A single-institution pre-post comparison of subcutaneous immunoglobulin replacement therapy in allogeneic haematopoietic cell transplantation recipients.

Immunoglobulin replacement therapy (IgRT) reduces the risk of infection in hypogammaglobulinaemia secondary to chronic lymphocytic leukaemia and multiple myeloma. However, the benefit of IgRT, especially subcutaneous IgRT (ScIgRT), has not been assessed in hypogammaglobulinaemia after allogeneic haematopoietic cell transplantation (allo-HCT). We performed a pre-post comparison of the clinical impact of ScIgRT after allo-HCT in a retrospective analysis of 209 patients who underwent allogeneic HCT at our institution from 2011 to 2019. Since ScIgRT became available at our institution in April 2017, we categorized patients treated from January 2011 to March 2017 as the Pre-ScIgRT group (n = 118) and those treated from April 2017 to December 2019 as the Post-ScIgRT group (n = 91). The 2-year overall survival rate was 65% in the Pre-ScIgRT group and 81% in the Post-ScIgRT group (p = 0.02). The cumulative incidence (CI) of non-relapse mortality at 2 years was 18% and 7% (p = 0.02). There were 78 infectious events in 44 patients in the Pre-ScIgRT group and 28 such events in 19 patients in the Post-ScIgRT group. The CI of the documented infection during the observation period was between 38% and 21% (p = 0.01). Our study suggests that ScIgRT may reduce infection rates and improve prognosis after allo-HCT.

Clinicopathological factors and tumor microenvironment markers predicting watch-and-wait discontinuation in 82 patients with follicular lymphoma.

OBJECTIVES: In this study, we aimed to determine the clinicopathological factors influencing the treatment-free period in patients with follicular lymphoma (FL) using a watch-and-wait (WW) strategy. METHODS: We retrospectively assessed histopathological parameters of 82 patients with FL. RESULTS: The median time from diagnosis to WW discontinuation was 62 months (range, 3-138), and median follow-up was 86 months (range, 3-183). Intermediate or high-risk Follicular Lymphoma International Prognostic Index score (P = .012), non-duodenal-type (P = .011), higher numbers of interfollicular CD4+ (P = .038) and intrafollicular FOXP3+ cells (P = .024) in the tumor microenvironment, and Ki-67 index ≥10% (P = .031) were significant adverse factors for WW discontinuation in univariate analyses. CONCLUSION: Patients with adverse factors for WW discontinuation should be carefully observed during follow-up.

The role of local radiotherapy following rituximab-containing chemotherapy in patients with transformed indolent B-cell lymphoma.

OBJECTIVES: This study aimed to evaluate the outcomes of local radiotherapy (LRT) in patients with histologic transformation (HT) following rituximab-containing chemotherapy. METHODS: We retrospectively analysed 92 patients with biopsy-confirmed HT undergoing rituximab-containing chemotherapy at our institution between 2003 and 2015. RESULTS: Of the 36 patients with limited-stage disease at diagnosis of HT, 29 (78%) received LRT. The estimated 5-year progression-free survival (PFS) rate was significantly better in patients who underwent LRT than in those who did not (93% and 42%, respectively; P < 0.05). Multivariate analyses employing age, sex, performance status, LRT and treatment response demonstrated that LRT was an independent prognostic factor for PFS (hazard ratio [HR]: 11.8; 95% confidence interval [CI]: 1.28-108.1; P < 0.05). Of the 32 patients who underwent LRT for HT lesion treatment, 31 (97%) did not show disease progression within radiation fields; among them, 27 patients (84%) survived without disease progression during the follow-up period. One patient developed hypothyroidism due to LRT; the others had no acute or late-onset complications of LRT. CONCLUSIONS: Our data support the recommendation of LRT for HT lesion treatment following rituximab-containing chemotherapy in select patients with localised HT, as a rational treatment approach with potentially limited toxicity.

Immunohistochemical CD20-negative change in B-cell non-Hodgkin lymphomas after rituximab-containing therapy.

