Expression of L-type amino acid transporter 1 is a poor prognostic factor for Non-Hodgkin's lymphoma.

L-type neutral amino acid transporter 1 (LAT1) is a heterodimeric membrane transport protein involved in neutral amino acid transport. LAT1 is highly expressed in various malignant solid tumors and plays an essential role in cell proliferation. However, its role in malignant lymphoma remains unknown. Here, we evaluated LAT1 expression level in tissues from 138 patients with Non-Hodgkin lymphoma (NHL). Overexpression of LAT1 was confirmed in all types of NHL and we found that there is a significant correlation between the level of LAT1 expression and lymphoma grade. The LAT1 expression was higher in aggressive types of lymphomas when compared with static types of lymphomas, suggesting that active tumor proliferation requires nutrient uptake via LAT1. The expression level of LAT1 was inversely correlated with patients' survival span. Furthermore, pharmacological inhibition of LAT1 by a specific inhibitor JPH203 inhibits lymphoma cell growth. In conclusion, our study demonstrated that LAT1 expression can be used as a prognostic marker for patients with NHL and targeting LAT1 by JPH203 can be a novel therapeutic modality for NHL.

Black Fungus Complicated with COVID-19 in a Man with Underlying Non-Hodgkin's Lymphoma.

COVID-19 is a disease reported to suppress cellular immunity. This may lead to the development of opportunistic infections, among others black fungus, or mucormycosis. On the other hand, pre-existing defect in immunity may render patients susceptible to both mucormycosis and COVID-19. Mucormycosis is a relatively rare fungal infection with rapid progression unless diagnosed promptly and treated adequately, and urgent surgical and medical intervention is lifesaving. The manifestation of mucormycosis largely depends on the presence of exposure to the pathogen and the existing risk factor of the host. As black fungus is locally invasive, the majority of cases will involve tissue damage with local destruction and contiguous spread to nearby structure. We here with present a case of black fungus complicated with COVID-19 in a man with underlying non-Hodgkin's lymphoma.

Cancer-related Fatigue in Relation to Chronotype and Sleep Quality in (Non-)Hodgkin Lymphoma Survivors.

Cancer-related fatigue has been related to circadian disruptions and lower levels of sleep quality. However, it is unknown whether the circadian phase, which is associated with chronotype and timing of sleep, is related to fatigue after cancer. The aims of this study were to investigate the associations between (1) chronotype and cancer-related fatigue and (2) sleep quality and cancer-related fatigue. In this cross-sectional questionnaire study, 458 (non-)Hodgkin lymphoma survivors (n = 231 female, mean age 49.7 years) completed a Visual Analogue Scale for fatigue (VAS-fatigue) from 0 (no fatigue) to 10 (worst imaginable fatigue), the Munich Chronotype Questionnaire (MCTQ), and the Pittsburgh Sleep Quality Index (PSQI) between October 2018 and July 2019. A hierarchical linear regression analysis was used to evaluate the associations between the dependent variable fatigue and chronotype (based on early, intermediate, or late average midsleep) in Model 1, and fatigue and sleep quality in Model 2. The results showed no indications for an association between chronotype and fatigue (all p values ≥ 0.50). There were associations between two (out of seven) aspects of sleep quality and fatigue: subjective sleep quality (p < 0.001) and daily dysfunctioning (p < 0.001). Therefore, it is more likely that fatigue is associated with self-reported sleep quality rather than with chronotype. However, experimental studies with objective, physiological data on circadian phase and sleep quality are necessary to confirm the conclusions of this cross-sectional study.

The Effect of Foot Massage on Peripheral Neuropathy-Related Pain and Sleep Quality in Patients With Non-Hodgkin's Lymphoma.

