Successful treatment of paraneoplastic pemphigus and bronchiolitis obliterans associated with follicular lymphoma with obinutuzumab and bendamustine.

We herein report the rare case of a 72-year-old female who presented with paraneoplastic pemphigus (PNP) and bronchiolitis obliterans (BO) associated with follicular lymphoma (FL), who was successfully treated with obinutuzumab (GA101; G) and bendamustine (B). The patient had severe erosive stomatitis and bilateral conjunctival hyperemia that persisted for more than 6 months. A huge mass was found in the abdominal cavity, and a biopsy revealed grade 1 FL (stage IV). Based on a lip biopsy result, the patient was diagnosed with PNP associated FL. The patient received bendamustine and obinutuzumab (BG) chemotherapy and FL and PNP responded very well, but BO was additionally associated during the course of BG. BO progressed without exacerbation as BG therapy progressed to a 2 year maintenance therapy with G, and combination of azithromycin, inhaled bronchodilator therapy, and corticosteroid. She was followed up at the outpatient department with no pulmonary function decline or FL and PNP recurrence. Our case suggests that BG could be a promising treatment option for PNP and BO.

Anti-VEGF Antibody Protects against Alveolar Exudate Leakage Caused by Vascular Hyperpermeability, Resulting in Mitigation of Pneumonitis Induced by Immunotherapy.

Immune-related pneumonitis is an important toxicity associated with checkpoint inhibitor therapy with anti-PD-1 or anti-PD-L1 antibodies, often necessitating discontinuation of treatment. Development of methods to mitigate checkpoint inhibitor-related pneumonitis is required.The contributions of PD-L1, PD-L2, and VEGF to the pathogenesis of pneumonitis were examined in an IL2- plus IL18-induced mouse pneumonitis model (IL pneumonitis model). Furthermore, the incidences of pneumonitis were retrospectively examined in patients with non-small cell lung cancer treated with the anti-PD-L1 mAb atezolizumab plus chemotherapy, with or without the anti-VEGF mAb bevacizumab, in the phase III IMpower150 trial. PD-1 signal blockade by anti-PD-L1 and anti-PD-L2 antibodies aggravated pneumonitis in the IL pneumonitis model. An anti-VEGF antibody prevented PD-1 signal blockade from aggravating pneumonitis in this model. PD-1 signal blockade induced interstitial T-cell infiltration in the lungs, but VEGF blockade did not affect this T-cell infiltration. The anti-VEGF antibody protected against vascular-to-alveolar leakage of protein and fluid due to PD-1 signal blockade in a murine model. In the IMpower150 trial, incidence rates of pneumonitis of any grade were 4.3% in the group without bevacizumab and 2.8% in the group with bevacizumab. In patients with pneumonitis, outcomes of "Not recovered/Not resolved" were reported for 29.4% in the group without bevacizumab compared with 9.1% in the group with bevacizumab. Our findings suggest that anti-VEGF antibodies in combination with checkpoint inhibitors may be a treatment method that can control checkpoint inhibitor-related pneumonitis.

[B-cell acute lymphoblastic leukemia with glycophorin A expression].

This study reports a case of a 49-year-old woman having B-cell acute lymphoblastic leukemia with glycophorin A, a representative erythroid marker, expression. According to the WHO criteria for mixed phenotype acute leukemia (MPAL), erythroid lineage is not defined, and to the best of our knowledge, only one other case with erythroid/B-cell biphenotypic acute leukemia has been reported previously. To establish the disease entity and clarify the pathophysiology of erythroid/lymphoid MPAL, additional cases need to be analyzed.

Both T cell priming in lymph node and CXCR3-dependent migration are the key events for predicting the response of atezolizumab.

Anti-PD-L1 antibodies benefit many cancer patients, even those with "non-inflamed tumor". Determining which patients will benefit remains an important clinical goal. In a non-inflamed tumor mouse model, we found that PD-L1 was highly expressed on antigen-presenting cells (APCs) especially on CD103+ CD11c+ dendritic cells in tumor-draining lymph nodes (dLNs), suppressing T-cell priming by APCs. In this model, anti-PD-L1 antibodies enhanced T-cell priming and increased CXCR3+ activated T-cells in dLNs, which was followed by the trafficking of T-cells to tumors in response to CXCR3 ligands. As predictive biomarker, each APCs-related gene expression (AP score) alone or T-cells trafficking-related chemokine gene expression (T score) alone were still less than perfect among the 17 mouse models examined. However a combining score of AP score and T score (AP/T score) precisely identified anti-PD-L1-sensitive tumors. In the phase 3 trial of atezolizumab vs docetaxel in advanced NSCLC patients (OAK), the AP/T score could identify atezolizumab-treated NSCLC patients who achieved significant improvement in overall survival. This biomarker concept would be a clinically valuable for prediction of anti-PD-L1 antibody efficacy.

