Impact of Sarcopenia on Outcome of Exercise Therapy in Older Non-Hodgkin Lymphoma Patients.

PURPOSE: The aim of this study was to investigate the effects of exercise therapy on physical function and quality of life (QOL) in older patients with non-Hodgkin lymphoma undergoing inpatient chemotherapy, including differences between patients with and without sarcopenia. METHODS: Thirty-one inpatients aged 70 years or older participated in this study. Grip and knee extensor strength, 6-minute walking test, body composition, nutritional status, fatigue and health-related QOL at admission and discharge were compared. In addition, the patients were classified into sarcopenic and non-sarcopenic groups, and a comparison between admission and discharge and 2-way ANOVA were performed. RESULTS: Overall, grip strength and skeletal muscle mass were significantly lower at discharge than at admission (P < .05); however, QOL significantly improved (P < .05). In the non-sarcopenia group, grip strength, right knee extension muscle strength, and skeletal muscle mass were all significantly lower at discharge than at admission (P < .05); however, this was not the case in the sarcopenia group. In terms of QOL, improvements were observed in different items in the non-sarcopenia and sarcopenia groups. There was a significant interaction between admission to discharge time period and sarcopenia regarding left grip strength, right knee extensor strength, and QOL. CONCLUSION: Exercise therapy is effective in improving QOL in older non-Hodgkin lymphoma patients undergoing inpatient chemotherapy. However, the effect of exercise therapy and optimal exercise load may differ between non-sarcopenia and sarcopenia patients. Therefore, it is necessary to consider exercise therapy in the future, taking into account the presence or absence of sarcopenia.

Eyewash with balanced salt solution after intravitreal methotrexate injection in a case of vitreoretinal lymphoma: a simple but effective way to prevent ocular surface toxicity.

Intravitreal methotrexate injection (400 µg/0.1 mL) is the current mainstay for managing vitreoretinal lymphoma. Various complications associated with intravitreal methotrexate are cataract, keratopathy, maculopathy, sterile endophthalmitis, optic atrophy, vitreous haemorrhage, etc. The most common adverse effect of intravitreal methotrexate is keratopathy occurring in more than half of cases. The severity may range from diffuse punctate keratopathy to severe epitheliopathy leading to photophobia, pain, visual blurring, epiphora, etc. This may become a reason for reduced compliance with treatment. The management of these complications includes oral folic acid, topical folinic acid supplementations and reduced frequency or cessation of methotrexate intravitreal injections. Here, we report a simple method of eyewash in a large amount of balanced salt solution after the intravitreal injection procedure to reduce the severity of keratopathy, which helped the patient tolerate the treatment.

A prospective analysis of red blood cell membrane polyunsaturated fatty acid levels and risk of non-Hodgkin lymphoma.

Published studies report inconsistent associations of polyunsaturated fatty acid (PUFA) intake with non-Hodgkin lymphoma (NHL) risk. We conducted a nested case-control study in Nurses' Health Study and Health Professionals Follow-Up Study participants to evaluate a hypothesis of inverse association of pre-diagnosis red blood cell (RBC) membrane PUFA levels with risk of NHL endpoints. We confirmed 583 NHL cases and matched 583 controls by cohort/sex, age, race and blood draw date/time. We estimated odds ratios (OR) and 95% confidence intervals (CI) for risk of NHL endpoints using logistic regression. RBC PUFA levels were not associated with all NHL risk; cis 20:2n-6 was associated with follicular lymphoma risk (OR [95% CI] per one standard deviation increase: 1.35 [1.03-1.77]), and the omega-6/omega-3 PUFA ratio was associated with diffuse large B-cell lymphoma risk (2.33 [1.23-4.43]). Overall, PUFA did not demonstrate a role in NHL etiology; the two unexpected positive associations lack clear biologic explanations.

Association between Meat, Fish, and Fatty Acid Intake and Non-Hodgkin Lymphoma Incidence: The Japan Public Health Center-Based Prospective Study.

