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Extranodal involvement predicts poor outcomes of diffuse large B cell lymphoma (DLBCL), but the impact of the metabolic tumor burden (MTV) of extranodal sites using positron emission tomography has not been clarified. This study aimed to assess the impact of extranodal MTV on overall survival (OS). We retrospectively analyzed 145 newly diagnosed DLBCL patients and verified the prognostic impact of each extranodal and nodal MTV. Multivariate Cox hazards modelling using both extranodal and nodal MTV as covariables identified extranodal MTV as a significant factor for OS (hazard ratio [HR] 1.072, 95% confidence interval [CI] 1.019–1.129, P = 0.008), but not nodal MTV. Multivariate Cox modelling using restricted cubic splines demonstrated that the impact of total MTV depends on the MTV of extranodal sites, not of nodal sites. When both the number and MTV of extranodal involvements were used as covariables, extranodal MTV remained a significant predictor of OS (HR 1.070, 95%CI 1.017–1.127, P = 0.009), but the number of extranodal sites did not. Extranodal MTV potentially had a more significant role on prognosis than nodal MTV. When considering prognostic impacts, the MTV of extranodal involvement is significantly more important than the number.

Hemoglobin vesicles (HbVs), liposomes containing concentrated hemoglobin extracted from outdated human red blood cells (RBC), are artificial oxygen carriers with a small particle size. To evaluate the reperfusion of capillaries with HbVs in a tracheal transplant model and compare it with that of RBC. Isogenic mice were used as donors and recipients in a parallel trachea transplant model. Both ends of the donor trachea were anastomosed end-laterally to the recipient trachea to form in parallel. After transplantation, 0.3 mL of HbV solution (Hb concentration, 10 g/dL) was administered via the tail vein. The recipients were euthanized 1, 4, 6, and 8 h after surgery (n = 5 in each group). The tracheas were harvested, and tracheal subepithelial capillaries (SEC) reperfusion was histologically evaluated. A significant number of particles defined as HbV by electron microscopy were observed in the SEC of the grafted tracheas 4 h after the transplant surgery and HbV administration when no RBC were found in the SECs. The number increased 6 and 8 h later. Our findings suggest that HbVs, which are smaller than RBC, can reperfuse the capillaries of grafts earlier than RBCs after transplantation and contribute to the oxygenation of transplanted tissues.

Highlights • Granulation or cicatrization on the tracheal lumen increases after injury or ischemia caused by tubes or cuffs, results in narrowing of the trachea within a few months after extubation. • We have described a case of tracheal stenosis that manifested 35 years after endotracheal intubation for neonatal resuscitation. • The scar tissue was ablated using argon plasma coagulation, and no recurrence has been observed for more than 3 years. • Delayed postintubation tracheal stenosis should be taken into consideration, when a patient suffers from suffocating tracheal stenosis., Introduction Postintubation tracheal stenosis involves granulation or cicatrization of the tracheal epithelium. It is progressive and can become life-threatening within a few months after extubation. Presentation of case We here report a case of tracheal stenosis with a delayed manifestation, presenting 35 years after endotracheal intubation for neonatal resuscitation. A female patient complained of dyspnea during pregnancy. Bronchoscopy revealed 75% constriction of the tracheal lumen by cicatrization, from the 2nd to 4th tracheal rings. After child-birth, the scar tissue was ablated using argon plasma coagulation. Discussion The patient had no significant medical history, such as severe airway infection or cervical/chest trauma, which might have caused the circumferential cicatricial tracheal stenosis, other than the endotracheal intubation she had undergone for neonatal resuscitation. Therefore, we considered this to reflect postintubation tracheal stenosis with delayed manifestation. Conclusion Delayed postintubation tracheal stenosis should be taken into consideration, when a patient suffers from suffocating tracheal stenosis.