Retraction Note to: High-dose therapy and autologous stem cell transplantation for relapsed or high-risk diffuse large B-cell lymphoma: a nationwide survey.

This article has been retracted. Please see the Retraction Notice for more detail: https://doi.org/10.1007/s12185-020-03018-1.

Gastric lymphoma complicated by phlegmonous gastritis and Guillain-Barré syndrome: A case report.

INTRODUCTION: Complications such as severe infection may occur during the chemotherapy of malignant lymphoma. Phlegmonous gastritis (PG) is a rare acute bacterial infection associated with high mortality, requiring early diagnosis, and prompt management. In addition, Guillain-Barré syndrome (GBS) occasionally requires early treatment and intensive care management due to the occurrence of severe neuropathy and respiratory failure. PATIENT CONCERNS: A 70-year-old male was diagnosed with primary gastric diffuse large B-cell lymphoma (DLBCL) after the detection of several polypoid tumors with ulcers. The patient underwent chemotherapy for DLBCL and exhibited adverse effects (i.e., fever, vomiting, epigastric pain, and neutropenia). Computed tomography indicated widespread thickening in the gastric wall. Furthermore, approximately 2 weeks later, the patient presented with gradual symmetric lower extremity weakness and respiratory failure due to paralysis of the respiratory muscle. DIAGNOSES: DLBCL was diagnosed through a gastric tumor biopsy. On the basis of the computed tomography findings, a culture of gastric juice, nerve conduction studies, and clinical symptoms, this case of gastric lymphoma was complicated with PG and GBS. INTERVENTIONS: The patient was treated with antimicrobial therapy and administration of granulocyte colony-stimulating factor for PG, and with intravenous immunoglobulin and intensive care management for GBS. OUTCOMES: Despite the aggressive progress of the condition, the patient improved without relapse of DLBCL. CONCLUSION: PG was regarded as a precedent infection of GBS. In this article, we present the first reported case of gastric lymphoma complicated with PG and GBS.

Recurrent intragenic exon rearrangements of SOBP and AUTS2 in non-Hodgkin B-cell lymphoma.

Expression of intragenic exon rearrangements (IERs) has reportedly been detected in both normal and cancer cells. However, there have been few reports of occurrence of these rearrangements specific to neoplasms including malignant lymphoma. In this study, we detected IERs of ten genes (NBPF8, SOBP, AUTS2, RAB21, SPATA13, ABCC4, WDR7, PHLPP1, NFATC1 and MAGED1) in non-Hodgkin B cell lymphoma (B-NHL) cell line KPUM-UH1 using a high-resolution single nucleotide polymorphism array and reverse transcription polymerase chain reaction using reversely directed divergent primers within exons involved in genomic intragenic gains followed by sequencing analysis. Among them, the IERs involved in SOBP (6q21) exon 2 and 3 and AUTS2 (7q11.22) exon 2-4 were the molecular lesions specific to tumors and were frequently detected in B-NHL samples. These IERs constitute novel genetic alterations of B-NHL, which might be associated with tumorigenesis and be useful as genetic biological markers.

High-dose therapy and autologous stem cell transplantation for relapsed or high-risk diffuse large B-cell lymphoma: a nationwide survey.