BACKGROUND: Meat, fish, and fatty acid intakes have been reported to be associated with non-Hodgkin lymphoma (NHL), although results have been inconclusive. We hypothesized that red meat and SFA intakes increase NHL risk, and fish and PUFA intakes decrease NHL risk. OBJECTIVES: We investigated the association between NHL incidence and meat, fish, and various fatty acid type intakes using the Japan Public Health Center-based Prospective Study. METHODS: The current cohort study included 93,366 participants aged 45-74 y who were eligible for analysis; they were followed up until December 2012. Participants answered an FFQ between 1995 and 1999. We analyzed the effects of meat, fish, total fatty acid, SFA, and PUFA intakes on NHL incidence using the Cox proportional hazard model. RESULTS: The median age was 57 y (IQR: 51-63 y), and 46.5% of the participants were men. Participants were followed up for 1,345,001 person-years, and 230 patients with NHL were identified. Total fatty acid and SFA intakes were associated with an increased incidence of NHL, with an adjusted HR of 1.56 (95% CI: 1.04, 2.34 highest compared with lowest quartile; P-trend = 0.062), and 1.63 (95% CI: 1.11, 2.41; P-trend = 0.074), respectively. In subtype analysis, total fatty acid and SFA intakes were also associated with increased incidence of follicular lymphoma but were not significantly associated with diffuse large B-cell lymphoma. Conversely, total meat, processed meat, unprocessed meat, red meat, poultry, fish, MUFA, PUFA, n-3 (ω-3) PUFA, and n-6 (ω-6) PUFA intakes were not significantly associated with the incidence of NHL or its subtypes. CONCLUSIONS: Total fatty acid and SFA intakes were associated with increased incidence of NHL in the Japanese adult population. Further large-scale studies are warranted to test whether fatty acid intakes affect the development of NHL.

Multifunctional theranostic nanoparticles for multi-modal imaging-guided CAR-T immunotherapy and chemo-photothermal combinational therapy of non-Hodgkin's lymphoma.

Accurate and effective tumor diagnosis, detection, and treatment are key for improving the survival rates of patients. Chimeric antigen receptor T (CAR-T) cell therapy has shown remarkable clinical success in eradicating hematologic malignancies. However, the hostile microenvironment in solid tumors severely prevents CAR-T cells from migrating and from infiltrating and killing malignant cells. Tumor microenvironment modulation strategies have attracted much attention in the field of cancer immunotherapy. Multifunctional nanoplatforms that integrate the advantages of different therapeutic techniques can allow for the multimodal synergistic treatment of tumors. In this study, a biocompatible, tumor-targeting, on-demand approach combining CAR-T cell immunotherapy and a chemo-photothermal therapy nanoplatform (FA-Gd-GERTs@Ibrutinib) based on gadolinium-loaded gap-enhanced Raman tags (Gd-GERTs) has been developed for multimodal imaging, and it provides a reliable treatment strategy for solid tumor immunotherapy via microenvironment reconstruction. In our study, folate (FA) receptor targeted molecules are used to improve the accuracy and sensitivity of computed tomography/magnetic resonance/Raman multimodal tumor imaging. The photothermal effect of the nanoprobe can promote the angiogenesis of lymphoma tissue, destroy the extracellular matrix, loosen compact tissue, stimulate chemokine secretion, and effectively enhance the infiltration ability in the case of non-Hodgkin's lymphoma, without dampening the CD19 CAR-T cell activity. The treatment results in tumor-bearing mice proved the existence of excellent synergistic therapy; photothermal therapy improves the accumulation and effector function of CAR-T cells within solid tumors. It is believed that multifunctional nanomaterials with targeted multi-modal imaging capabilities that support combination therapy can provide an efficient route for accurate diagnosis and efficient treatment.

Isolation and characterization of anti-inflammatory and anti-proliferative compound, for B-cell Non-Hodgkin lymphoma, from Nyctanthes arbor-tristis Linn.