Despite the importance of a prompt diagnosis to improve cancer patients' survival, little has been reported on diagnostic delay in diffuse large B-cell lymphoma (DLBCL). A single-centre, retrospective study was conducted to examine the association between diagnostic wait time (DWT), the interval from the initial hospital visit to diagnosis, and survival in patients with DLBCL. A total of 193 patients were enrolled from 2007 to 2017 in our institution. A covariate-adjusted Cox proportional hazards model with restricted cubic spline was used to evaluate the impact of DWT on survival, with a subgroup analysis according to the International Prognostic Index (IPI). DWT was not associated with survival in the entire DLBCL population, but the impact of DWT on survival differed between IPI < 3 and ≥ 3; prolongation of DWT steadily exacerbated the prognosis in patients with IPI ≥ 3, whereas there was a patient population with IPI < 3 who had a high mortality rate despite rather early diagnosis. The opposite trend in the effect of DWT on survival between patients with IPI < 3 and ≥ 3 offset survival in all DLBCL patients. DWT had no observable impact on outcomes in the entire DLBCL population, but longer DWT worsened the prognosis, particularly in patients with IPI ≥ 3.

Background The management of severe adverse events (AEs) is important in safely and effectively providing chemotherapy to older adults with diffuse large B-cell lymphoma (DLBCL). However, reports on simple and DLBCL-specific predictive models for treatment-related toxicity in elderly individuals are scarce. The aim of this study was to examine the usefulness of Geriatric 8 (G8) in predicting treatment-related severe AEs, nonhematological toxicity, and febrile neutropenia in older adults with DLBCL in real-world practice. Materials and Methods We conducted a multicenter, retrospective study on 398 consecutive patients with DLBCL (aged ≥65 years) who received standard therapy at three centers in Japan (University of Fukui Hospital, the Fukui Prefectural Hospital, and the Japanese Red Cross Fukui Hospital), between 2007 and 2017. Result Multivariate logistic analysis demonstrated that the G8 score was an independent predictive factor for severe AEs. Moreover, a logistic regression model with restricted cubic spline showed a nonlinear association between the incidence of severe AEs and the G8 score. According to receiver operating characteristic analysis, the most discriminative cutoff value of the G8 for the incidence of severe AEs was 11, with an area under the curve value of 0.670. AEs occurred most often in the first course of chemotherapy and decreased as the course progressed. Conclusion The G8 score, an easy-to-use geriatric assessment tool, can be a useful prediction model of treatment-related severe AEs during standard therapy in older adults with DLBCL. Implications for Practice In older patients with diffuse large B-cell lymphoma (DLBCL), to accurately predict the risk of severe adverse events (AEs) in advance is essential for safe and effective treatment. This study demonstrated that the Geriatric 8 score, a simple and established geriatric assessment tool, indicated a high predictive ability for occurrence of therapy-related severe AEs in elderly patients with DLBCL who were treated with standard treatment.

Background Pralatrexate (PDX) is a novel antifolate approved for the treatment of patients with relapsed/refractory peripheral T-cell lymphoma, but some patients exhibit intrinsic resistance or develop acquired resistance. Here, we evaluated the mechanisms underlying acquired resistance to PDX and explored potential therapeutic strategies to overcome PDX resistance. Methods To investigate PDX resistance, we established two PDX-resistant T-lymphoblastic leukemia cell lines (CEM and MOLT4) through continuous exposure to increasing doses of PDX. The resistance mechanisms were evaluated by measuring PDX uptake, apoptosis induction and folate metabolism-related protein expression. We also applied gene expression analysis and methylation profiling to identify the mechanisms of resistance. We then explored rational drug combinations using a spheroid (3D)-culture assay. Results Compared with their parental cells, PDX-resistant cells exhibited a 30-fold increase in half-maximal inhibitory concentration values. Induction of apoptosis by PDX was significantly decreased in both PDX-resistant cell lines. Intracellular uptake of [14C]-PDX decreased in PDX-resistant CEM cells but not in PDX-resistant MOLT4 cells. There was no significant change in expression of dihydrofolate reductase (DHFR) or folylpolyglutamate synthetase (FPGS). Gene expression array analysis revealed that DNA-methyltransferase 3β (DNMT3B) expression was significantly elevated in both cell lines. Gene set enrichment analysis revealed that adipogenesis and mTORC1 signaling pathways were commonly upregulated in both resistant cell lines. Moreover, CpG island hypermethylation was observed in both PDX resistant cells lines. In the 3D-culture assay, decitabine (DAC) plus PDX showed synergistic effects in PDX-resistant cell lines compared with parental lines. Conclusions The resistance mechanisms of PDX were associated with reduced cellular uptake of PDX and/or overexpression of DNMT3B. Epigenetic alterations were also considered to play a role in the resistance mechanism. The combination of DAC and PDX exhibited synergistic activity, and thus, this approach might improve the clinical efficacy of PDX.

