‘Les liaisons dangereuses’: Hepatitis C, Rituximab and B-cell non-Hodgkin’s lymphomas

Rituximab has provided a revolutionary contribution to the treatment of B-cell non-Hodgkin’s lymphomas (NHL). A high prevalence of hepatitis C virus (HCV) infection has been described in B-cell NHL patients. Cases of liver dysfunction in HCV-positive patients have been reported with Rituximab-containing regimens. In this paper we review the recent data regarding the effects of Rituximab in NHL patients with HCV infection. We also added a section devoted to improving communication between oncohaematologists and hepatologists. Furthermore, we propose a common methodological ground to study hepatic toxicity emerging during chemotherapy.

SENEX-mediated CDK4/6 inhibition promotes senescence and confers apoptosis resistance in B-cell non-Hodgkin lymphoma

Background:The primary cause of treatment failure in patients with refractory or relapsed B-cell non-Hodgkin lymphoma(r/r B-NHL)is resistance to current therapies,and therapy-induced senescence(TIS)stands out as a crucial mechanism contributing to tumor drug resistance.Here,we analyzed SENEX/Rho GTPase Activating Protein 18(ARHGAP18)expression and prognostic significance in doxorubicin-induced B-NHL-TIS model and r/r B-NHL patients,investigating its target in B-NHL cell senescence and the effect of combining specific inhibitors on apoptosis resistance in B-NHL-TIS cells.Methods:Raji cells were transfected with the human SENEX shRNA recombinant lentiviral vector(Sh-SENEX)and the empty vector negative(NC)to construct a stable transfection cell line with knockdown of SENEX.Effect of SENEX-silencing on B-NHL-TIS formation,cell function and cell cycle-related pathways was analyzed.Using doxorubicin(DOX)-inducible senescent B-NHL cells combined with the specific cyclin dependent kinase 4/6(CDK4/6)inhibitor Palbociclib to observe that blocking CDK4/6 effects on TIS formation.SENEX expression of 21 B-NHL patients and 8 healthy controls were analyzed by qRT-PCR,and the correlation between its expression and clinical indicators were evaluated.Results:The downregulation of SENEX expression promotes G1-S phase transition and apoptosis while inhibiting cell proliferation,collectively suppressing the formation of TIS in B-NHL.Blockade of CDK4/6 promotes the DOX-induced G1 phase arrest to enhance TIS formation in B-NHL cells which can reverse the regulatory effect of silencing SENEX on B-NHL cell cycle regulation and senescence.The expression levels of SENEX were notably elevated in B-NHL patients compared to healthy controls,and Elevated expression levels of SENEX were associated with poor prognosis of B-NHL patients.Conclusions:SENEX enhances apoptosis resistance in B-NHL by inhibiting CDK4/6,thereby preventing G1-S phase transition and promoting TIS formation.

2022 Chinese expert consensus and guidelines on clinical management of toxicity in anti-CD19 chimeric antigen receptor T-cell therapy for B-cell non-Hodgkin lymphoma

Adoptive cellular immunotherapy with chimeric antigen receptor(CAR)T cells has emerged as a novel modality for treating relapsed and/or refractory B-cell non-Hodgkin lymphoma(B-NHL).With increasing approval of CAR T-cell products and advances in CAR T cell therapy,CAR T cells are expected to be used in a growing number of cases.However,CAR T-cell-associated toxicities can be severe or even fatal,thus compromising the survival benefit from this therapy.Standardizing and studying the clinical management of these toxicities are imperative.In contrast to other hematological malignancies,such as acute lymphoblastic leukemia and multiple myeloma,anti-CD19 CAR T-cell-associated toxicities in B-NHL have several distinctive features,most notably local cytokine-release syndrome(CRS).However,previously published guidelines have provided few specific recommendations for the grading and management of toxicities associated with CAR T-cell treatment for B-NHL.Consequently,we developed this consensus for the prevention,recognition,and management of these toxicities,on the basis of published literature regarding the management of anti-CD19 CAR T-cell-associated toxicities and the clinical experience of multiple Chinese institutions.This consensus refines a grading system and classification of CRS in B-NHL and corresponding measures for CRS management,and delineates comprehensive principles and exploratory recommendations for managing anti-CD19 CAR T-cell-associated toxicities in addition to CRS.