ETHNOPHARMACOLOGICAL RELEVANCE: Nyctanthes arbor-tristis Linn. is native to Indo-Pak sub-continent and has high medicinal values in Ayureda. This plant has been used traditionally for the treatment of sciatica, rheumatism, chronic fever, diabetes, snakebite, dysentery, cachexia and cancer. Studies have shown many pharmacological properties such as anti-cancer efficacy against Dalton's ascetic lymphoma, cytotoxicity against T-cell leukemia, anti-inflammatory, anti-diabetic and anti-oxidant effects. AIM OF THE STUDY: Aim of the study was to explore the anti-inflammatory and anti-proliferative potential of N. arbor-tristis. MATERIAL AND METHODS: Ethanol extract of fresh and uncrushed aerial parts of N. arbor-tristis was used in the present study. A new compound nyctanthesin A was isolated following a bioactivity-guided fractionation and chromatographic separations. Its chemical structure was elucidated through spectral studies including 1D, 2D-NMR experiments and HREIMS. The intracellular reactive oxygen species (ROS) and nitric oxide (NO) generation from phagocytes were detected by chemiluminescence technique and Griess method, respectively. TNF-α and TGF-ß production was quantified by ELISA. Anti-lymphoma and cytotoxic activities were assessed by alamar blue and MTT assays, respectively. The transcription and protein expression level of Bcl-2, COX-2, p38 MAPK, PDL-1, NF-κB, c-Myc and PNF-κB was performed by qRT-PCR and protein blot assays, respectively. RESULTS: Petroleum ether insoluble fraction of the ethanol extract of fresh and uncrushed aerial parts of N. arbor-tristis revealed anti-inflammatory potential by inhibiting ROS. A previously undescribed compound nyctanthesin A was isolated from this fraction and characterized by UV, IR, NMR and HREIMS. It showed significant anti-inflammatory property by inhibiting ROS, NO and TNF-α production. The strong anti-proliferative effects on B- cell lymphoma cells, DOHH2 and Raji, revealed its anti-lymphoma potential along with non-toxic profile against BJ and NIH-3T3 fibroblast cells of normal origin. The qRT-PCR results showed marked inhibition of Bcl-2, COX-2, p38 MAPK, PDL-1, c-Myc, NF-κB, and PNF-κB at transcription level in DOHH2 cells with comparatively lesser but significant effects in Raji cells, where the expression of Bcl-2 gene was not affected. The protein expression of PNF-κB in DOHH2 cells was inhibited by 66% (P < 0.05) and COX-2 in both cell lines was inhibited by 50% (P < 0.05) at 60 µg/mL. A moderate non-significant inhibition of TGF-ß (∼20%) was observed in both cell lines at 100 µg/mL CONCLUSIONS: Scientific evidences reported here validate the anti-inflammatory and anti-cancer potential of the plant.

Nutritional status of patients with lymphoproliferative neoplasms before and after the first-line treatment.

BACKGROUND: Nutritional disorders in cancer patients, including lymphoproliferative neoplasms, occur with varying frequency. OBJECTIVES: The primary aim of the study was to analyze the changes in the nutritional status of patients with lymphoproliferative neoplasms following first-line chemotherapy. MATERIALS AND METHODS: 46 patients, with a median age of 62 years, participated in a prospective single-center study. Their demographic, biochemical and clinical features were analyzed. The study consisted of several stages that were conducted at two time points. P values < 0.05 were considered statistically significant. RESULTS: The study included patients with multiple myeloma (48%), non-Hodgkin's lymphoma (28%) or chronic lymphocytic leukemia (24%). After the end of the first-line chemotherapy, a decrease in the concentration of albumin (p = 0.04), transferrin (p = 0.38) and total cholesterol (p = 0.76) were found. Statistically greater unintended weight loss occurred before treatment initiation (p < 0.001). Moreover, a significant decrease in the mean values of the phase angle (p < 0.01) was noted. CONCLUSIONS: Most patients before the oncological therapy did not show clinical or biochemical symptoms of malnutrition. However, after the treatment was completed, the parameters of the nutritional status showed its deterioration.

Advances in treatment of elderly primary central nervous system lymphoma.