Reflecting the increasing risk in elderly patients with diffuse large B cell lymphoma (DLBCL), prognostic predictors other than the International Prognostic Index have attracted more attention. This study presents the first analysis of the prognostic utility of the Geriatric Nutritional Risk Index (GNRI) in combination with the Charlson Comorbidity Index (CCI) for overall survival (OS) in elderly DLBCL patients. A multicentre retrospective was conducted on a cohort of 451 patients (≥65 years). The GNRI and CCI were independent predictors in a multivariate Cox proportional hazard model. There was a nonlinear correlation between the GNRI and OS in a Cox model with restricted cubic spline. Multivariate receiver operating characteristic curves showed a significant improvement in prediction accuracy when the GNRI was added to CCI. Adding the GNRI to CCI yielded a significant category-free net reclassification improvement (0·556; 95% CI: 0·378-0·736, P < 0·001) and integrated discrimination improvement (0·094; 95% CI: 0·067-0·122, P < 0·001). The decision curve analysis demonstrated the clinical net benefit associated with the adoption of the GNRI. The GNRI was not only a predictor of OS but also remarkably improved the prognosis prediction accuracy when incorporated with the CCI, having the ability to stratify the prognosis of elderly DLBCL patients.

We reported a surgical case of methotrexate-associated lymphomatoid granuloma. A 69-year-old female had been treated with methotrexate for rheumatoid arthritis for 35 months. The patient underwent partial resection of the right upper pulmonary lobe for lung cancer when she was 67 years old. A nodule was detected in the left lung field on a chest radiograph performed during the postoperative follow-up period. Computed tomography revealed a 28-mm nodule in the lower left pulmonary lobe. A transbronchial biopsy examination did not lead to a diagnosis. The pulmonary nodule subsequently increased in size. We suspected a malignant tumor and performed lower left lobectomy. A pathological examination revealed lymphomatoid granuloma. Finally, the patient was diagnosed with methotrexate-associated lymphomatoid granuloma based on her history of oral methotrexate treatment.

BackgroundHaemoglobin vesicles (HbVs) are red blood cell (RBC) substitutes with a phospholipid bilayer membrane and a polyethylene modified surface (diameter=250 nm; P50=28 Torr). They can be preserved for years and can be used in patients of all blood types without the risk of infection. Their oxygen affinity can be modified by changing the allosteric effectors.MethodsLeft pneumonectomy was performed under mechanical ventilation on rats, followed by rapid exsanguination of ~30% of the total circulating blood volume. Rat RBCs shed in 5% human serum albumin (HSA) solution (rat RBC), HbV with high oxygen affinity in 5% albumin solution (low-P50 HbV, P50=9 Torr), normal HbV suspended in 5% albumin (HbV, P50=28 Torr) or 5% HSA was infused for resuscitation. Haemodynamics and oxygenation were evaluated.ResultsSystemic arterial blood pressure significantly decreased after exsanguination and increased after each infusion. In the HbV, low-P50 HbV and rat RBC groups, all rats were liberated from mechanical ventilation and blood pressure was stabilised, whereas 50% of the rats in the HSA group died within 1 hour after weaning from mechanical ventilation. The PaO2 in arterial blood for 1 hour after liberation from mechanical ventilation in the rat RBC, HbV and low-P50 HbV groups was 59.4±12.5, 58.3±10.1 and 70.5±14.5 mm Hg, respectively. The PaO2 in the low-P50 HbV group was significantly higher than those in the rat RBC and HbV groups (p=0.05 for both). Serum lactate elevations due to hypoxic damage were minimised by HbV, low-P50 HbV as well as rat RBCs.ConclusionsThe oxygen-carrying ability of HbV was comparable to that of rat RBCs, even under impaired lung function after pneumonectomy. HbVs with high oxygen affinity may have more beneficial effects on oxygenation in pulmonary resection.

