pH optima between 5.0 and 6.0) and it was also chelator-dependent. In humans, oral methionine loading tests resulted in a 45% increase in the area-under-the-curve for plasma total homocysteine concentrations, when iron was given together with methionine. CONCLUSION: Our data suggest that iron-dependent chemical formation of homocysteine can occur in vivo, and contribute to the plasma total homocysteine pool, since this formation can occur ceaselessly. We hypothesize that plasma total homocysteine concentrations reflect, in part, non-protein-bound iron in the body.     

Consolidation with 90Yttrium‐ibritumomab tiuxetan after bendamustine and rituximab for relapsed follicular lymphoma

Bendamustine and rituximab (BR) are widely used in patients with follicular lymphoma (FL) previously treated with conventional immunochemotherapy, but the role of consolidation radioimmunotherapy in these patients is unknown. This study evaluated the efficacy and safety of consolidation with ⁹⁰Yttrium‐ibritumomab tiuxetan (⁹⁰Y‐IT) after re‐induction therapy with BR in patients with previously treated FL. This study included adult patients with relapsed FL who had undergone one or two prior therapies. Re‐induction therapy with BR was administered every 4 weeks up to 4–6 cycles. If patients achieved at least partial response, ⁹⁰Y‐IT was administered as consolidation therapy. The primary endpoint was 2‐year progression‐free survival (PFS) after consolidation. A total of 24 FL patients (median age 60 years) who had undergone one (n = 17) or two (n = 7) prior treatments received BR. After BR therapy, 22 patients proceeded to consolidation with ⁹⁰Y‐IT, resulting in an overall 88% response rate to the protocol treatment. Within a median observation period of 46.8 months, the estimated 2‐year PFS rate after the consolidation among the 22 patients receiving ⁹⁰Y‐IT was 59% (95% confidence interval [CI], 38%–77%). Patients whose remission after previous treatment had lasted ≥2 years had a significantly higher 2‐year PFS rate than patients whose remission after previous treatment had been <2 years (68% vs. 33%, Wilcoxon p = 0.0211). Major adverse events during the protocol treatment and within 2 years after the consolidation were hematological toxicities, but they were generally acceptable. Consequently, the estimated 2‐year overall survival after the consolidation was 95% (95% CI, 74%–99%). In conclusion, in a subset of patients with previously treated FL, ⁹⁰Y‐IT consolidation after BR re‐induction conferred a durable remission, indicating that consolidation therapy using ⁹⁰Y‐IT may be a novel therapeutic option for patients with relapsed FL (UMIN000008793).     

Heat shock protein 47 confers chemoresistance on pancreatic cancer cells by interacting with calreticulin and IRE1α

Pancreatic ductal adenocarcinoma (PDAC) is one of the most chemoresistant cancers. An understanding of the molecular mechanism by which PDAC cells have a high chemoresistant potential is important for improvement of the poor prognosis of patients with PDAC. Here we show for the first time that disruption of heat shock protein 47 (HSP47) enhances the efficacy of the therapeutic agent gemcitabine for PDAC cells and that the efficacy is suppressed by reconstituting HSP47 expression. HSP47 interacts with calreticulin (CALR) and the unfolded protein response transducer IRE1α in PDAC cells. Ablation of HSP47 promotes both the interaction of CALR with sarcoplasmic/endoplasmic reticulum Ca²⁺-ATPase 2 and interaction of IRE1α with inositol 1,4,5-triphosphate receptor, which generates a condition in which an increase in intracellular Ca²⁺ level is prone to be induced by oxidative stimuli. Disruption of HSP47 enhances NADPH oxidase-induced generation of intracellular reactive oxygen species (ROS) and subsequent increase in intracellular Ca²⁺ level in PDAC cells after treatment with gemcitabine, resulting in the death of PDAC cells by activation of the Ca²⁺/caspases axis. Ablation of HSP47 promotes gemcitabine-induced suppression of tumor growth in PDAC cell-bearing mice. Overall, these results indicated that HSP47 confers chemoresistance on PDAC cells and suggested that disruption of HSP47 may improve the efficacy of chemotherapy for patients with PDAC.     

Tertiary lymphoid structures show infiltration of effective tumor-resident T cells in gastric cancer

Several studies have reported that tissue-resident memory T cells (TRM cells) or tertiary lymphoid structures (TLSs) are associated with a good prognosis. The aim of this study was to clarify the association of TRM cells and TLSs in the tumor immune microenvironment in gastric cancer (GC). We performed immunohistochemical and immunofluorescence staining to detect the presence of CD103⁺ T cells and to assess the association between CD103⁺ T cells and TLSs. CD103⁺ T cells were observed in the tumor epithelium accompanied by CD8⁺ T cells and were associated with a better prognosis in GC. Furthermore, CD103⁺ T cells were located around TLSs, and patients with CD103^high had more rich TLSs. Patients who had both CD103^high cells and who were TLS-rich had a better prognosis than patients with CD103^low cells and who were TLS-poor. Moreover, for patients who received PD-1 blockade therapy, CD103^high and TLS-rich predicted a good response. Flow cytometry was performed to confirm the characteristics of CD103⁺CD8⁺ T cells and showed that CD103⁺CD8⁺ T cells in GC expressed higher levels of PD-1, granzyme B, and interferon-γ than CD103⁻CD8⁺ T cells. Our results suggested that CD103⁺CD8⁺ cells in GC are correlated with TLSs, resulting in enhanced antitumor immunity in GC.     

A phase I study of combined trabectedin and pegylated liposomal doxorubicin therapy for advanced relapsed ovarian cancer

Background

Advanced relapsed ovarian cancer has a poor prognosis, and treatment options are limited.

Methods

This phase I trial investigated the dosage, safety, pharmacokinetics and efficacy of trabectedin plus pegylated liposomal doxorubicin (PLD) in Japanese patients with advanced relapsed ovarian, fallopian tube, or primary peritoneal cancer. Patients received trabectedin 0.9 or 1.1 mg/m² immediately after PLD 30 mg/m²; both drugs were given by intravenous infusion. Treatment was repeated every 21 days until disease progression or unacceptable toxicity. The maximum tolerated dose (MTD) was determined in an initial dose escalation phase, and this was used in a subsequent safety assessment phase. Safety and tumor response were monitored throughout the trial, and drug concentrations for pharmacokinetic analysis were measured during cycle 1.

Results

Eighteen patients were included. The MTD of trabectedin was determined as 1.1 mg/m². Gastrointestinal adverse events were experienced by all patients, but were mostly grade 1 or 2 in intensity. Most patients had grade?≥?3 elevations in transaminase levels or grade?≥?3 reductions in neutrophil count, but these events were generally manageable through dose reduction and/or supportive therapies, as appropriate. There were no deaths during the trial. Trabectedin exposure increased in a dose-dependent manner. The overall response rate was 27.8%.

Conclusions

Trabectedin, in combination with PLD, may have clinical benefits in Japanese patients with relapsed advanced ovarian cancer. The recommended dosage of trabectedin for further study in this population is 1.1 mg/m² once every 21 days.

Clinical trial registration number: JapicCTI-163164