The management of older individuals (≥60 years) with primary central nervous system lymphoma remains a clinical challenge. Identification of optimal therapy and delivering adequate dose intensity are two of the major issues in treating elderly patients. Premorbid performance status and comorbidities influence individualised treatment approaches and geriatric assessment tools are increasingly utilised. Optimal induction treatment remains high-dose methotrexate-based immunochemotherapy, delivery is feasible in the majority of patients and the goal of treatment remains achieving complete remission. Consolidation strategies are also relevant in the elderly, aiming to maximise duration of response and quality of life (QoL). Potential options include high-dose therapy with haematopoietic stem cell consolidation, non-myeloablative chemotherapy and whole-brain radiotherapy. Efficacy of novel agents, such as Bruton tyrosine kinase inhibitors and lenalidomide, have been reported; these represent an alternative for elderly patients unfit for chemotherapy. Prognosis remains poor, improvement of outcomes in this age group is urgently needed.

Acupuncture for improving a case of widespread herpes zoster after non-Hodgkin's lymphoma chemotherapy.

BACKGROUND: Herpes zoster presents as clustered blisters on one side of the body, accompanied by nerve pain. This is caused by reactivation of the varicella zoster virus, and it occurs primarily in people with weakened immunity. Tumor and chemotherapy drugs can impair the patient's immune function, induce herpes zoster and prolong the course of disease.In these patients, skin changes can last for months and blisters can recur and cause serious complications such as postherpetic neuralgia.Acupuncture is a common alternative therapy for herpes zoster in East Asia. CASE PRESENTATION: We report a case of an elderly male patient with widespread herpes zoster in the trunk after non-Hodgkin's lymphoma chemotherapy. The patient had received conventional treatment with valaciclovir and mecobalamin within 24 hours of symptom onset. Because neither the clustered blisters nor the nerve pain were improved a week later, acupuncture and related techniques were applied. These included electro-acupuncture, surrounding acupuncture, fire acupuncture, and cupping. The patient recovered 20 days after the herpes zoster attack, and there were no adverse reactions during the treatment process. CONCLUSIONS: This case suggests that acupuncture and related techniques are effective interventions for this condition.This case report is innovative because it shows that acupuncture as an adjuvant treatment can improve the skin lesions in patients with HZ after tumour chemotherapy, relieve pain, and shorten the course of HZ.

No Association Observed between Coffee Intake and Risk of Non-Hodgkin Lymphoma among Postmenopausal Women.

BACKGROUND: Some preliminary studies indicate that components in coffee may have anticarcinogenic effects. However, the association between coffee-drinking habits and the risk of non-Hodgkin lymphoma (NHL) remain controversial. OBJECTIVE: To examine the relationship between coffee intake and NHL incidence in a large prospective study of postmenopausal US women. DESIGN AND PARTICIPANTS/SETTING: The participants included 74,935 women from the Women's Health Initiative Observational Study who were recruited from 1993 through 1998. Information about coffee-drinking habits was collected at baseline via self-administered questionnaires. MAIN OUTCOME MEASURES: Newly diagnosed NHL was validated by medical records and pathology records. Separate analyses were performed for the following three subtypes of NHL: diffuse large B-cell lymphoma (n = 244), follicular lymphoma (n = 166), and chronic lymphocytic leukemia/small lymphocytic lymphoma (n = 64). STATISTICAL ANALYSES PERFORMED: Age-adjusted and multivariable-adjusted Cox proportional hazards models were used to determine associations of coffee intake (specifically, the total amount of coffee consumed daily, coffee types, and coffee preparation methods) with risk of NHL. RESULTS: A total of 851 women developed NHL during a median 18.34 years of follow-up (range = 0.01 to 24.30 years; ± 6.63 years). Overall, no associations were observed between coffee intake and risk of NHL regardless of the total amount of daily coffee intake (P value for trend = 0.90), caffeinated (P = 0.55) or decaffeinated coffee intake (P = 0.78), and filtered or unfiltered coffee intake (P = 0.91) after controlling for sociodemographic factors, lifestyle risk factors, and clinical risk factors/current medical conditions. No significant associations were observed between coffee intake with specific subtypes of NHL. A statistically significant interaction was found between alcohol intake, coffee intake, and incident NHL (P value for interaction = 0.02) based on the adjusted analysis. Specifically, among women who frequently consumed alcohol (> 7 drinks/week), those who had moderate coffee intake (2 to 3 c coffee/day) had a significantly reduced risk of developing NHL (hazard ratio 0.61, 95% CI 0.36 to 0.98), compared with those who did not drink coffee. CONCLUSIONS: The findings from this study do not support an association between coffee consumption and NHL risk, irrespective of the total amount of daily coffee intake, coffee types, or coffee preparation methods.