Chemotherapy-induced nausea and vomiting(CINV)were prospectively evaluated using MASCC Antiemesis Tool(MAT) in patients with hematological malignancies in our institution. A total of 33 patients receiving 46 chemotherapy courses were evaluated. Although vomiting was not observed in the acute phase, nausea was seen in 22.6% and 32.3% of the patients in the acute and delayed phases, respectively. Thirty percent(25 cases)of the patients receiving highly emetogenic chemotherapy presented nausea in both the phases, while 40%(18 cases)of the patients receiving moderately emetogenic chemotherapy presented nausea in the delayed phase. The oral intake was quantitated retrospectively in 31 patients with non- Hodgkin's lymphoma, who were hospitalized and received CHOP±R. Prior to the initiation of the chemotherapy, 13 patients received the first generation 5-HT3 receptor antagonist granisetron, while 18 patients received the second generation palonosetron. Oral intake was greater in the patients who were administered palonosetron. Thus, the present study suggested that antiemetic treatment could be improved at our institution.

A 68-year-old male patient, who was diagnosed with MGUS (IgG-λ) 11 years ago, was referred to our hospital because of a progressing pancytopenia. He was diagnosed with multiple myeloma (MM) and was hospitalized because of fever and pneumonia. Although empiric antibiotic and antifungal therapies were promptly initiated, his pneumonia worsened. Chest CT images revealed diffuse interstitial pneumonia. Although bortezomib/dexamethasone therapy was initiated as a treatment for MM and pneumonia, he showed little response. His pneumonia worsened and progressed to acute respiratory distress syndrome. Using mPSL (500 mg/day), sivelestat, and MM treatment switching to lenalidomide/dexamethasone (Rd), his respiratory status and CT findings rapidly improved. He received Rd therapy as an outpatient; however, after the completion of six cycles of therapy, his MM progressed, with a recurrence of pneumonia and high fever again. The onset of pneumonia was closely associated with MM progression. His pneumonia improved by treatment with mPSL half-pulse and MM treatment switching to carfilzomib/Rd. In the present study, we report the case of a patient with myeloma, who presented with multiple interstitial pneumonia, resulting in respiratory failure twice in concordance with myeloma progression.

Ischemia-reperfusion injury resulting in post-transplant lung dysfunction involves a complicated network of cytokines that has yet to be fully investigated. We analyzed temporal changes in cytokine levels in epithelial lining fluid (ELF) from the distal airways of a canine lung transplantation model.Ischemic time was set to 18 hours to enhance lung injury in a left single-lung transplantation model. ELF was collected via bronchoscopic microsampling, a minimally-invasive technique allowing repeated sampling, hourly up to 5 hours after reperfusion started. We compared levels of pro-inflammatory cytokines in ELF with those at baseline (time zero), and with a sham-operated control group.Concentrations of tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6) significantly increased immediately after the start of lung reperfusion in the transplant group relative to the sham group (P0.005 and P0.05, respectively); both were sustained through the 5 hours. Interferon gamma (IFN-γ levels were significantly reduced 3 h after reperfusion started (P0.05).We found time- and cytokine-dependent changes in TNF-α, IL-6, and IFN-γ in ELF from the lung transplantation model. These specific changes in the cytokine profile may relate to the mechanism underlying post-transplant lung dysfunction.

Objective We retrospectively compared the clinical efficacy and toxicity of rituximab (R)-THP-COP (pirarubicin, cyclophosphamide, vincristine, and prednisolone) with that of R-CHOP (rituximab, adriamicin, cyclophosphamide, vincristine, and prednisolone) in previously untreated old patients with diffuse large B-cell lymphoma (DLBCL). Patients and Methods Patients admitted to our institution between 2004 and 2013 were examined. The patients received either R (375 mg/m2, day 1)-THP-COP (pirarubicin 50 mg/m2 day 1, cyclophosphamide 750 mg/m2 day 1, vincristine 1.4 mg/m2 day 1, and prednisolone 100 mg day 1-5) or R-CHOP (adriamicin 50 mg/m2 day 1, cyclophosphamide 750 mg/m2 day 1, vincristine 1.4 mg/m2 day 1, and prednisolone 100 mg day 1-5). The doses of chemotherapeutic agents were adjusted depending on the patient's age and associated complications. The treatment was performed for 6 to 8 cycles. Results Among 74 patients with DLBCL (median 76, range 65-90 years; male 39, female 35), 29 received R-THP-COP, while 45 received R-CHOP. The overall response rates were 94.6% (complete response 86.4%, partial response 8.1%). The 2-year overall and progression-free survival rates were 77.6% and 68.5% for the R-THP-COP regimen and 79.2% and 78.9% for R-CHOP, respectively. No significant differences were found between these two regimens regarding the clinical efficacies. The most frequent adverse event was neutropenia (72.4% for the R-THP-COP regimen, 88.9% for the R-CHOP regimen). The cardiac function as evaluated by ejection fraction values was not impaired in either regimen. Conclusion R-THP-COP was effective and safe as an alternative to R-CHOP.