This study, which was conducted on patients with non-Hodgkin's lymphoma, aimed to evaluate the effect of foot massage on peripheral neuropathic pain and sleep quality. The survey was conducted between November 2018 and April 2019. Research data were collected through questionnaire, visual analogue scale (VAS), Douleur Neuropathique 4/Neuropathic Pain 4 (DN4) Questions, and Pittsburgh Sleep Quality Index. Classical foot massage was applied to participants in the intervention group, and they received 3 sessions a week, with each session lasting for 20 minutes over a period 4 weeks. After each massage session, pain levels were again assessed using the VAS and DN4 questionnaires. It has been shown that foot massage intervention reduces the patients' pain levels and has a positive effect on their sleep quality. Accordingly, foot massage can be recommended to patients with non-Hodgkin's lymphoma to reduce their peripheral neuropathy-related pain and improve their sleep quality.

Role of CD47 in Hematological Malignancies.

CD47, or integrin-associated protein, is a cell surface ligand expressed in low levels by nearly all cells of the body. It plays an integral role in various immune responses as well as autoimmunity, by sending a potent "don't eat me" signal to prevent phagocytosis. A growing body of evidence demonstrates that CD47 is overexpressed in various hematological malignancies and its interaction with SIRPα on the phagocytic cells prevents phagocytosis of cancer cells. Additionally, it is expressed by different cell types in the tumor microenvironment and is required for establishing tumor metastasis. Overexpression of CD47 is thus often associated with poor clinical outcomes. CD47 has emerged as a potential therapeutic target and is being investigated in various preclinical studies as well as clinical trials to prove its safety and efficacy in treating hematological neoplasms. This review focuses on different therapeutic mechanisms to target CD47, either alone or in combination with other cell surface markers, and its pivotal role in impairing tumor growth and metastatic spread of various types of hematological malignancies.

Molecular features of a large cohort of primary central nervous system lymphoma using tissue microarray.

The objective of this study was to evaluate the distribution and prognostic impact of a broad range of molecular attributes in a large cohort of immunocompetent patients with primary central nervous system lymphoma (PCNSL) by using tissue microarray. Patients diagnosed with PCNSL were initially identified in the BC Cancer Lymphoid Cancer clinical and pathology databases. Tissue microarrays were constructed by using archival formalin-fixed paraffin-embedded diagnostic biopsy tissue. Immunohistochemistry and fluorescent in situ hybridization studies were performed. A total of 115 patients with PCNSL with diffuse large B-cell lymphoma (DLBCL) histology were identified. The majority of cases (≥75%) had a non-germinal center B-cell phenotype according to immunohistochemistry algorithms, but cell of origin did not affect progression-free or overall survival. MYC (40%), BCL2 (75%), and programmed death-ligand 1 (29%) protein expression were common, but their corresponding gene rearrangements were rare (≤1% each), suggesting that alternate mechanisms were driving expression. There were no dual rearrangements involving MYC and BCL2. Only 22% of cases had membranous expression of major histocompatibility complex class II, suggesting a mechanism for escape from immune surveillance. Epstein-Barr virus-encoded RNA was positive in 1 immunocompetent patient. BCL6 protein expression (77%) and BCL6 rearrangements (31%) were frequent; the latter was the only factor associated with a poor prognosis in the overall cohort and in the subgroup of 52 patients treated with high-dose methotrexate-based regimens. This large population-based study shows that prominent molecular features of PCNSL are unique and different from those of systemic DLBCL. These results may better inform drug development in PCNSL.

Fertility preservation with successful pregnancy outcome in a patient with transplanted heart and non-Hodgkin's lymphoma - a case report.

BACKGROUND: Fertility preservation must be discussed with reproductive age women before cancer treatment. Heart transplantation raises complex issues in pregnancy. Pregnancy in a heart transplant woman after pelvic irradiation involves close multidisciplinary follow-up to avoid complications in the mother and the foetus. We report the first live birth in a heart transplant woman after pelvic irradiation, chemotherapy and fertility preservation. CASE PRESENTATION: A 36-year-old heart transplant woman with pelvic non-Hodgkin lymphoma spared her fertility, with cryopreservation of oocytes and embryos, before chemotherapy and pelvic irradiation. After multidisciplinary discussion and pre-conception evaluation, pregnancy was achieved. A close follow-up by a multidisciplinary team allowed a normal pregnancy without maternal or foetal complications and the delivery of a healthy infant. CONCLUSIONS: Achieving pregnancy in heart transplant women with iatrogenic ovarian failure after oncologic treatment including pelvic irradiation is possible and can be successful. Careful and close surveillance by a multidisciplinary team is mandatory due to increased risk of maternal and foetal complications.