[Cutaneous pseudolymphoma after hirudotherapy : Case report and review]. / Kutane Pseudolymphome nach Hirudotherapie : Fallbericht und Literaturübersicht.

The term cutaneous pseudolymphoma (C-PSL) is defined in the literature as a benign, reactive lymphoproliferation that clinically and/or histopathologically imitates cutaneous lymphoma. The exact etiopathogenesis has not been fully elucidated to date. A distinction is made between primary, idiopathic PSL without an identifiable cause and secondary PSL with a known stimulus. We report the occurrence of pseudolymphoma after treatment with medicinal leeches (hirudotherapy). To the best of our knowledge, a total of only nine cases of cutaneous PSL after hirudotherapy have been reported in the literature to date.

[Gastric MALT lymphoma - from pathogenetic insights to consequent deescalation of therapy]. / Gastrale MALT-Lymphome ­ von pathogenetischen Erkenntnissen zu konsequenter Deeskalation der Therapie.

Gastric MALT- (mucosa-associated-lymphoid-tissue) lymphoma represents the most frequent gastrointestinal lymphoma. For decades, surgery and later on radiation and chemotherapy were regarded as established therapy. Some 30 years ago, the pathogenetic role of Helicobacter pylori infection for the development of gastric MALT-lymphoma became evident. During the following years, the pathogenetic insights were consequently implemented into clinical medicine. This lead to a radical change of the therapeutic approach to these lymphoma. Nowadays, Helicobacter pylori eradication is the internationally established therapy of first choice. It is followed by lymphoma regression in most cases. The long-term prognosis of patients after exclusive eradication therapy is excellent, even if endoscopic and/or histological residuals persist and a watch-and-wait strategy is favored.The pathogenetic insights und their clinical application implicated a consequent deescalation of therapy of gastric MALT-lymphoma. This review summarizes the single steps of this development and gives a recommendation for the actual management of patients with gastric MALT lymphoma.

Novel Therapies for Follicular Lymphoma and Other Indolent Non-Hodgkin Lymphomas.

OPINION STATEMENT: When selecting therapy for patients with indolent non-Hodgkin lymphoma (iNHL) including follicular (FL), marginal zone (MZL), small lymphocytic (SLL), and lymphoplasmacytic lymphoma (LPL)/Waldenström macroglobulinemia (WM), there are several factors to consider. With a median age around 70 at diagnosis, many patients have accumulated comorbid conditions that may limit treatment options. Although incurable for most, iNHL is a chronic disease with a median overall survival measured in years to decades. This long natural history changes the risk-to-benefit balance with a lower acceptance of toxicity early in the treatment course compared to that of aggressive lymphomas. Despite a recent rapid increase in available therapies, overall progress in iNHL has been slow for several reasons. Initial trials grouped iNHLs together making it challenging to appreciate the differential activity among subtypes. We have not been able to develop prognostic models that maintain validity in the era of chemotherapy-free options. Predictive markers have been elusive and without identified molecular signatures, it is challenging to select and sequence therapy. With these clinical factors in mind, in addition to the heterogeneity among and within iNHLs, I do not have a standard treatment algorithm and feel each patient should have an individualized treatment approach. This review focuses on recent updates and controversies in the management of iNHL with a focus on FL and MZL.

Is Autologous Stem Cell Transplantation a Safe and Effective Alternative to Whole Brain Radiation as Consolidation Therapy in Patients With Primary Central Nervous System Lymphoma?: A Critically Appraised Topic.