Heterochronous multiple primary prostate cancer and lymphoma:A case report

BACKGROUND Multiple primary malignant tumors(MPMTs)are rare type of cancer,especially when solid tumors are the first and lymphoma is the second primary malignancy.We report a patient with heterochronous MPMTs consisting of prostate cancer and rectal diffuse large B-cell lymphoma(DLBCL).CASE SUMMARY We report a 77-year-old male patient diagnosed with prostate cancer who was treated with radiation therapy and one year of endocrine therapy with bicalutamide(50 mg per day)and an extended-release implant of goserelin(1/28 d).Seven years later,rectal DLBCL with lung metastases was found.CONCLUSION Although rare,the possibility of prostate cancer combined with a double primary cancer of DLBCL can provide a deeper understanding.

HCV infection, B-cell non-Hodgkin's lymphoma and immunochemotherapy: Evidence and open questions

There is plenty of data confirming that hepatitis C virus (HCV) infection is a predisposing factor for a B-cell non-Hodgkin's lymphoma (B-NHL) outbreak, while relatively few reports have addressed the role of HCV in affecting B-NHL patients' outcome. HCV infection may influence the short-term outcome of B-NHL because of the emergence of severe hepatic toxicity (HT) during immunochemotherapy. Furthermore, the long term outcome of HCV-related liver disease and patients' quality of life will possibly be affected by Rituximab maintenance, multiple-lines of toxicity during chemotherapy and hematopoietic stem cell transplantation. In this review, data dealing with aggressive and low-grade B-NHL were separately analyzed. The few retrospective papers reporting on aggressive B-NHL patients showed that HCV infection is a risk factor for the outbreak of severe HT during treatment. This adverse event not infrequently leads to the reduction of treatment density and intensity. Existing papers report that low-grade B-NHL patients with HCV infection may have a more widespread disease, more frequent relapses or a lower ORR compared to HCV-negative patients. Notwithstanding, there is no statistical evidence that the prognosis of HCV-positive patients is inferior to that of HCV-negative subjects. HCV-positive prospective studies and longer follow-up are necessary to ascertain if HCV-positive B-NHL patients have inferior outcomes and if there are long term sequels of immunochemotherapies on the progression of liver disease.

Unusual Presentation of Non-Hodgkin’s B-Cell Lymphoma with Unilateral Right Limb Lymphedema

Background: In clinical practice and setting of general practice it is common to see patients with leg edema. To correctly identify the etiology of the edema and then properly manage the cause is not always easy. The unilateral lymphedema of the lower limb has rarely been reported as an initial presentation for lymphoma, especially in females, usually without classic signs or symptoms, but often with inguinal lymphadenopathy or abdominal masses. Case Report: In this article, we report a rare case of unilateral lower limb edema in a healthy obese woman who complained about the appearance of the disease for several months and for whom deep vein thrombosis and other diseases had been excluded. The histological examination of the biopsy of an enlarged lymph node in the right groin, which was compressing the iliac and femoral vein, revealed the presence of B cell non-Hodgkin lymphoma with high-grade malignancy. Conclusions: A common challenge for primary care physicians is to determine the cause and find an effective treatment for leg edema of unclear etiology. Non-Hodgkin’s B-cell Lymphoma should be considered in the differential diagnosis in patients with unilateral leg edema when the swelling is chronic and deep venous thrombosis is promptly excluded.

