Risk factors for acute kidney injury after high-dose methotrexate therapy: a single-center study and narrative review.

PURPOSE: To assess the risk factors associated with high-dose methotrexate (HDMTX) (≥ 1 g/m2) treatment-induced acute kidney injury (AKI). METHODS: Patients who received HDMTX from July 2014 to August 2019 in one medical center were enrolled. The patients' demographic, laboratory, and medication data were collected and compared between groups with or without AKI. Risk factors of HDMTX-induced AKI were explored using univariate and multivariate logistic regression analyses. Additionally, we searched and summarized previous studies to identify key correlates of AKI in a narrative review. RESULTS: We enrolled 59 patients who had received 200 HDMTX courses. The incidence of HDMTX-induced nephrotoxicity was 9.5%. Multivariate logistic regression revealed that male sex (odds ratio [OR], 4.20; P = .037), and angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs) (OR, 5.18; P = .016) were significantly associated with AKI. Diuretics with urinary acidification, such as loop diuretics, were also a key factor in AKI (OR, 4.91; P = .018). Furthermore, a forest plot identified 21 predictors from nine additional cohort studies showing correlations with the development of AKI. CONCLUSION: Male sex, ACEIs/ARBs, and diuretics with urinary acidification are associated with AKI. Furthermore, laboratory data should be monitored to assess AKI risk before HDMTX therapy, especially in elderly patients with obesity, diabetes, or acute lymphoblastic leukemia.

A phase II randomised trial of induction chemotherapy followed by concurrent chemoradiotherapy in locally advanced pancreatic cancer: the Taiwan Cooperative Oncology Group T2212 study.

BACKGROUND: The objective of this study was to evaluate the efficacy and safety of induction chemotherapy (ICT), GOFL (gemcitabine, oxaliplatin plus fluorouracil (5-FU)/leucovorin) versus modified FOLFIRINOX (irinotecan, oxaliplatin plus 5-FU/leucovorin), followed by concurrent chemoradiotherapy (CCRT) in locally advanced pancreatic adenocarcinoma (LAPC). METHODS: Chemo-naive patients with measurable LAPC were eligible and randomly assigned to receive biweekly ICT with either mFOLFIRINOX or GOFL for 3 months. Patients without systemic progression would have 5-FU- or gemcitabine-based CCRT (5040 cGy/28 fractions) and were then subjected to surgery or continuation of chemotherapy until treatment failure. The primary endpoint was 9-month progression-free survival (PFS) rate. RESULTS: Between July 2013 and January 2019, 55 patients were enrolled. After ICT, 21 (77.8%) of 27 patients who received mFOLFIRINOX and 17 (60.7%) of 28 patients who received GOFL completed CCRT. Of them, one and five had per-protocol R0/R1 resection. On intent-to-treat analysis, the 9-month PFS rate, median PFS and overall survival in mFOLFIRINOX and GOFL arms were 30.5% versus 35.9%, 6.6 (95% confidence interval: 5.9-12.5) versus 7.6 months (3.9-12.3) and 19.6 (13.4-22.9) versus 17.9 months (13.4-23.9), respectively. Grade 3-4 neutropenia and diarrhoea during induction mFOLFIRINOX and GOFL were 37.0% versus 21.4% and 14.8% versus 3.6%, respectively. CONCLUSION: Induction GOFL and mFOLFIRINOX followed by CCRT provided similar clinical outcomes in LAPC patients. GOV IDENTIFIER: NCT01867892.

Quantification of HBV core antibodies may help predict HBV reactivation in patients with lymphoma and resolved HBV infection.