BACKGROUND: High-dose chemotherapy followed by autologous stem cell transplantation (HD-ASCT) is a promising alternative to whole brain radiation therapy (WBRT) in the treatment of primary central nervous system lymphoma (PCNSL). The objective of this study was to critically assess current evidence supporting the use of HD-ASCT as first-line consolidative therapy in PCNSL. METHODS: The objective was addressed through the development of a critically appraised topic that included a clinical scenario, structured question, literature search strategy, critical appraisal, assessment of results, evidence summary, commentary, and bottom-line conclusions. Participants included consultant and resident neurologists, a medical librarian, clinical epidemiologists, and a content expert in the field of neuro-oncology. RESULTS: A recent, open-label, noncomparative randomized phase II trial was selected for critical appraisal. This trial evaluated the efficacy and toxicity of consolidative therapy with HD-ASCT and WBRT in PCNSL in 2 separate treatment arms. A total of 140 patients with newly diagnosed PCNSL between the ages of 18 and 60 years were included. The primary endpoint of 2-year progression-free survival was met in 63% of patients in the WBRT arm and 87% in the HD-ASCT arm. Notably, an overall improvement in neurocognitive scores was observed following HD-ASCT, while WBRT was associated with worsened cognitive outcomes. CONCLUSIONS: In young patients with newly diagnosed PCNSL, consolidative therapy with HD-ASCT appears to be associated with less neurocognitive toxicity and may be more effective than WBRT at preventing relapses, however, at the cost of a higher treatment-related mortality.

Primary Central Nervous System Lymphoma Mimicking Wernicke's Encephalopathy.

Primary central nervous system lymphoma (PCNSL) is a rare disease that can be confused with Wernicke encephalopathy (WE). We have reported here the case of a 31-year-old malnourished man who presented with headache, fever, vomiting, diarrhea, and confusion. His imaging and laboratory findings were indicative of WE. His condition improved after treatment with a high dose of vitamin B1 and intravenous administration of methylprednisolone. However, after continuing to take vitamin B1 for 2 weeks, his symptoms and neuroimaging findings worsened. Increased standardized uptake values of positron emission tomography with 2-deoxy-2-[fluorine-18]fluoro-D-glucose integrated with computed tomography (18F-FDG-PET) and interleukin-10 (IL-10) in the cerebrospinal fluid led to the diagnosis of PCNSL. After treatment with methotrexate and calcium leucovorin, the symptoms and neuroimaging abnormalities disappeared at the 6-month follow-up examination. The possibility of PCNSL should be considered if the routine treatment for WE are ineffective. 18F-FDG PET and IL-10 may provide a new method for the early diagnosis of PCNSL.

Does Cost-Effectiveness Analysis Overvalue Potential Cures? Exploring Alternative Methods for Applying a "Shared Savings" Approach to Cost Offsets.

OBJECTIVES: To evaluate alternative methods to calculate and/or attribute economic surplus in the cost-effectiveness analysis of single or short-term therapies. METHODS: We performed a systematic literature review of articles describing alternative methods for cost-effectiveness analysis of potentially curative therapies whose assessment using traditional methods may suggest unaffordable valuations owing to the magnitude of estimated long-term quality-adjusted life-year (QALY) gains or cost offsets. Through internal deliberation and discussion with staff at the Health Technology Assessment bodies in England and Canada, we developed the following 3 alternative methods for further evaluation: (1) capping annual costs in the comparator arm at $150 000 per year; (2) "sharing" the economic surplus with the health sector by apportioning only 50% of cost offsets or 50% of cost offsets and QALY gains to the value of the therapy; and (3) crediting the therapy with only 12 years of the average annual cost offsets or cost offsets and QALY gains over the lifetime horizon. The impact of each alternative method was evaluated by applying it in an economic model of 3 hypothetical condition-treatment scenarios meant to reflect a diversity of chronicity and background healthcare costs. RESULTS: The alternative with greatest impact on threshold price for the fatal pediatric condition spinal muscular atrophy type 1 was the 12-year cutoff scenario. For a hypothetical one-time treatment for hemophilia A, capping cost offsets at $150 000 per year had the greatest impact. For chimeric antigen receptor T-cell treatment of non-Hodgkin's lymphoma, capping cost offsets or using 12-year threshold had little impact, whereas 50% sharing of surplus including QALY gains and cost offsets greatly reduced threshold pricing. CONCLUSIONS: Health Technology Assessment bodies and policy makers will wrestle with how to evaluate single or short-term potentially curative therapies and establish pricing and payment mechanisms to ensure sustainability. Scenario analyses using alternative methods for calculating and apportioning economic surplus can provide starkly different assessment results. These methods may stimulate important societal dialogue on fair pricing for these novel treatments.