Primary gastric non-Hodgkin lymphomas:Recent advances regarding disease pathogenesis and treatment

Primary gastric lymphomas(PGLs)are distinct lymphoproliferative neoplasms described as heterogeneous entities clinically and molecularly.Their main histological types are diffuse large B-cell lymphoma(DLBCL)or mucosaassociated lymphoma tissue.PGL has been one of the main fields of clinical research of our group in recent years.Although gastric DLBCLs are frequent,sufficient data to guide optimal care are scarce.Until today,a multidisciplinary approach has been applied,including chemotherapy,surgery,radiotherapy or a combination of these treatments.In this minireview article,we provide an overview of the clinical manifestations,diagnosis and staging of these diseases,along with their molecular pathogenesis and the most important related clinical published series.We then discuss the scientific gaps,perils and pitfalls that exist regarding the aforementioned studies,in parallel with the unmet need for future research and comment on the proper methodology for such retrospective studies.Aiming to fill this gap,we retrospectively evaluated the trends in clinical presentation,management and outcome among 165 patients with DLBCL PGL who were seen in our institutions in 1980-2014.The study cohort was divided into two subgroups,comparing the main 2 therapeutic options[cyclophosphamide doxorubicin vincristine prednisone(CHOP)vs rituximab-CHOP(R-CHOP)].A better outcome with immunochemotherapy(R-CHOP)was observed.In the next 2 mo,we will present the update of our study with the same basic conclusion.

Composite diffuse large B-cell lymphoma and classical Hodgkin's lymphoma of the stomach:Case report and literature review

The combination of classical Hodgkin’s lymphoma(cHL)and non-Hodgkin lymphoma coexisting in the same patient is not common,especially in one extranodal location.Here we present a rare case of composite diffuse large B-cell lymphoma(DLBCL)and cHL occurring simultaneously in the stomach of a 53-year-old female who presented with upper abdominal discomfort and gas pain.Surgery was performed and the disease was diagnosed pathologically as composite lymphoma of DLBCL and cHL using hematoxylin-eosin and immunohistochemical staining.Epstein-Barr virus(EBV)infection was not detected by in situ hybridization for EBV-encoded RNA or immunohistochemistry for EBV latent membrane protein-1.Polymerase chain reaction analysis from the two distinct components of the tumor demonstrated clonal immunoglobulinκlight chain gene rearrangements.The patient died approximately 11 mo after diagnosis in spite of receiving eight courses of the CHOP and two courses of the rituximab-CHOP(RCHOP) chemotherapy regimen.This case report showed that the two distinct components,DLBCL and cHL,appeared to originate from the same clonal progenitor cell,and that EBV infection was not essential for transformation during the course of tumorigenesis.

Positron emission tomography/computerized tomography in the evaluation of primary non-Hodgkin's lymphoma of prostate

Primary malignant lymphoma of the prostate is exceedingly rare.Here we report a case of a 65-year-old man who presented with increased urinary frequency,urinary urgency,and urinary incontinence for two years.Benign prostatic hypertrophy was suspected at primary impression.Ultrasound revealed a hypoechoic lesion of the prostate.The total serum prostate-specific antigen was within normal range.Positron emission tomography/computerized tomography(PET/CT)showed a hypermetabolic prostatic lesion.Prostate biopsy was consistent with a non-germinal center diffuse large B cell lymphoma.There was complete remission of the prostatic lesion following six cycles of chemotherapy as shown on the second PET/CT imaging.18F-fluoro-deoxy glucose PET/CT is not only a complement to conventional imaging,but also plays a significant role in the diagnosis and evaluation of treatment response of prostatic lymphoma.

Gastrointestinal B-cell lymphomas:From understanding B-cell physiology to classification and molecular pathology

The gut is the most common extranodal site where lymphomas arise. Although all histological lymphoma types may develop in the gut, small and large B-cell lymphomas predominate. The sometimes unexpected finding of a lymphoid lesion in an endoscopic biopsy of the gut may challenge both the clinician (who is not always familiar with lymphoma pathogenesis) and the pathologist (who will often be hampered in his/her diagnostic skill by the limited amount of available tissue). Moreover, the past 2 decades have spawned an avalanche of new data that encompasses both the function of the reactive B-cell as well as the pathogenic pathways that lead to its neoplastic counterpart, the B-cell lymphoma. Therefore, this review aims to offer clinicians an overview of B-cell lymphomas in the gut, and their pertinent molecular features that have led to new insights regarding lymphomagenesis. It addresses the question as how to incorporate all presently available information on normal and neoplastic B-cell differentiation, and how this knowledge can be applied in daily clinical practice (e.g., diagnostic tools, prognostic biomarkers or therapeutic targets) to optimalise the managment of this heterogeneous group of neoplasms.