BACKGROUND & AIMS: Absence or low anti-HBV surface antibody (anti-HBs) is associated with an increased risk of HBV reactivation in patients with lymphoma and resolved HBV infection receiving rituximab-containing chemotherapy. Quantification of anti-HBV core antibody (anti-HBc) is a new marker associated with the natural history and treatment response of chronic HBV infection. This study investigated whether baseline anti-HBc and anti-HBs levels may better predict HBV reactivation. METHODS: We prospectively measured the HBV DNA levels of patients with lymphoma and resolved HBV infection receiving rituximab-cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisolone-based chemotherapy and started an antiviral therapy upon HBV reactivation, defined as a greater than 10-fold increase in HBV DNA compared with previous nadir levels. Anti-HBs and anti-HBc were quantified by a double-sandwich assay. Receiver-operating-characteristic-curve analysis was used to determine the optimal baseline anti-HBc/anti-HBs levels for predicting HBV reactivation. RESULTS: HBV reactivation occurred in 24 of the 197 patients enrolled, with an incidence of 11.6/100 person-years. For the 192 patients with enough serum samples for analysis, low anti-HBs (<56.48 mIU/ml) and high anti-HBc (≥6.41 IU/ml) at baseline were significantly associated with high risk of HBV reactivation (hazard ratio [HR] 8.48 and 4.52, respectively; p <0.01). The multivariate analysis indicated that (1) patients with both high anti-HBc and low anti-HBs at baseline (36 of 192 patients) had an HR of 17.29 for HBV reactivation (95% CI 3.92-76.30; p <0.001), and (2) HBV reactivation may be associated with inferior overall survival (HR 2.41; 95% CI 1.15-5.05; p = 0.02). CONCLUSIONS: Baseline anti-HBc/anti-HBs levels may predict HBV reactivation in these patients with lymphoma and help optimize prophylactic antiviral therapy for high-risk patients. LAY SUMMARY: In this study, we identified a subgroup of patients with lymphoma and resolved hepatitis B virus infection that had a high risk of hepatitis B virus reactivation after receiving rituximab-containing chemotherapy. These findings will help optimize a preventive strategy, especially in hepatitis B virus endemic regions with limited healthcare resources. Clinical trial number: NCT 00931229.

Chemotherapy-induced hepatitis B reactivation in lymphoma patients with resolved HBV infection: a prospective study.

UNLABELLED: Fatal hepatitis B virus (HBV) reactivation in lymphoma patients with "resolved" HBV infection (hepatitis B surface antigen [HBsAg] negative and hepatitis B core antibody [anti-HBc] positive) can occur, but the true incidence and severity remain unclear. From June 2009 to December 2011, 150 newly diagnosed lymphoma patients with resolved HBV infection who were to receive rituximab-CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone)-based chemotherapy were prospectively followed. HBV DNA was checked at baseline, at the start of each cycle of chemotherapy, and every 4 weeks for 1 year after completion of rituximab-CHOP chemotherapy. Patients with documented HBV reactivation were treated with entecavir at a dosage of 0.5 mg/day for 48 weeks. HBV reactivation was defined as a greater than 10-fold increase in HBV DNA, compared with previous nadir levels, and hepatitis flare was defined as a greater than 3-fold increase in alanine aminotransferase (ALT) that exceeded 100 IU/L. Incidence of HBV reactivation and HBV-related hepatitis flares was 10.4 and 6.4 per 100 person-year, respectively. Severe HBV-related hepatitis (ALT >10-fold of upper limit of normal) occurred in 4 patients, despite entecavir treatment. Patients with hepatitis flare exhibited significantly higher incidence of reappearance of HBsAg after HBV reactivation (100% vs. 28.5%; P=0.003). CONCLUSION: In lymphoma patients with resolved HBV infections, chemotherapy-induced HBV reactivation is not uncommon, but can be managed with regular monitoring of HBV DNA and prompt antiviral therapy. Serological breakthrough (i.e., reappearance of HBsAg) is the most important predictor of HBV-related hepatitis flare. (Hepatology 2014;59:2092-2100).

Recurrent spontaneous massive hemothorax from intrathoracic extramedullary hematopoiesis resulting in respiratory failure.

Extramedullary hematopoiesis (EMH) is a compensatory response to many chronic anemic disorders. Intrathoracic EMH, usually presenting as paravertebral masses over the posterior mediastinum, is a rare entity and is usually asymptomatic. Hemothorax is a rare but possibly fatal complication. Local radiation for intrathoracic EMH is considered effective in preventing its recurrence. Here we describe a patient who had had α-thalassemia for many years and developed a spontaneous left-sided hemothorax from EMH. A chest film and a chest computed tomography (CT) scan had showed multiple paravertebral masses over the lower thoracic spine with left-sided pleural effusion. A pathological diagnosis of EMH was made by video-assisted thoracoscopic surgery. The patient had not received preventive local chest radiation. Ten years later, he suffered from a life-threatening hemothorax complicated by acute respiratory failure without traumatic history. A CT scan showed posterior mediastinal masses over the lower thoracic spine with right-sided pleural effusion. Thoracoscopy was performed to remove the blood clot in the pleural space for successful weaning from mechanical ventilation. This is the first case of intrathoracic EMH to have recurrent hemothorax associated with acute respiratory failure.