[Effects of aerobic glycolysis on pathogenesis and drug resistance of non-Hodgkin lymphoma].

It has been shown that aerobic glycolysis (AG) plays an important role in the pathogenesis and resistance mechanism of non-Hodgkin lymphoma (NHL) in recent years. Signaling pathway related to abnormal activation of AG can increase the level of AG in lymphatic and hematopoietic cells, while the enzymes related to the activity of AG are involved in the pathogenesis and prognosis of NHL. Drugs that inhibit AG can also inhibit NHL cells in vitro. Drugs inhibiting AG may increase the sensitivity of chemotherapeutic agents and prevent drug resistance. In this article, the role of signaling pathway proteins and regulatory genes related to AG in the pathogenesis and drug resistance of NHL are reviewed, and the AG as a target in the clinical diagnosis and treatment of NHL is discussed.

A Novel Predictor of Chemotherapeutic Cardiotoxicity in Patients with Non-Hodgkin Lymphoma.

BACKGROUND: It is known that chemotherapeutic agents cause myocardial cell damage leading to left ventricular dysfunction and heart failure. Fragmented QRS is an indication of fibrosis developing as a result of myocardial cell damage. The aim of this study is to assess whether there is a relationship between the chemotherapeutic treatment and the development of the fragmented QRS complex in electrocardiography (ECG). PATIENTS AND METHODS: Among 130 patients who were diagnosed with non-Hodgkin lymphoma and received an R-CHOP treatment regimen, the potential emergence of fragmented QRS on ECG as well as the changes in the left ventricular ejection fraction (LVEF) (on transthoracic echocardiography) in response to various chemotherapeutic regimens were sought. RESULTS: New development of a fragmented QRS pattern was observed in 53 of the 130 patients (40.8%). These patients were found to have lower LVEF values along with higher numbers of chemotherapy courses and cumulative doses. In the logistic regression analysis, age (OR = 1.042; 95% CI 1.009-1.076; p = 0.012) and number of courses (OR = 1.848; 95% CI 1.409-2.423; p < 0.001) were found to be the most important predictors of fragmented QRS development. In subjects with a fragmented QRS pattern, there was a significant difference between the initial and repeat LVEF values (p < 0.001). Importantly the emergence of a fragmentation pattern occurred much earlier compared to the drop in LVEF values (10.62 ± 4.04 vs. 15.24 ± 7.49 months). CONCLUSION: Development of a fragmented QRS pattern in response to cancer therapy emerges as a new parameter potentially predictive of chemotherapy-induced cardiotoxicity.

Seizures in patents with primary central nervous system lymphoma: Prevalence and associated features.

OBJECTIVE: Primary central nervous system (CNS) lymphoma (PCNSL) is a rare, aggressive, yet highly chemosensitive form of non-Hodgkin lymphoma which is associated with significant morbidity. Very little is known about the long-term risk for and features of seizures associated with this condition. METHODS: We performed a retrospective and longitudinal analysis of 36 patients with pathologically and radiographically confirmed primary CNS lymphoma to evaluate the incidence, prevalence and features associated with seizures. Demographic, radiographic, histological and electroencephalographic (EEG) data were included as part of the study. RESULTS: One-third of patients with primary CNS lymphoma had clinical seizures of which two-thirds occurred at time of initial presentation, while the remainder developed during a mean follow-up time of 1.49 years. The incidence rate of first seizure in PCNSL was 224.4 per 1000 persons, per year. There was a trend towards association with seizures in patients with cortical lesions relative to patients with subcortical lesions. EEG revealed epileptiform discharges in 44.4% of patients with both PCNSL and clinical seizures which suggests that it is a useful diagnostically in a substantial proportion of patients. CONCLUSIONS: A significant percentage of patients with primary CNS lymphoma develop comorbid seizures during their disease course. Increased awareness and collaboration between neuro-oncologists and epileptologists may enhance and improve care for these patients.