A 14-year-old girl presented with progressively worsening intermittent orthopnea. Imaging studies showed cardiomegaly, extensive pericardial effusion, and a mediastinal tumor. By pericardial drainage, approximately 8,000-mL fluid was collected over 10 days. Left thoracoscopic pericardial fenestration and mediastinal tumor biopsy were performed, revealing lymphangiomatosis. Chylous pleural effusion developed post-surgery. Although control was attempted, her condition worsened. Eight months later, she died of sudden cardiopulmonary arrest. Autopsy revealed systemic spread of the primary lesion from the hyperplastic lymph ducts to the parietal pleura and mediastinum confirming systemic lymphangiomatosis.

Background Diffuse large B-cell lymphoma (DLBCL) is the most common type of NHL featured by rapid progression. Given its rapid progression, prompt diagnosis and treatment are essential for achieving long-term survival in DLBCL. In solid cancers, it is known that prolonging diagnostic wait time (DWT), interval from diagnosis to initiation of treatment, could result in stage progression and a worse survival. In DLBCL patients, a prolonged DWT is also expected to be associated with a worse survival, however, little is known about this issue. The purpose of this investigation was to verify the impact of DWT on survival in DLBCL patients using a Cox hazards model with restricted cubic spline (RCS) because this model was more suitable to reflect real-world clinical practice than the linear model. It has been reported a possible association between the International Prognostic Index (IPI) and prognosis, hence the Cox hazards model with RCS was used to examine the differential effects of IPI on survival in association with DWT. Methods We conducted a single center, retrospective study of all consecutive patients seen from 2007 to 2017 at our Hospital. The inclusion criteria were newly diagnosed de novo DLBCL, aged 18 years and older, and treated with standard therapies. We define the standard regimens as R-CHOP [rituximab (RTX), cyclophosphamide (CPA), adriamycin, vincristine (VCR), and prednisolone (PSL)] and R-THP-COP (RTX, CPA, tetrahydropyranyl adriamycin, VCR, and PSL). The primary outcome was overall survival (OS). Exclusion criteria were central nerve system involvement, transformed DLBCL, and receiving non-standard therapies. Furthermore, the subgroup analysis according to IPI was performed. Results Among 179 patients, the median age was 72 (27 - 91) years, the median DWT was 39.5 (0 - 223) days and 53.9% patients had IPI ≥3, the median follow-up time was 29.2 (0.03 - 137.6) months, and 59 (31.3%) patients died during the follow-up period. A multivariate Cox proportional hazards model for OS showed DWT was not associated with worse OS in the entire study population. However, the Cox hazards model with RCS in the all study population revealed that there was nearly U-shaped association between DWT and OS. The Cox hazards model with RCS for each group depending on IPI score (0-5) showed the effect between DWT and OS differed by IPI. The mortality risk increased proportionally as DWT was prolonged in three groups with IPI 3 to 5, but rather negative correlations were seen between in three groups with IPI 0 to 2. Opposite tendencies between IPI ≥3 and Discussion These results demonstrated that the impact of DWT on OS differed depending on the IPI, while DWT did not affect OS of the entire DLBCL patients. DWT steadily increased the risk of mortality in IPI ≥3 group. On the other hand, in IPI 3 at the initial visit should be expedited the diagnosis if there was suspicious of DLBCL, because DWT is a critical predictor determining prognosis in such patients. Moreover, in suspected DLBCL cases, computed tomography, positron emission tomography contributing to identify the IPI, and bone marrow biopsy might be needed immediately when the definitive IPI is uncertain at the initial visit. Conclusions In conclusion, DWT did not associate with survival of entire DLBCL patients who treated with standard therapies, but the impact of DWT on survival differed depending on IPI. Especially in patients with IPI ≥3 at the diagnosis, steadily increased mortality risk was observed. Disclosures Yamauchi: Astellas, AbbVie: Consultancy; Pfizer, Chugai, Teijin, Solasia: Research Funding.