Diffuse large B-cell lymphoma of the cerebellopontine angle in a patient with sudden hearing loss and facial palsy.

Primary lymphoma of the cerebellopontine angle (CPA) is rare in the central nervous system. To our knowledge, there have only been 14 cases reported worldwide so far. Here, we report our findings in a 57-year-old man, who presented with bilateral sudden hearing loss followed by left facial palsy within 1 month. Radiologic study and magnetic resonance imaging showed a homogeneous enhancing mass, 1.6 x 0.5 x 1.1cm in size, in the left CPA cistern region with mild extension to the left internal auditory canal. The tumor was removed through left retromastoid craniectomy, and the histopathologic diagnosis of the tumor was confirmed as diffuse large B-cell type malignant lymphoma. After a series of tumor surveys, there was no evidence of other original lymphoma. The patient was treated with chemotherapy (including intra-Ommaya injection with methotrexate and Ara-C and systemic injection with vincristine, methotrexate and ifosfamide) for the primary CPA lymphoma. He was still alive 19 months after the initial treatment.

Primary cardiac lymphoma with unusual presentation: A report of two cases.

Primary cardiac tumors are rare, with an incidence of 0.056% according to autopsy reports. The most common type is myxoma, while other types, including sarcoma, lipoma, papillary fibroelastoma, rhabdomyoma, fibroma, hemangioma, teratoma, lymphoma and mesothelioma also occur. Primary cardiac tumors usually cause embolization, pericardial effusion and arrhythmia, leading to heart failure. Only 10% of primary cardiac tumors are malignant, approximately 95% of which are sarcomas, while the remaining 5% are cardiac lymphomas and mesotheliomas. The present study reported a case of primary cardiac lymphoma (PCL) with bilateral renal involvement and a case of PCL with bilateral adrenal gland involvement. The prognosis of PCL is poor due to the low rate of early detection and treatment. The definitive diagnosis is dependent on pathology, and timely treatment with chemotherapy can be effective. The two cases developed life-threatening arrhythmia and responded to the initial chemotherapy. In the first case, complete remission was achieved after finalization of therapy. However, the second case refused further chemotherapy and succumbed to his condition after two months.

Distinct clinical characteristics of paroxysmal nocturnal hemoglobinuria in patients in Southern Taiwan: A multicenter investigation.

Paroxysmal nocturnal hemoglobinuria (PNH) is an extremely rare acquired disorder. The aim of this study was to investigate the demographics, clinical manifestations, and outcomes of PNH patients in southern Taiwan. Data on PNH patients diagnosed over a 30-year period (1985-2015) were retrospectively collected from four tertiary medical centers in southern Taiwan. Blood samples were collected for hematologic panel testing and flow cytometry detection of PNH clones. Radiologic studies were performed to assess the frequency of complications. Twenty-four patients were enrolled in this study. The median duration of disease in the study participants was 10.8 years. The median granulocyte PNH clone size was 92.5% (range, 1.3%-99.8%), and the median lactate dehydrogenase (LDH) level was 2920.2 ± 1462.0 IU/L. The incidence of thromboembolism and impaired renal function was 16.7% and 29.2%, respectively. The primary treatment strategies included steroids (79.2%), androgens (42.0%), eculizumab (33.3%), immunosuppressants (16.7%), and anticoagulants (4.2%). In eight patients treated with eculizumab, there was a marked reduction in the LDH levels of 14.89-fold-1.63-fold that of the upper limit of normal; seven patients exhibited decreased transfusion requirements. Twenty-one patients were alive with regular follow-up at the time of publication. Our study demonstrates that PNH patients in southern Taiwan may exhibit different clinical characteristics and outcomes relative to patients in other countries. There was a trend toward a greater PNH granulocyte clone size, which may lead to more hemolysis. In our study, the percentage of patients with impaired renal function, but not the percentage of patients with thrombotic events, was higher than values reported worldwide and in the observational cross-sectional International PNH Registry. More large-scale studies with comprehensive data on the clinical response to different treatments are needed.

Enhanced cytotoxicity of natural killer cells following the acquisition of chimeric antigen receptors through trogocytosis.