Permeability measurement using dynamic susceptibility contrast magnetic resonance imaging enhances differential diagnosis of primary central nervous system lymphoma from glioblastoma.

OBJECTIVES: To test if adding permeability measurement to perfusion obtained from dynamic susceptibility contrast MRI (DSC-MRI) improves diagnostic performance in the differentiation of primary central nervous system lymphoma (PCNSL) from glioblastoma. MATERIALS AND METHODS: DSC-MRI was acquired in 145 patients with pathologically proven glioblastoma (n = 89) or PCNSL (n = 56). The permeability metrics of contrast agent extraction fraction (Ex), apparent permeability (Ka), and leakage-corrected perfusion of normalized cerebral blood volume (nCBVres) and cerebral blood flow (nCBFres) were derived from a tissue residue function. For comparison purposes, the leakage-corrected normalized CBV (nCBV) and relative permeability constant (K2) were also obtained using the established Weisskoff-Boxerman leakage correction method. The area under the receiver operating characteristics curve (AUC) and cross-validation were used to compare the diagnostic performance of the single DSC-MRI parameters with the performance obtained with the addition of permeability metrics. RESULTS: PCNSL demonstrated significantly higher permeability (Ex, p < .001) and lower perfusion (nCBVres, nCBFres, and nCBV, all p < .001) than glioblastoma. The combination of Ex and nCBVres showed the highest performance (AUC, 0.96; 95% confidence interval, 0.92-0.99) for differentiating PCNSL from glioblastoma, which was a significant improvement over the single perfusion (nCBV: AUC, 0.84; nCBVres: AUC, 0.84; nCBFres: AUC, 0.82; all p < .001) or Ex (AUC, 0.80; p < .001) parameters. CONCLUSIONS: Analysis of the combined permeability and perfusion metrics obtained from a single DSC-MRI acquisition improves the diagnostic value for differentiating PCNSL from glioblastoma in comparison with single-parameter nCBV analysis. KEY POINTS: • Permeability measurement can be calculated from DSC-MRI with a tissue residue function-based leakage correction. • Adding Exto CBV aids in the differentiation of PCNSL from glioblastoma. • CBV and Exmeasurements from DSC-MRI were highly reproducible.

Primary B-cell Spinal Cord Lymphoma of the Cervical Spine.

Non-Hodgkin lymphomas are a heterogeneous group of tumours, with diffuse large B-cell lymphomas (DLBCL) being particularly common. Cases of DLBCLs developing in the central nervous system, especially in the spinal cord, are extremely rare and thus pose significant diagnostic and therapeutic problems, particularly for orthopaedists and neurologists since these are the specialists the patients first consult. The tumours often appear in immunosuppressed patients and standard chemotherapy is ineffective. This paper presents the case of a 44-year-old male with a lymphoma located in the spinal cord at the C7-Th1 level. The symptoms appeared suddenly and progressed rapidly, with dissociated sensory loss and limb paresis being the most pronounced. Imaging studies and the rapid symptom progression suggested neoplastic disease. An emergency surgical procedure was performed in order to decompress the spinal cord and thus limit neurological deficits. Tumour resection allowed for making a diagnosis. By four weeks after the surgery, the tumour had grown larger than before the procedure. Chemotherapy with MTX and Ara-C and intrathecal MTX resulted in full remission. Consolidation was achieved with radiotherapy. Currently, with the low incidence of such tumours, there are no standards of management in patients with DLBCLs of the CNS. The literature contains only a few case reports on successfully treated spinal cord DLBCLs.