Successful treatment of Epstein-Barr virus-associated primary central nervous system lymphoma due to post-transplantation lymphoproliferative disorder, with ibrutinib and third-party Epstein-Barr virus-specific T cells.

Primary central nervous system lymphoma (PCNSL) occurring following organ transplantation (post-transplantation lymphoproliferative disorder [PTLD]) is a highly aggressive non-Hodgkin lymphoma. It is typically treated with high-dose methotrexate-based regimens. Outcomes are dismal and clinical trials are lacking. It is almost always Epstein-Barr virus (EBV) associated. Two patients (CA1-2) presented with EBV-associated PCNSL after renal transplant. CA1 was on hemodialysis and had prior disseminated cryptococcus and pseudomonas bronchiectasis, precluding treatment with methotrexate. CA2 was refractory to methotrexate. Both were treated off-label with the first-generation Bruton's tyrosine kinase inhibitor ibrutinib for 12 months. Cerebrospinal fluid penetration at therapeutic levels was confirmed in CA1 despite hemodialysis. Both patients entered remission by 2 months. Sequencing confirmed absence of genetic aberrations in human leukocyte antigen (HLA) class I/II and antigen-presentation/processing genes, indicating retention of the ability to present EBV-antigens. Between Weeks 10 and 13, they received third-party EBV-specific T cells for consolidation with no adverse effects. They remain in remission ≥34 months since therapy began. The strength of these findings led to an ongoing phase I study (ACTRN12618001541291).

Achyranthes aspera L. leaf extract induced anticancer effects on Dalton's Lymphoma via regulation of PKCα signaling pathway and mitochondrial apoptosis.

ETHNOPHARMACOLOGICAL RELEVANCE: Epidemiological studies promote the inclusion of natural-products in diet due to their inhibitory effects on various types of cancer. Among them, Achyranthes aspera L. (Family Amaranthaceae) is a medicinal plant in Ayurvedic pharmacopeia, found in India, Southeast Asia, America, and Sub-Saharan Africa. It is endowed with anti-inflammatory, anti-oxidant, and anti-cancer activities. However, its potential effect on Non-Hodgkin lymphomas (NHLs), has not yet been clarified. AIM OF THE STUDY: In the present study, we aimed to investigate the effect of Achyranthes aspera L. leaf extracts on highly aggressive murine NHL called Dalton's Lymphoma (DL) in vitro and in vivo. MATERIAL AND METHODS: GC-HRMS analysis was carried out for the identification of compounds present in A. aspera leaf extract. The cytotoxicity of various A. aspera leaf extracts was evaluated on DL cells by MTT assay. Chromatin condensation, nuclear fragmentation, and morphological changes were observed by microscopy technique. Flow cytometry was used to measure the changes in mitochondrial membrane potential (ΔΨm) and apoptosis. In addition, the expressions of apoptosis-related proteins were detected by western blotting. Meanwhile, the in vivo anti-tumor effect of leaf extract was tested in DL induced Balb/c mice. RESULT: GC-HRMS analysis of A. aspera methanolic leaf extract (AAML) revealed the presence of ten pharmacologically active compounds. The results showed that AAML suppressed cell proliferation, decreased mitochondrial membrane potential, changed the morphological structure, and induced apoptosis. Moreover, AAML could promote the release of cytochrome c by regulating Bcl-2 family proteins and then activated caspase-9/ -3 to triggered cell apoptosis. At the same time in DL cells treated with AAML, the protein kinase Cα (PKCα) pathway was inhibited in a concentration-dependent manner. Remarkably, in vivo, AAML mediated suppression of DL growth in Balb/c mice was accompanied by attenuation of the PKCα pathway and induction of apoptosis. Our result suggested that AAML promotes mitochondrial apoptotic cascade in DL cells by suppressing the PKCα signaling pathway. CONCLUSION: The study suggests that AAML could potently suppress DL progression by promoting apoptosis via mitochondrial-cascade and attenuation of the PKCα signaling pathway.

Low grade, indolent lymphomas of the head and neck: Comparative toxicity of standard versus very low dose radiation therapy.