CD20- change after rituximab-containing therapy is considered one of the main reasons of rituximab resistance of B-cell non-Hodgkin lymphomas (B-NHLs). However, the clinicopathological characteristics of B-NHL with CD20- change are not entirely understood. In this study, 252 B-NHL patients who were CD20+ at initial diagnosis, whose diseases relapsed or were refractory after rituximab-containing therapy, and who were re-biopsied between 2000 and 2018, were included. The median number of rituximab administration was 11 (range, 1-48). Completely negative (cCD20-) and partially negative (pCD20-) change of CD20 was observed in 49 (20%) and 16 (6%) cases, respectively. Among cCD20- and pCD20- cases, 74% and 62% of the cases changed to CD20- at the second relapse or later, respectively. Overall survival was significantly shorter in cCD20- follicular lymphoma (FL) cases than in CD20+ FL cases. Seven histopathological patterns, such as CD20- change without histological change, histological transformation (HT) to CD20- diffuse large B-cell lymphoma, and proliferation of plasmablastic/plasmacytoid tumor cells, were associated with CD20- change. HT occurred more frequently in FLs with CD20- change than in FLs continuously expressing CD20 (P < 0.0001), regardless of the timing of HT. Nine out of 25 cases (36%) showed regain or heterogeneous regain of CD20 expression. In conclusion, 20% and 6% of the 252 B-NHL cases show cCD20- and pCD20- changes with 7 histological patterns after rituximab-containing therapy. Because changes in morphology and CD20 expression after rituximab-containing therapy vary, and recovery of CD20 expression is not rare, careful follow-up and re-biopsy in B-NHL patients are recommended.

Extramedullary Relapse of Acute Myelogenous Leukemia after Allogeneic Hematopoietic Stem Cell Transplantation.

The clinical significance of extramedullary relapse (EMR) of acute myelogenous leukemia (AML) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains poorly defined. Here we report the clinical outcomes of patients who underwent allo-HSCT for AML at our institution between 2000 and 2012. A total of 293 patients with AML who underwent allo-HSCT were included. The median duration of follow-up in survivors was 1840 days. Disease status at the time of allo-HSCT was complete remission in 192 patients and nonremission in 101 patients. A total of 110 patients experienced AML relapse after allo-HSCT, including 18 with EMR only, 83 with bone marrow relapse (BMR) only, and 9 with both EMR and BMR. The 5-year cumulative incidence of EMR after allo-HSCT was 9.5%, whereas that of BMR only was 28.9%. In multivariate analysis, peripheral blood stem cell transplantation was associated with an increased risk of EMR. The 2-year overall survival after post-transplantation relapse was 7.5% in patients with BMR only, 11.1% in those with both EMR and BMR, and 27.5% in those with EMR only (P < .05). Although the short-term survival was better in patients with EMR only, they rarely achieved long-term survival. Appropriate strategies for both post-transplantation EMR and BMR are needed.

Mucosa-associated lymphoid tissue lymphoma with t(11;18)(q21;q21) translocation: long-term follow-up results.

Translocation (11;18)(q21;q21) is found in mucosa-associated lymphoid tissue (MALT) lymphoma, resulting in API2/MALT1 gene fusion. It is known that t(11;18)-positive MALT lymphoma shows a tendency to disseminate and be resistant to Helicobacter pylori eradication by antibiotics. However, the prognostic features including recurrence and histological transformation (HT) remain unknown. We conducted a single-institute retrospective analysis of 464 patients with newly diagnosed MALT lymphoma, evaluating the impact of t(11;18) on clinical outcomes. One hundred and six patients were screened for the translocation by fluorescence in situ hybridization and/or reverse transcriptase-polymerase chain reaction. Of these patients, 26 patients (25%) were diagnosed as MALT lymphoma with t(11;18). The patients had a significantly shortened progression-free survival (PFS at 10 years; 26% v 57%; P = 0.004) compared to those without t(11;18). However, this did not translate into overall survival or incidence of HT. We confirmed previous reports stating that t(11;18)-positive MALT lymphoma showed disseminated disease and refractoriness to H. pylori eradication therapy. Patients with t(11;18) had more frequent monoclonal gammopathy, especially of IgM subtype (31% v 8%; P = 0.008), some of which developed class switch. These findings characterize the features of t(11;18)-positive MALT lymphoma, suggesting that it comprises a distinct clinical entity of MALT lymphoma.