IntroductionPercutaneous cryoablation has been adopted for small, malignant peripheral pulmonary lesions and has yielded favourable results as a less invasive local treatment. A transbronchial approach may reduce the risks of complications, such as pneumothorax and pleural haemorrhage. A fundamental animal experiment on transbronchial cryoablation was performed to examine its immediate safety and effectiveness.MethodsExperimental cryoablation was performed on swine lungs using a rigid cryoprobe, 2.4 mm in diameter. The probe was introduced from the right main bronchus into the distal bronchus via thoracotomy, perforated the end of the conducting bronchus and reached the lung parenchyma. The temperature of the cryoprobe tip reaches approximately −130°C during freezing and approximately 20°C during thawing. After three freeze-thaw cycles, the cryoprobe was removed.ResultsNo significant haemorrhage was bronchoscopically observed in the airways throughout the experiment. The chronological changes and spatial distribution of the temperature of the pulmonary tissue circumferential to the point of the cryoprobe were similar to those seen with transpleural cryoablation and the less than −20°C thermal zone seemed to be established within a radius of at least 12 mm. The central destruction zone of alveolar structures was histologically similar to the thermal zone, while the conducting bronchus structure and the accompanying pulmonary artery were not severely affected.ConclusionExperimental transbronchial cryoablation with a rigid cryoprobe could effectively freeze and destroy peripheral lung alveoli without any significant immediate adverse effects. This may suggest the potential clinical application of transbronchial cryoablation for peripheral malignant lung lesions.

Background/Aim: Tumor lysis syndrome (TLS) is a life-threatening complication associated with cancer chemotherapy. We retrospectively evaluated the risk of developing TLS in patients with symptomatic multiple myeloma undergoing chemotherapy. Patients and Methods: Sixty-four patients (median age=71 years, range=48-87 years, 35 males/29 females) who were treated at our Institution between April 2006 and December 2015 were evaluated. Results: A total of 124 chemotherapy courses were administered, of which 63 courses were bortezomib-based regimens and 34 courses were immunomodulatory drug (IMiD)-based regimens. TLS occurred in 13 (10.5%) out of 124 chemotherapy courses with five (4.0%) cases of laboratory TLS and eight (6.5%) cases of clinical TLS. The incidences of TLS were 17.5% for bortezomib-containing regimens and 3.2% for non-bortezomib-based regimens. No TLS occurred in the patients treated with IMiD-containing regimens. TLS occurred more frequently in the patients with elevated uric acid, creatinine, or beta-2-microglobulin levels at baseline. The patients with disease classified as advanced International Staging System also developed TLS more frequently. All the patients who developed clinical TLS received bortezomib-containing regimens (8/63, 12.7%). Among them, patients with elevated values of uric acid or creatinine developed clinical TLS more often than those without such elevation. The incidence of clinical TLS was 33.3% if the patients had renal dysfunction at baseline and were subsequently treated with bortezomib-based regimens (8/24 cases). Conclusion: Patients with renal dysfunction or a high uric acid level receiving bortezomib-based chemotherapy have a high risk of developing TLS.

As a less invasive alternative to bronchoalveolar lavage (BAL), bronchoscopic microsampling (BMS) was developed to identify molecules present in the epithelial lining fluid (ELF) of the distal airways. Here, we evaluated the utility of BMS for serial collection of ELF in a canine lung transplant model.ELF was collected hourly by BMS up to 5 hours after reperfusion in a canine left lung transplant model. Tumor necrosis factor (TNF)-α levels in ELF were measured using an enzyme-linked immunosorbent assay and were compared with those in BAL fluid.Serial collection of ELF by BMS in graft lungs was possible without adverse effects. However, the partial pressure of oxygen was markedly decreased because of ischemia-reperfusion lung injury. Probe ELF absorption ranged from 1-18 µL. TNF-α expression was significantly elevated and detected for 5 hours after reperfusion, whereas it was very low in the sham-operated group (p0.05). TNF-α concentration in BAL fluid was less than one-hundredth of that in ELF.BMS was safe and effective for serial ELF collection in grafted lungs. Temporal changes in TNF-α corresponded with ischemia-reperfusion lung injury. This is the first study to adopt BMS to elucidate pulmonary function after lung transplantation.