To investigate the use of high-dose therapy and autologous stem cell transplantation (ASCT) for relapsed or high-risk diffuse large B-cell lymphoma (DLBCL) between 1990 and 2007, we conducted a nationwide survey using the registry database of the Japan Society for Hematopoietic Cell Transplantation. Of the 1222 patients in the database, 576 (47%) received ASCT in first complete remission (CR1), 140 (12%) in first partial remission, 281 (23%) in sensitive relapse, 150 (12%) in resistant or sensitivity-unknown relapse, and 75 (6%) in primary refractory status. With a median follow-up of 22 months, the 2-year overall survival (OS) and progression-free survival rates were 71% and 68%, respectively. The cumulative incidences of 2-year non-relapse mortality and relapse/progression were 6% and 26%, respectively. Relapse/progression after ASCT in the rituximab era (2002-2007) was significantly lower than that in the pre-rituximab era (1990-2001; P < 0.001). Older age, male gender, poor performance status at ASCT, non-CR1 at ASCT, ASCT performed in 1990-2001, and LEED or MCEC regimen were adverse predictors of OS. Because ASCT for newly diagnosed high-risk DLBCL has not been performed recently, a registry database study to assess the impact of ASCT for relapsed or refractory DLBCL in the rituximab era is warranted.

T2 ∗ Relaxation Time Obtained from Magnetic Resonance Imaging of the Liver Is a Useful Parameter for Use in the Construction of a Murine Model of Iron Overload.

Aim: Iron overload is a life-threatening disorder that can increase the risks of cancer, cardiovascular disease, and liver cirrhosis. There is also a risk of iron overload in patients with chronic kidney disease. In patients with renal failure, iron storage is increased due to inadequate iron utilization associated with decreased erythropoiesis and also to the inflammatory status. To evade the risk of iron overload, an accurate and versatile indicator of body iron storage in patients with iron overload is needed. In this study, we aimed to find useful iron-related parameters that could accurately reflect body iron storage in mice in order to construct a murine model of iron overload. Methods: To select an appropriate indicator of body iron status, a variety of parameters involved in iron metabolism were evaluated. Noninvasively measured parameters were R1, R2, and R2 ∗ derived from magnetic resonance imaging (MRI). Invasively measured parameters included serum hepcidin levels, serum ferritin levels, and liver iron contents. Histopathological analysis was also conducted. Results/Conclusion: Among the several parameters evaluated, the MRI T2 ∗ relaxation time was able to detect iron storage in the liver as sensitively as serum ferritin levels. Moreover, it is expected that using an MRI parameter will allow accurate evaluation of body iron storage in mice over time.

Prediction of delayed platelet engraftment after autologous stem cell transplantation for B-cell non-Hodgkin lymphoma.

Delayed platelet engraftment (DPE) is occasionally observed despite prompt neutrophil engraftment after autologous peripheral blood stem cell transplantation (auto-PBSCT). To identify risk factors for DPE and to develop a simple and clinically applicable system for predicting the time required for platelet recovery, we conducted a multi-institutional retrospective study in 144 patients with B-cell non-Hodgkin lymphoma who underwent auto-PBSCT. In a median observation period of 930 days (range: 25-5272 days), 139 patients successfully achieved platelet engraftment (≥50.0 × 109/L). The median duration for platelet engraftment was 19 days, and 130 patients had platelet engraftment within 40 days after auto-PBSCT; however, the other 14 patients failed to achieve platelet engraftment within 60 days. These 14 patients with DPE required a significantly greater number of apheresis procedures and had a lower pre-apheresis absolute lymphocyte count (PA-ALC) compared to those without DPE. Importantly, multivariate analysis revealed that the number of transplanted CD34+ cells (≤2.0 × 106/kg), number of required apheresis procedures (≥3 days), and PA-ALC (≤1.0 × 109/L) were independently associated with a longer time for platelet engraftment after auto-PBSCT. By incorporating these three independent factors as variables, we generated a new scoring system for prediction of the time and probability for platelet engraftment after auto-PBSCT.

Combined rituximab, bendamustine, and dexamethasone chemotherapy for relapsed or refractory indolent B-cell non-Hodgkin lymphoma and mantle cell lymphoma: a multicenter phase II study.

This multicenter phase II study (UMIN000008145) aims to investigate the efficacy and safety of six cycles of combination therapy (RBD) comprising rituximab, bendamustine, and dexamethasone (DEX) for relapsed or refractory (RR) indolent B-cell non-Hodgkin lymphoma (B-NHL) and mantle cell lymphoma (MCL). Although the initial study protocol comprised 20 mg/body DEX on days 1 and 2, and 10 mg/body on days 3-5 [high-dose (HD-) DEX group], the dose of DEX was later decreased to 8 mg/body on days 1 and 2 [low-dose (LD-) DEX group] due to frequent cytomegalovirus (CMV) antigenemia and recurrent retinitis. We enrolled 33 patients, and LD-DEX and HD-DEX were administered in 15 and 18 patients, respectively. The overall response and the 3-year progression-free survival rates were 88% and 75.5%, respectively. The leading adverse event was myelosuppression. Incidence of grade 3-4 leukocytopenia, neutropenia, and lymphocytopenia was 55%, 67%, and 91%, respectively. The most frequent nonhematological adverse events were CMV antigenemia and rash (33% and 30%, respectively). Incidence of CMV antigenemia over 10/100,000 white blood cells was significantly lower with LD-DEX than that with HD-DEX (P = 0.0127). In conclusion, RBD showed significant effectiveness for RR indolent B-NHL and MCL.