Biomarker discordance between primary breast cancer and bone or bone marrow metastases.

BACKGROUND: Discordance in biomarker expression between primary and metastatic tumor sites has been reported in several studies; yet, few have examined this feature in bone lesions. METHODS: We retrospectively enrolled patients with breast cancer metastasis to the bone or bone marrow, excluding cases where samples from both the primary and metastatic lesions were not available. Expression patterns of the estrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor 2 (HER2) and Ki67 were compared in primary tumors and bone or bone marrow lesions. RESULTS: Forty-six patients with a median age of 52 years (range, 34-72 years) were included in the study. Discordant rates of ER, PgR and HER2 were 20%, 46% and 0%, respectively. Physicians usually determined treatment options considering the results of biomarker re-evaluation. It is unlikely that biomarker discordance was related to prior treatment. CONCLUSIONS: Biomarker discordance in bone or bone marrow lesions is common in patients with breast cancer. An accurate and thorough analysis of biomarkers and metastatic tumor properties is important for clinical decision-making.

EBV-encoded RNA1-positive cells in the bone marrow specimens of patients with EBV-negative lymphomas and sarcomas.

Epstein-Barr virus (EBV) infection is associated with pathogenesis of various cancers, including extranodal natural killer/T-cell lymphoma, nasal type (ENKL). ENKL tumor cells are positive for EBV-encoded RNA1 (EBER1), which is the most useful marker to identify ENKL tumor cells in histopathology. Currently, EBER1 in situ hybridization (ISH) is recommended to evaluate bone marrow (BM) involvement of ENKL. However, the actual burden of EBER1-positive cells in normal BM specimens remains unclear. In the present study, we performed EBER1 ISH on 111 BM specimens, which were obtained during an initial staging procedure in patients with EBV-negative cancers and were also negative for BM involvement. One or more EBER1-positive cells per whole specimen were observed in 38 specimens (34%). The number of EBER1-positive cells was distributed as follows: single positive cell, n = 17; two positive cells, n = 13; three positive cells, n = 3; and four positive cells, n = 5. These findings suggest that four or fewer EBER1-positive cells can be observed in BM specimens of patients with non-EBV-related cancers. The clinical implications of a small number of EBER1-positive cells in BM specimens of patients with ENKL should be evaluated in further studies.

Influence of the watch and wait strategy on clinical outcomes of patients with follicular lymphoma in the rituximab era.

We analyzed the effects of the initial approach to patients with follicular lymphoma (FL) on outcomes in order to investigate whether the watch and wait (WW) strategy is still an acceptable approach in the rituximab era. We retrospectively analyzed 348 patients who were initially diagnosed with FL between 2000 and 2012. We compared the clinical outcomes of the WW cohort and immediate treatment cohort. Among 348 patients (median age of 57 years, range: 19-85), 101 were initially managed with WW and 247 were immediately treated. The median follow-up duration was 75 months (range: 7-169). The estimated median time to treatment failure (TTF) in the treatment following WW cohort and immediate treatment cohort were 92 months (95 % CI, 60.1-NA) and 77 months (95 % CI, 65.1-107.6), respectively, which were not significantly different (P = 0.272) . In a multivariate analysis, clinical stage was identified as a predictive factor of TTF (HR 1.19, 95 % CI, 1.03-1.38, P < 0.05). Neither overall survival rate nor cumulative risk of transformation between the WW cohort and immediate treatment cohort was significant. The results of the present study suggested that the WW strategy is still an acceptable approach for selected FL patients in the rituximab era.

[A case of primary intestinal tuberculosis in which small intestine perforation developed].