Natural killer (NK) cells have the capacity to target tumors and are ideal candidates for immunotherapy. Viral vectors have been used to genetically modify in vitro expanded NK cells to express chimeric antigen receptors (CARs), which confer cytotoxicity against tumors. However, use of viral transduction methods raises the safety concern of viral integration into the NK cell genome. In this study, we used trogocytosis as a non-viral method to modify NK cells for immunotherapy. A K562 cell line expressing high levels of anti-CD19 CARs was generated as a donor cell to transfer the anti-CD19 CARs onto NK cells via trogocytosis. Anti-CD19 CAR expression was observed in expanded NK cells after these cells were co-cultured for one hour with freeze/thaw-treated donor cells expressing anti-CD19 CARs. Immunofluorescence analysis confirmed the localization of the anti-CD19 CARs on the NK cell surface. Acquisition of anti-CD19 CARs via trogocytosis enhanced NK cell-mediated cytotoxicity against the B-cell acute lymphoblastic leukemia (B-ALL) cell lines and primary B-ALL cells derived from patients. To our knowledge, this is the first report that describes the increased cytotoxicity of NK cells following the acquisition of CARs via trogocytosis. This novel strategy could be a potential valuable therapeutic approach for the treatment of B-cell tumors.

Prognostic value of platelet count in diffuse large B-cell lymphoma.

BACKGROUND: Besides International Prognostic Index, many parameters have proven prognostic significance in aggressive lymphoma. However, the most appropriate system of risk stratification in diffuse large B-cell lymphoma (DLBCL) is not yet clear. In this study, we attempt to clarify the prognostic value of platelet count at the onset of lymphoma. MATERIALS AND METHODS: Between January 2000 and December 2009, 100 patients with DLBCL receiving R-CEOP (rituximab, cyclophosphamide, epirubicin, vincristine, and prednisolone) in a single institution were enrolled. Patient characteristics and survival outcomes were retrospectively analyzed. RESULTS: Before front-line treatment, 17 patients with thrombocytopenia (< 150 × 10(9)/L) and 83 patients without thrombocytopenia were enrolled. Thrombocytopenic patients initially presented with more B symptoms (P = .040), more bone marrow involvement (P = .001), later staging (P = .001), and higher International Prognostic Index (P < .001). Thrombocytopenia was shown to be an independently poor prognostic factor in the multivariate analysis of overall survival (hazard ratio [HR], 3.405; 95% confidence interval [CI], 1.431-8.101; P = .006) and progression-free survival (HR, 4.299; 95% CI, 1.786-10.343; P = .001). CONCLUSION: Platelet count at diagnosis is a simple but useful indicator for predicting survival outcomes of DLBCL. Although the mechanisms of thrombocytopenia may be complex in lymphoma, further investigations are warranted to illustrate the predictive merit.

Myelodysplasia followed by Good's Syndrome: a unique manifestation associated with thymoma.

Good's syndrome, also known as thymoma with combined immunodeficiency, is rare. The immunodeficiency may precede, arise concurrently with or follow the diagnosis of thymoma. In addition to myasthenia gravis and Good's syndrome, paraneoplastic syndromes associated with thymoma can also be manifested with hematological disorders, such as pure red cell aplasia, aplastic anemia, agranulocytosis, hemolytic anemia, pernicious anemia, and paroxysmal nocturnal hemoglobinuria. Myelodysplastic syndrome is a group of clonal hematopoietic stem cell diseases characterized by cytopenia(s), dysplasia in one or more lineages, ineffective hematopoiesis, and potential precursors of acute leukemia. One proposed pathogenesis of myelodysplasia is autoantibodies that directly reject against hematopoietic cells, but this situation is rare in thymoma. Herein, we report a thymoma patient with unique paraneoplastic syndromes who developed myelodysplasia prior to Good's syndrome. Early and accurate diagnosis of myelodysplastic syndrome is important for disease management, especially in patients whose myelodysplastic syndrome is possibly derived from autoimmunity. For thymoma patients with recurrent infections, comprehensive immunologic studies to exclude the possibility of Good's syndrome and prophylactic intravenous immunoglobulin infusion in suitable candidates are warranted.

Nonmucosa-associated lymphoid tissue lymphomas of gastric and intestinal origin differ in their clinical features: a single institute experience.