Cisplatin Augments Antitumor T-Cell Responses Leading to a Potent Therapeutic Effect in Combination With PD-L1 Blockade.

BACKGROUND: Immune checkpoint inhibitors have marked antitumor effect. However, monotherapy benefits only a limited population of patients, and further improvement of their effects is required. Here the therapeutic effect and immune response during anti-PD-L1 plus cisplatin combination therapy were investigated in a mouse model. MATERIALS AND METHODS: E.G7-OVA, expressing ovalbumin (OVA) gene as a model tumor antigen, was subcutaneously inoculated into syngeneic mice and treated with anti-PD-L1 with/without cisplatin. The tumor growth and activation status of immune cells were evaluated. RESULTS: The anti-PD-L1 plus cisplatin combination resulted in a potent antitumor effect leading to tumor shrinkage compared to anti-PD-L1 or cisplatin alone, even though each alone, significantly inhibited tumor growth compared to the control group. During treatment, all groups, including that treated with cisplatin alone, had increased CD8+ T-cell infiltration into tumor tissues compared with the control group, and the therapeutic effect was diminished by CD8+ cell depletion. Aside from its direct cytotoxic effect, cisplatin alone increased chemokine levels and expression of immune checkpoint molecules on CD8+ T-cells in the tumor site. The combination effectively activated OVA-specific CD8+ T-cells. Furthermore, anti-PD-L1 alone and in combination with cisplatin, but not cisplatin alone, induced interferon-gamma-producing CD4+ T-cells. CONCLUSION: These findings provide a rationale for anti-PD-L1 plus cisplatin becoming a promising combination therapy for patients with cancer.

Topoisomerase I inhibitor, irinotecan, depletes regulatory T cells and up-regulates MHC class I and PD-L1 expression, resulting in a supra-additive antitumor effect when combined with anti-PD-L1 antibodies.

Anti-PD-L1 antibodies inhibit interactions between PD-L1 and PD-1 and interactions between PD-L1 and B7-1, thereby reinvigorating anticancer immunity. Although there are numerous ongoing clinical studies evaluating combinations of standard chemotherapies and anti-PD-L1 antibodies, irinotecan has not yet been investigated in this context so there is little information about its compatibility with anti-PD-L1 antibodies. Here we investigated the efficacy of anti-PD-L1 antibody in combination with irinotecan and the role of irinotecan in the tumor-immunity cycle in an FM3A murine tumor model. Despite a transient decrease in lymphocytes in the peripheral blood after irinotecan treatment, the antitumor activity of anti-PD-L1 antibody plus irinotecan was significantly greater than each agent alone. Irinotecan in combination with anti-PD-L1 antibody enhanced proliferation of CD8+ cells in both tumors and lymph nodes, and the number of tumor-infiltrating CD8+ cells was higher than either irinotecan or anti-PD-L1 antibody monotherapy. Irinotecan was found to decrease the number of Tregs in lymph nodes and tumors, and specific depletion of Tregs by anti-folate receptor 4 antibodies was found to enhance the proliferation of CD8+ cells in this model. In addition, irinotecan augmented MHC class I expression on tumor cells and concurrently increased PD-L1 expression on tumor cells and tumor-infiltrating immune cells. These results indicate that irinotecan may enhance the effect of T cell activation caused by anti-PD-L1 treatment by reducing Tregs and augmenting MHC class I-mediated tumor antigen presentation, and concurrent upregulation of PD-L1 expression can be blocked by the anti-PD-L1 antibody. These interactions may contribute to the superior combination effect.

[Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis subsequent to rabbit antithymocyte globulin administration and successfully treated with rituximab in a patient with aplastic anemia].