Localized malignant pleural mesothelioma (LMPM) is a rare tumor; previously only 52 cases have been reported in the English literature. This type of tumor should be distinguished from diffuse malignant pleural mesothelioma, because a good outcome may be obtained by surgical resection. We report a case of LMPM which grew rapidly within 1 year. Surgical resection was performed, and at present, 6 months since the operation, the patient remains free of the disease.

症例は57歳男性．健診で胸部異常陰影を指摘された．胸部CTにて右第5肋骨後方に骨皮質を外側へ圧排する55×18 mmの腫瘤を認め，骨シンチでは99mTc-HMDPの異常集積を認めなかったが，PET-CTではSUV max 58.0の18F-FDG集積がみられた．他部位には異常集積は認めなかった．肋骨悪性腫瘍の可能性を否定できず，右第5肋骨切除術を施行した．病理組織学的に形質細胞腫との診断であった．多発性骨髄腫を否定するために術後腸骨より骨髄穿刺を施行するも異常所見は認めず，最終的に肋骨原発の孤立性形質細胞腫と診断された．追加治療は施行せず，術後32ヵ月経過した現在，無再発生存中である．肋骨に原発した孤立性形質細胞腫は稀な疾患であり，報告する．

Background Pralatrexate (PDX) is a novel dihydrofolate reductase (DHFR) inhibitor which is designed to have a high affinity for reduced folate carrier (RFC1), DHFR, and folylpolyglutamate synthetase (FPGS), resulting in greater internalization and accumulation in tumor cells than methotrexate. PDX has been approved by the U.S. FDA and many international health care ministries for the treatment of relapsed and refractory peripheral T-cell lymphoma (R/R PTCL). A recent case match control analysis has confirmed a survival advantage for patients enrolled on PROPEL compared to a well-matched population of patients receiving standard of care. Recently, PDX has demonstrated compelling activity in combination with romidepsin in R/R PTCL patients, where is role is likely to expand. In this study we explored the mechanisms of resistance to PDX and approaches to overcome them, including combination strategies using PDX-resistant (PDX-R) leukemic cell lines. Methods T-lymphoblastic leukemia cell lines, CCRF-CEM (CEM), MOLT-4 (MOLT4), and MOLT-3 (MOLT3), were used. To establish PDX-R cell lines, the cells were initially incubated with low-concentrations of PDX, and then concentrations of the drug were gradually increased. After acquisition of PDX-R, the single-cell separation was performed by a limiting dilution. Microarray analysis was performed in CEM, MOLT4 and each PDX-R counterpart. Results The 50% inhibitory concentration (IC50) values of PDX against CEM, MOLT4 and MOLT3 were 0.6 nM, 2.4 nM and 1.4 nM, respectively, while the PDX-R cell lines exhibited IC50 values of 20 nM, 80 nM and 40 nM, respectively. After 48-hour treatment with PDX, annexin-V positivity was significantly reduced in PDX-R cells (in CEM, MOLT4 and MOLT3 was 78.7%, 77.7%, 97.4% vs 4.4%, 5.9%, 6.6%, respectively). The expression of RFC1 was not altered in PDX-R cells, nor was any acquired mutation of RFC1 detected in cell lines. Intracellular uptake of [14C]-PDX was modestly decreased in CEM/PDX-R, while there was no difference of it in MOLT4/PDX-R, suggesting that the resistance mechanism was not due to the inability to internalize drug. Gene expression array revealed that the expression of DNA-methyltransferase 3 beta (DNMT3b) was significantly elevated in both CEM/PDX-R (12.8 times) and MOLT4/PDX-R (2.8 times) cells, whereas there was no significant difference in that of DHFR, FPGS and thymidylate synthase. When we explored the profile of cross-resistances in PDX-R cells, it was surprising that PDX-R cells were more sensitive to nucleoside analogs, including cytarabine (AraC) and forodesine (FDS). After 72 hours of FDS-treatment, induction of apoptosis was seen in both parental and PDX-R cells, suggesting that the mechanisms of PDX-R is not cross resistant. In addition, there was no cross-resistance to bortezomib or panobinostat in PDX-R cell lines. Discussion We established PDX-R cell lines which were around 30-fold resistant to PDX compared to their parental counterparts. The characteristics of PDX-R cells are as follows: (i) intact internalization of PDX, (ii) intact apoptotic mechanisms, (iii) no cross-resistance to BOR or LBH, (iv) collateral sensitive to nucleoside analogs, such as AraC and FDS. These data suggest that the mechanism of acquired resistance to PDX may be associate with not only cellular uptake of PDX, but also DNA methylation and/or nucleic-acid metabolism. These findings may be underscored by the fact that nucleoside analogs exhibited greater potency in the PDX-R cells in vitro. Next steps are focused on exploring the methylation status of these genes involved in PDX activity, and their merits of combining with hypomethylating agents. Conclusions We established PDX-R T-lymphoblastic leukemia cell lines which show collateral sensitivity to nucleoside analogs. The mechanisms of PDX resistance is not always cellular uptake of PDX, epigenetic alteration might contribute to the development PDX-resistance. Nevertheless, the new T-lymphoma-targeting agent, FDS can be effective in this setting. Our results may encourage further investigation to overcome resistance of PDX for patients with R/R PTCL. Disclosures O'Connor: ADC Therapeutics: Research Funding; Seattle Genetics: Research Funding; Celgene: Research Funding.