Characteristics of pulmonary complications in non-Hodgkin's lymphoma patients treated with rituximab-containing chemotherapy and impact on survival.

Patients with non-Hodgkin's lymphoma (NHL) receiving rituximab-containing chemotherapy are at risk of developing respiratory complications, but comprehensive information on these complications and their impact on survival is lacking. We performed a retrospective cohort analysis on 123 NHL patients who received rituximab-containing chemotherapy between 2009 and 2016 in order to describe the incidence, etiologies and effect on survival of respiratory complications defined by new or worsening respiratory symptoms requiring diagnostic work-up or hospitalization. Thirty patients (24%) developed respiratory complications during a follow-up time of 825 (555-1338) days after chemotherapy. They had a higher prevalence of congestive heart failure and lung or pleural involvement at diagnosis as compared to patients who did not develop complications. Overall, 58 episodes of pulmonary complications were observed after median (interquartile) times from the first and last rituximab doses of 205 (75-580) days and 27 (14-163) days respectively. Infectious etiologies accounted for 75% of the respiratory complications, followed by heart failure exacerbation, lymphomatous involvement, and ARDS. Two Pneumocystis jirovecii pneumonias were observed, and no complication was ascribed to rituximab toxicity. Respiratory complications required ICU admission in 19 cases (33%) and invasive mechanical ventilation in 14 cases (24%). Using a time-dependent Cox regression analysis, we observed that the occurrence of respiratory complications was associated with a 170% increase in death hazard (hazard ratio 2.65, 95% CI 1.60-4.40, p = 0.001). In conclusion, respiratory complications in NHL patients receiving chemotherapy are relatively frequent, severe, and mostly infectious and are associated with increased mortality.

Simultaneous determination of plasma methotrexate and 7-hydroxy methotrexate by UHPLC-MS/MS in patients receiving high-dose methotrexate therapy.

The plasma concentrations of methotrexate (MTX) and its major metabolite 7-hydroxy methotrexate (7-OH-MTX) are highly correlated with the toxicities in patients with high-dose MTX therapy. Routine monitoring of MTX and 7-OH-MTX plasma levels is useful for dose adjustment of rescue drugs and toxicity prevention. A UHPLC-MS/MS method for simultaneous determination of plasma MTX and 7-OH-MTX was developed, validated, and applied in 181 plasma samples. The ion transition was m/z 455.2 → 308.2 for MTX and m/z 471.2 → 324.1 for 7-OH-MTX. The flow rate was 0.4 mL/min with a run time of 2.6 min. The calibration range was 0.002-2 µM for MTX, and 0.01-10 µM for 7-OH-MTX. The intra-day and inter-day inaccuracy and imprecision were -5.50% to 10.93% and less than 9.20% for both analytes. The internal standard (MTX-D3) normalized recovery and matrix factor were consistent at four quality control levels. 14 h, 38 h, and 62 h after dosing, MTX and 7-OH-MTX plasma levels were significantly higher in patients with impaired renal function compared to those with normal renal function. 7-OH-MTX plasma levels were significantly higher in patients with impaired liver function compared to those with normal liver function.

Lifetime physical inactivity is associated with increased risk for Hodgkin and non-Hodgkin lymphoma: A case-control study.

BACKGROUND: Although physical activity is a well-established risk factor for several cancer types, studies evaluating its association with lymphoma have yielded inconclusive results. In such cases where physical activity is not clearly associated with cancer risk in a dose-dependent manner, investigators have begun examining physical inactivity as an independent exposure of interest. METHODS: Associations of self-reported, lifetime physical inactivity with risk of developing Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) were evaluated in a hospital-based case control study using data from the Patient Epidemiology Data System at Roswell Park Comprehensive Cancer Center. Participants included 87 patients with HL and 236 patients with NHL as well as 348 and 952 cancer-free controls, respectively. Multivariable-adjusted logistic regression models were fit to calculate odds ratios (OR) and 95% confidence intervals (CI) estimating the association between physical inactivity and lymphoma risk. RESULTS: We observed significant, positive associations between lifetime recreational physical inactivity and risk of both HL (OR = 1.90, 95% CI: 1.15-3.15) and NHL (OR = 1.35, 95% CI: 1.01-1.82). CONCLUSIONS: The current analysis provides evidence for a positive association between physical inactivity and risk of both HL and NHL. These results add to a growing body of research suggesting that lifetime physical inactivity may be an important independent, modifiable behavioral risk factor for cancer.