Rabbit antithymocyte globulin (ATG) is an effective immunosuppressive therapy for patients with aplastic anemia (AA). However, Epstein-Barr virus-associated lymphoproliferative disorder (EBV-LPD) is a rare but serious complication of the therapy. An 81-year-old man was diagnosed with severe AA on the occasion of melena. Because cyclosporine monotherapy did not improve his condition, rabbit ATG was additionally administered. Thirty-one days after the administration of rabbit ATG, the patient presented with fever and general malaise. His liver and renal function tests showed rapid decline, and the patient went into shock. Although atypical lymphocytes in the peripheral blood, hepatosplenomegaly, and lymphadenopathy were not detected, the peripheral blood EBV-DNA load and serum ferritin levels were high, and his bone marrow aspiration specimen revealed hemophagocytic findings, leading to a diagnosis of EBV-LPD. He was treated with rituximab and recovered immediately. A total of 480 days have passed since the patient was administered the rabbit ATG, and he remains in AA remission without EBV-LPD relapse. This case suggests that rituximab is an effective therapy for EBV-LPD manifesting as EBV-associated hemophagocytic lymphohistiocytosis and indicates that monitoring the EBV-DNA load contributes to the diagnosis.

Capecitabine reverses tumor escape from anti-VEGF through the eliminating CD11bhigh/Gr1high myeloid cells.

The anti-VEGF humanized antibody bevacizumab suppresses various malignancies, but tumors can acquire drug resistance. Preclinical studies suggest myeloid-derived suppressor cells (MDSCs) may be associated with tumor refractoriness to anti-VEGF treatment. Here we report a novel mechanism of tumor escape from anti-VEGF therapy. Anti-VEGF treatment enhanced intratumoral recruitment of CD11bhigh/Gr-1high polymorphonuclear (PMN)-MDSCs in anti-VEGF-resistant Lewis lung carcinoma tumors. This effect was diminished by the anticancer agent capecitabine, a pro-drug converted to 5-fluorouracil, but not by 5-fluorouracil itself. This process was mediated by enhanced intratumoral granulocyte-colony stimulating factor expression, as previously demonstrated. However, neither interleukin-17 nor Bv8, which were previously identified as key contributors to anti-VEGF resistance, was involved in this model. Capecitabine eliminated PyNPase-expressing MDSCs from both tumors and peripheral blood. Capecitabine treatment also reversed inhibition of both antitumor angiogenesis and tumor growth under anti-VEGF antibody treatment, and this effect partially inhibited in tumors implanted in mice deficient in both PyNPases. These results indicate that intratumoral granulocyte-colony stimulating factor expression and CD11bhigh/Gr-1high PMN-MDSC recruitment underlie tumor resistance to anti-VEGF therapy, and suggest PyNPases are potentially useful targets during anti-angiogenic therapy.

Diabetes mellitus as a cause or comorbidity of chronic kidney disease and its outcomes: the Gonryo study.

BACKGROUND: Diabetes mellitus (DM) is a major cause of end-stage kidney disease (ESKD). However, the difference in renal outcomes between DM patients with non-diabetic renal disease (DM and NDRD) and those with diabetic nephropathy (DN) is controversial. The aim of the present study was to evaluate the differences among patients with DN, DM, and NDRD, and non-DM chronic kidney disease (CKD) in a prospective observational study. METHODS: We extracted the data of 2484 patients from 11 nephrology care centers and categorized into three groups as described above. The primary outcome was ESKD requiring renal replacement therapy. RESULTS: During the median follow-up of 4.44 years, 281 patients (11.3%) developed ESKD. Renal outcomes of DM and NDRD patients were similar to those of non-DM patients (p ≥ 0.05). At CKD stage G3b, the hazard ratios (95% confidence intervals) of ESKD were 7.10 (2.46-20.49) in DN patients and 0.89 (0.19-4.24) in DM and NDRD. The annual change in the estimated glomerular filtration rate (eGFR) in DN patients was significantly larger than that in other groups at stage G3b (-9.7%/year). CONCLUSIONS: We found that DN patients have a higher risk for ESKD than DM and NDRD or non-DM patients. In particular, GFR rapidly declined in DN at stage G3b. DM and NDRD patients can accomplish equally beneficial renal outcomes as non-DM CKD, regardless of their similar metabolic profiles as DN. In conclusion, we should prudentially consider the risk stratification of DM whether cause or comorbidity of CKD.