We report herein on a case of the primary intestinal tuberculosis in which small intestine perforation developed. A 60-year-old man with congestive heart failure developed fever and sudden onset of abdominal pain while he was in the hospital. Computed tomography of the abdomen showed a large amount of free-air and the thickening of a part of the ileum. Perforation of the gastrointestinal tract was diagnosed, The patient underwent emergency exploratory laparotomy and a partial resection of the ileum was performed. The presence of nodules in the ileum suggested possible tuberculosis of the intestine. Pathologically caseating epithelioid granulomas were noted and the diagnosis of tuberculosis of the ileum was made although microbiologically tuberculous bacilli were not documented. The patient was successfully treated with antituberculosis chemotherapy. Although intestinal tuberculosis is a rare cause of intestinal perforation, it is important to include intestinal tuberculosis as one of the cases.

Differentiating Between Epstein-Barr Virus-positive Lymphoid Neoplasm Relapse and Post-transplant Lymphoproliferative Disorder After Sex-mismatched Hematopoietic Stem Cell Transplantation.

After allogeneic hematopoietic stem cell transplantation (HSCT), accurate differentiation between donor-derived post-transplant lymphoproliferative disorder (PTLD) and relapse of recipient-derived lymphoproliferative disorder (LPD) is crucial for determining treatment. Conventional diagnostic approaches for PTLD include histopathological examination, flow cytometry, and chimerism analysis of bulk tumor tissue. However, these methods are inconclusive in cases in which the primary disease is an Epstein-Barr virus (EBV)-positive LPD and is of the same lineage as that of the post-HSCT LPD tumor cells. Particularly, in cases where the number of tumor cells in the tissue is low, it is difficult to determine the origin of tumor cells. In this study, we developed a new method to simultaneously detect signals using sex chromosome fluorescence in situ hybridization, immunofluorescence staining, and EBV-encoded small RNA in situ hybridization on a single section of formalin-fixed paraffin-embedded histopathological specimen. The utility of the method was validated using specimens from 6 cases of EBV-positive LPD after sex-mismatched HSCT that were previously difficult to diagnose, including Hodgkin lymphoma-like PTLD that developed after HSCT for Hodgkin lymphoma and recurrence of chronic active EBV infection. This method successfully preserved the histologic structure after staining and allowed accurate determination of tumor cell origin and lineage at the single-cell level, providing a definitive diagnosis in all cases. This method provides a powerful tool for the diagnosis of LPDs after sex-mismatched HSCT.

[Sodium-losing nephropathy caused by tacrolimus after allogeneic hematopoietic stem cell transplantation].

A 39-year-old woman (Case 1) and a 57-year-old woman (Case 2) underwent allogeneic bone marrow transplantation for acute lymphoblastic leukemia and follicular lymphoma, respectively. Both patients had received tacrolimus orally for treatment of or prophylaxis against graft-versus-host disease. Seventeen months (Case 1) and 2 months (Case 2) post-transplantation, when the trough level of tacrolimus was maintained around 10 ng/ml, the serum sodium levels of Cases 1 and 2 decreased to 123.5 mEq/l and 125.6 mEq/l, respectively. Urinary sodium excretions increased to 186.8 mEq/day and 375.7 mEq/day, respectively. Sodium-losing nephropathy due to tacrolimus was diagnosed, and reducing the dose of tacrolimus with no other intervention resulted in resolution of the hyponatremia. Although sporadic kidney transplantation cases with sodium-losing nephropathy due to tacrolimus have been reported, no prior cases with this complication after hematopoietic stem cell transplantation (HSCT) have been reported. Sodium-losing nephropathy should be recognized as one of the renal toxicities of tacrolimus in HSCT as well as kidney recipients.

A case of severe oral mucosal GVHD induced by heterologous SARS-CoV-2 vaccination after cord blood transplantation.

Patients who have undergone hematopoietic cell transplantation (HCT) are at a higher risk of severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) infection than the general population. Therefore, early vaccination is recommended for post-transplant patients. Although exacerbation of chronic graft-versus-host disease (cGVHD) after the initial vaccination has been reported, it is unknown whether severe cGVHD occurs when different RNA vaccines are combined. We treated a patient who developed severe oral mucosal cGVHD after receiving two different RNA vaccines. Visual inspection showed that the patient presented with typical mucocutaneous cGVHD, and cGVHD in this case responded well to low-dose steroids compared to common oral GVHD exacerbations. Histopathological findings revealed T cell, B cell, and conspicuous neutrophil infiltration. Multiple doses of SARS-Cov2 vaccination are required in post-transplant recipients. In conclusion, it is essential to obtain the vaccination history of allo-HSCT recipients with cGVHD exacerbation. Furthermore, reviewing the pathological findings may help treat patients with lower doses of steroids.