Disseminated intravascular coagulation (DIC) is a life-threatening condition that frequently occurs in patients with hematologic malignancies. Currently, recombinant human soluble thrombomodulin (rTM) is a therapeutic DIC drug that is manufactured and sold in Japan only. We evaluated the efficacy of rTM compared to that of gabexate mesilate (GM), which was previously used routinely for treating DIC in Japan, in patients with acute myeloid leukemia (AML). This retrospective study enrolled 43 AML patients, including 17 with acute promyelocytic leukemia (APL), that was complicated with DIC. DIC resolution rates in non-APL AML and rTM-treated APL patients were 68.4% and 81.8%, respectively. In non-APL AML patients, the duration of rTM administration was significantly shorter than that of GM (7 vs 11 days), suggesting that rTM could improve DIC earlier than GM, although rTM was used in patients with more severe DIC. Moreover, treatment with rTM significantly improved DIC score, fibrinogen, fibrin/fibrinogen degradation product (FDP), and prothrombin time (PT) ratio. Conversely, treatment with GM only improved the DIC score and FDP. In APL patients, the duration of rTM administration was also significantly shorter than that of GM. No severe side effects associated with the progression of bleeding were observed during rTM administration. These findings suggest that rTM is safe, and its anti-DIC effects are more prompt than GM for treating AML patients with DIC.

Sternal segment dislocation is rare in children, with only eight cases appearing in the literature. Four of the six reports recommended surgical treatment such as excision or open reduction and fixation [1-4], while the remaining two reports recommended conservative observation. Therefore, it remains unclear whether surgical treatment is necessary. We report a case of sternal segment dislocation in a child. Although the segment had rotated 90°, it was remodeled. We now believe that surgical treatment is not necessary for this condition.

我々は1994年より胸部外傷に対して積極的に胸腔鏡下手術を行ってきた．2005年6月まで34件の胸部外傷に対し胸腔鏡下手術を行った．年令は6から90歳（平均40.7歳），受傷原因は刺創21例，交通外傷11例，転落外傷2例であった．34例中2例は出血コントロール不良のため，標準開胸に切りかえた．胸腔鏡下手術を完遂できた32例の術式は，部分切除14例，止血7例，肺縫合もしくは修復術5例，審査胸腔鏡5例，気管支縫合術1例であった．鈍的外傷では（1）横隔膜破裂，血管損傷に対する審査胸腔鏡（2）持続する胸腔内気瘻（3）6時間で500ml以上の血胸，鋭的外傷では（1）刺創（2）汚染に対する胸腔洗浄，を手術適応とした．胸部外傷に対する手術療法はあくまで緊急開胸手術が主体であるが，その中に胸腔鏡下手術でも充分対応できる症例は存在する．