National Comprehensive Cancer Network guidelines recommend radiation therapy (RT) for localized indolent non-Hodgkin lymphomas (iNHL). Many referring physicians avoid RT to the head and neck (HN) due to fears of toxicity. Very low-dose radiation (4 Gy) for select patients produces sustained local control and recently gained popularity. We compared early and late toxicities of standard 24-30 Gy to 4 Gy in patients with HN iNHL. We retrospectively analyzed 266 consecutive patients with HN iNHL receiving RT from 1994 to 2017. Patient characteristics, outcomes, and toxicities were collected from medical records. Early (≤2 months post-RT) and late (>2 months post-RT) toxicities were graded per Common Terminology Criteria for Adverse Events version 4. Grades 1-2 were defined as "low-grade" and 3-4 "high-grade." Toxicity incidence was compared between 4 and >4 Gy, grouped by treated site (orbit, nonorbital head, neck, skin) and early versus late. Median follow-up was 23 months (2-145) and 68 months (2-256) for 4Gy and >4 Gy cohorts, respectively. Median dose for the >4 Gy cohort was 30 Gy (10.5-54 Gy). Early and late toxicity incidences were lower in the 4 Gy cohort compared to >4 Gy across all RT-sites: early toxicity, orbit, 42% versus 96%; nonorbital head, 24% versus 96%; neck, 22% versus 94%; skin, 31% versus 87%; late toxicity, orbit, 20% versus 71%; nonorbital head, 6% versus 66%; neck, 6% versus 57%; skin, 0% versus 46% (4 Gy vs. >4 Gy, respectively). Toxicities among both cohorts were largely low-grade. High-grade early and late toxicities did not occur in the 4 Gy cohort. There was 1 high-grade early toxicity (Grade 3 dry mouth) and 17 high-grade late toxicities (Grade 3 cataracts) in the >4 Gy cohort. RT to HN for iNHL is associated with minimal short- and long-term toxicity and excellent local control among 4 Gy and >4 Gy treatments. In this setting, "toxicity" concerns should not deter oncologists from potentially curative RT. In select patients where toxicity remains a concern, very low dose 4 Gy could be considered.

Ambulatory high-dose methotrexate administration as central nervous system prophylaxis in patients with aggressive lymphoma.

High-dose methotrexate (HD-MTX) at 3 g/m2 is one of the strategies for central nervous system (CNS) prophylaxis in the first-line treatment of aggressive lymphomas, especially in diffuse large B cell lymphoma patients with high-risk CNS-International Prognostic Index. The objective of our study was to retrospectively analyze the safety of 2 cycles of systemic HD-MTX administered as an ambulatory regimen. Between January 2013 and December 2016, 103 patients were carefully selected on 6 criteria, including age < 60, albumin > 34, performance status 0 or 1, normal renal and hepatic functions, good understanding of practical medical guidance, and no loss of weight. Strict procedures of HD-MTX infusion were observed including alkalinization, urine pH monitoring, and leucovorin rescue. Renal and hepatic functions were monitored at days 2 and 7. MTX clearance was not monitored. Toxicities and grades of toxicity were collected according to the NCI-CTCAE (version 4.0). Among the 103 selected patients, 92 (89%) patients successfully completed the planned 2 cycles of HD-MTX on an outpatient basis. Eleven patients completed only 1 cycle, 3 because of lymphoma progression and 8 because of toxicity including 3 grade II hepatotoxicity, 2 grade I/II renal toxicity, 1 grade III neutropenia, 1 active herpetic infection, and 1 grade III ileus reflex. Reported adverse events (AE) included 92 (84%) grade I/II and 18 (16%) grade III/IV. Grade III hepatotoxicity, mostly cytolysis, was the most frequent AE observed with 8 (8%) events. Grade III/IV hematologic toxicities concerned 9 patients with 8 grade III/IV neutropenia and 1 thrombocytopenia. Renal toxicity was rare, mild, and transient, observed with 4 (4%) grade I/II events. Ambulatory administration of HD-MTX at 3 g/m2 without MTX clearance monitoring is safe with strict medical guidance. It requires careful selection of patients before administration, and a renal and hepatic monitoring after the administration.