Neurolymphomatosis in non-Hodgkin lymphoma with cranial multineuritis: A case report.

RATIONALE: Neurolymphomatosis (NL) is a rare syndrome of lymphoma and leukemic infiltration of cranial or peripheral nerves. PATIENT CONCERNS: We report a case of non-Hodgkin Lymphoma (NHL) in a 24-year-old man presented with difficulty in swallowing, hypersalivation, hoarseness, ptosis, facial paralysis, and facial hypoesthesia associated with NL. DIAGNOSIS: NL was diagnosed based upon cranial magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) examination. INTERVENTIONS: The patient was treated with intrathecal methotreaxate (12.5 mg) and cytosine arabinoside (70 mg), systemic high-dose methotrexate therapy, and cranial radiotherapy. OUTCOME: Due to the deterioration of general condition of the patient, he was admitted to intensive care unit, but died 22 days after the onset of symptoms in spite of aggressive treatment. LESSONS: In this case, we present a patient with T cell lymphoma and multineuritis of NL diagnosed by MRI and as far as we know, this is the first reported case in which so many cranial nerves (3, 5, 7, 8, 9, and 10 th) were involved. Briefly, in a patient with hematologic malignancy and neurological complaints, NL should be considered. Early and effective use of imaging modalities such as positron emission tomography (PET-CT), MRI, and aggressive therapies are important for prolonged survival.

Uncommon cause of dysphagia: paraneoplastic achalasia.

Achalasia secondary to underlying neoplasm is a rare entity. Early recognition of secondary achalasia is important as its treatment involves management of underlying malignancy, while treatment of primary achalasia mainly involves lowering the lower oesophageal sphincter pressure with pneumatic dilatation or Heller's myotomy. We discuss an interesting case of achalasia secondary to non-Hodgkin's lymphoma.

Applicability of 2008 World Health Organization classification system of hematolymphoid neoplasms: Learning experiences.

BACKGROUND: 2008 World Health Organization (WHO) classification of hematolymphoid neoplasms (HLN) has classified them based on morphology, results of various ancillary techniques, and clinical features.[1] There are no studies looking at the applicability of WHO classification. AIMS: The aim of the study was to calculate proportions of all HLN subtypes seen during 1-year period based on 2008 WHO classification of HLN and study applicability and also shortcomings of practices in a tertiary care center in India. MATERIALS AND METHODS: This was a 1-year retrospective study (January 1st, to December 31st, 2010) where cases were identified using hospital/laboratory electronic records. Old follow-up and referral cases were excluded from the study. Only newly diagnosed cases classified into categories laid down by 2008 WHO classification of HLN included. RESULTS: Out of 2118 newly diagnosed classifiable cases, 1602 (75.6%) cases were of lymphoid neoplasms, 489 (23.1%) cases of myeloid neoplasms, 16 (0.8%) cases of histiocytic and dendritic cell neoplasms, and 11 (0.5%) cases of acute leukemias of ambiguous lineage. Overall, most common HLN subtype was diffuse large B-cell lymphoma (n = 361, 17.0%). Precursor B-lymphoblastic leukaemia/lymphoma (n = 177, 48.2%) was the most common subtype within pediatric age group. CONCLUSIONS: All major subtypes of HLN were seen at our center and showed trends almost similar to those seen in other Indian studies. Molecular/cytogenetic studies could not be performed on a significant number of cases owing to logistic reasons (unavailability of complete panels and also cost-related issues) and such cases could not be classified as per the WHO classification system.