BACKGROUND: The treatment policy and disease process of mucosa-associated lymphoid tissue (MALT) lymphomas are different from those of other gastrointestinal lymphomas. Chemotherapy has replaced curative surgery as the treatment of choice in gastric lymphomas but the optimal frontline treatment of intestinal lymphomas has yet to be defined. Hence, we attempted to identify the difference in features between gastric and intestinal nonMALT lymphomas. METHODS: Patients who were newly diagnosed with nonMALT lymphomas of gastrointestinal origin in our hospital between January 2001 and February 2010 were included in our study. Patient characteristics and outcomes were retrospectively analyzed. RESULTS: Among 59 gastric lymphoma patients and 25 intestinal lymphoma patients, the intestinal group were significantly younger and had better performance (p=0.002 and 0.042). Whereas gastrointestinal obstruction and intussusception were more common in the intestinal group (p=0.024 and 0.024), more bleeding episodes were displayed in the gastric counterpart (p=0.042). Histologically, diffuse large B-cell lymphoma was more prevalent in the stomach, and enteropathy associated T-cell lymphoma was found only in the intestine (p=0.006 and 0.024). Despite more intestinal lymphoma patients receiving surgery (p=0.002), the response rate, overall survival and progression-free survival were similar to the gastric counterpart (p=0.1060, 0.7758 and 0.1248). In the multivariate analysis of overall survival, chemotherapy (hazard ratio [HR] 0.2; 95% confidence interval [CI] 0.091-0.440; p<0.001) and International Prognostic Index (HR 1.7; 95% CI 1.181-2.448; p=0.004) proved prognostic in gastric lymphomas. Furthermore, T-cell lineage (HR 8.615; 95% CI 2.165-34.288; p=0.002) and poor performance (HR 9.374; 95% CI 1.497-58.712; p=0.017) were poor predictors in the intestinal counterpart. CONCLUSION: Intestinal lymphomas differ from gastric lymphomas in manifestation, histology, management and prognosis. Surgery still plays a role in intestinal lymphomas because presentations of surgical emergencies are more common. In addition, the outcome of gastric lymphomas compared with intestinal lymphomas is no longer superior if patients with MALT lymphomas are excluded. Because of the limited number of enrolled patients, further large-scale studies are warranted to validate these results.

Locally advanced female urethral adenocarcinoma of enteric origin: the role of adjuvant chemoradiation and brief review.

Primary female urethral adenocarcinoma (FUA) is rare and has a poor prognosis. The common manifestations include urethrorrhagia, urinary frequency, dysuria, urethral obstructions, focal tenderness, and urinary tract infection. These symptoms are neither diagnostic nor pathognomonic; therefore, a delay in diagnosis and even a misdiagnosis is hardly uncommon. The histogenesis of FUAs may have derived from urethritis glandularis, Mullerian ducts, Skene's glands, or mixed origins. Tumors of different embryologic origins displayed heterogeneous pathological morphology and immunohistochemistical phenotypes. Because of its rarity and the lack of large-scale studies, there is no current consensus on the optimal treatment of urethral adenocarcinomas. Here, we report two cases of locally advanced FUA of enteric origin. They manifested as slightest warning symptoms of urinary tract infection and stress urinary incontinence, respectively. One patient died of disease progression 2 months after curative operation. The other patient underwent surgery followed by adjuvant irinotecan-containing chemoradiation, and the effect was at least modest. Hence, we recommend adjuvant chemoradiation in locally advanced FUA. Individualizing cancer care of chemoregimens in accordance with the tumor origins may probably be beneficial in FUAs.

Diagnostic pitfalls of nonsecretory myeloma manifesting as multiple foci of periosseous plasmacytomas.

Nonsecretory myeloma, which comprises 1-5% of all myelomas, is a variant of plasma cell myeloma. It is defined as symptomatic myeloma without detectable monoclonal immunoglobulin levels on serum or urine immunofixation electrophoresis. Here, we report two cases of nonsecretory plasma cell myeloma that manifested as multi-foci periosseous plasmacytomas. Due to the inability to detect monoclonal immunoglobulin on serum or urine immunofixation electrophoresis and the lack of evidence of clonal plasma cells in the bone marrow, it was difficult to establish an early, accurate diagnosis. Misdiagnosing or mislabeling symptomatic myeloma patients with plasmacytoma results in the delay of their systemic treatment. Therefore, comprehensive imaging studies, the detection of free light chains, and histopathological confirmation from different sites and time points are necessary.