Gilteritinib in peritransplant period for relapsed or refractory FLT3-mutated acute myeloid leukemia: A case report of three patients.

Patients with relapsed or refractory acute myeloid leukemia (RR-AML) with mutations of FMS-like tyrosine kinase 3 (FLT3) have a poor prognosis even after allogeneic hematopoietic cell transplantation (allo-HCT). Multiple FLT3 inhibitors, including gilteritinib, have been developed and serve as treatment options for RR-AML. Here, we describe three cases of FLT3 mutated RR-AML that were successfully treated with gilteritinib administration before and after allo-HCT. Gilteritinib treatment before HCT was helpful in achieving remission. However, HCT often resulted in mild liver damage, and careful introduction of gilteritinib after HCT at a lower dose may be helpful for its safe usage. The three cases discussed had a successful clinical outcome in terms of disease control as well as the management of side effects associated with gilteritinib treatment.

A case of multiple myeloma with pancreatic involvement diagnosed via endoscopic ultrasound-guided fine needle aspiration.

This report highlights the importance of considering multiple myeloma in the differential diagnosis of a pancreatic tumor with bone lesions. sampling not only from the pancreatic lesion but also from bone lesions may reach an accurate diagnosis.

Antiemetic Strategies in Patients Who Undergo Hematopoietic Stem Cell Transplantation.

Hematopoietic stem cell transplantation (HSCT) is an integral part of the treatment strategy in patients with a hematological disorder. Chemotherapy-induced nausea and vomiting (CINV) is still an issue in patients who undergo HSCT. While several guidelines for the antiemetic therapy against CINV have been published, there is no detailed information about appropriate antiemetic drugs for each conditioning regimen in HSCT. Various studies reported that the triplet of 5-HT3RA, NK1RA, and dexamethasone appears useful in HSCT. However, each antiemetic has unique adverse effects or interactions with specific drugs. Here, we review the literature relating to clinical trials on the prevention of CINV, and summarize the information to clarify the benefit of antiemetic regimens.

The outcome of watchful waiting in patients with previously treated follicular lymphoma.

Watchful waiting (WW) is one of the standard approaches for newly diagnosed follicular lymphoma (FL) patients with low-tumor burden. However, the impact of WW in FL patients at the first progression, remains unclear. We reviewed 206 FL patients who experienced the first progression after responding to the initial treatment at our institution between 1998 and 2017. Patients were classified into either the WW cohort (132 patients) or the immediate treatment cohort (74 patients). Overall, the median follow-up from the first progression was 79.8 months (range, 2.1-227.0 months). In the WW cohort, the estimated median time to next treatment (TNT) was 19.7 months (95% confidence interval [CI], 13.4-30.2), and 76.5% (95% CI, 68.0-84.1) of the patients subsequently underwent the second-line treatment at 5 years. There was a significant difference in the median time to treatment failure in the WW cohort (72.8 months; 95% CI, 64.6-94.0) compared to the immediate treatment cohort (23.3 months; 95% CI, 13.4-38.8) (HR, 2.13; 95% CI, 1.48-3.06), whereas overall survival and the cumulative incidence of histological transformation were not significantly different between two cohorts. In a multivariate analysis, rituximab refractory status, progression of disease within 24 months from the induction of first-line therapy, and a high Follicular Lymphoma International Prognostic Index score at diagnosis were significantly associated with shorter TNT. Interestingly, 15 patients (11%) of the WW cohort experienced spontaneous tumor regression during WW, and their TNT (median, 82.1 months, 95% CI, 11.7-NA) was longer than that of the remaining patients in the WW cohort (median, 16.5 months, 95% CI, 13.0-25.4), with a significant difference (p = 0.01). The results of the present study suggested that WW could be a safe and reasonable option even at the first progression for the selected FL patients, without a negative impact on clinical outcomes.