Pediatric-type follicular lymphoma in a Crohn’s disease patient receiving anti-α4β7-integrin therapy:A case report

BACKGROUND Patients with autoimmune conditions receiving immunosuppressants are at risk of non-Hodgkin lymphomas(NHL).Vedolizumab(anti-α4β7-integrin antibody),a treatment-of-choice for Crohn’s disease(CD),reduces inflammatory lymphocyte trafficking into the intestinal mucosa.This effect is believed to be confined to the colon.CASE SUMMARY We report the case of a CD patient on vedolizumab for five years who developed pediatric-type follicular lymphoma.Work-up prior to therapy revealed a reduction in circulating T-lymphocytes and their suppressed response to mitogens.Rituximab,cyclophosphamide,vincristine,and prednisone chemoimmunotherapy resulted in durable lymphoma remission,and vedolizumab treatment was continued.While the patient’s T-lymphocyte population and immunoglobulin production recovered,the T-lymphocyte mitogen response remained suppressed.CONCLUSION This patient’s NHL may be linked to receiving anti-α4β7 therapy.Further research could be beneficial to determine if proactive surveillance for NHL and other systemic diseases is indicated in patients on vedolizumab.

Hepatitis viruses and non-Hodgkin's lymphoma: A review

Non-Hodgkin's lymphoma(NHL) is among the haematological malignancies with high prevalence worldwide, causing estimated 355 900 new cases and 191 400 deaths in 2008. High prevalence of NHL is documented in economically more developed areas while low prevalence is observed in less developed areas of the globe. A wide array of environmental factors have been reported to be either directly involved or in modifying the risk of NHL development. In addition to these factors, a number of infectious agents, chiefly viruses have also been implicated in the development of NHL. This article reviews the available literature to discuss the role of hepatitis viruses in NHL development, possible mechanisms of lymphomagenesis and also identify the areas in which further research is required to better understand this disease. A brief discussion on the clinical aspects such as classification, staging, treatment approaches have also been included in this article.

Simultaneous occurrence of a hepatocellular carcinoma and a hepatic non-Hodgkin's lymphoma infi ltration

To investigate the simultaneous occurrence of hepatocellular carcinoma and non-Hodgkin's lymphoma, we report the case of a 70 year old patient with a primary diagnosis of non-Hodgkin's lymphoma in 2002. In a routine follow up investigation of his chronic lymphocytic leukemia a newly detected mass in the Couinaud's segments 2 and 3 was found. No hepatitis C virus or hepatitis B virus infection or cirrhosis was evident. After laparoscopic segmentectomy the histological examination revealed a hepatocellular carcinoma. While the relation between liver parenchyma damages and hepatocellular carcinoma or non-Hodgkin's lymphoma is well known, only a few publications have focused on the coexistence of hepatocellular carcinoma and non-Hodgkin's lymphoma. With this case we demonstrate the coexistence of these diseases without having a pre- damaged liver parenchyma.

Case Report: Fever of Unknown Origin <br/>—An Unusual Presentation for Diffuse Large B-Cell Lymphoma

A 61-year-old male initially presented with fever of unknown origin. He had extensive work-up over two years including an infectious diseases panel, autoimmune studies, and Rheumatology and Hematology evaluations. The patient was initially diagnosed with Adult Still’s disease and underwent an out-patient right nodal fine-needle aspiration that was indeterminate. After continued failure of treatment for Adult Still’s disease, the patient had surgical resection of a right axillary lymph node that yielded the diagnosis of diffuse large B-cell lymphoma. Further work-up revealed Epstein-Barr virus positivity, the possible trigger behind his mutation for diffuse large B-cell lymphoma and its uncommon presentation. The patient met criteria for central nervous system prophylaxis and received multiple administrations throughout his therapy. He ultimately expired following recurrence of his disease at its initial site but without central nervous system involvement. We report an uncommon presentation of a patient with diffuse large B-cell lymphoma. This lymphoma can have numerous, vague presentations requiring a broad differential diagnosis and may lead to multiple evaluations prior to an ultimate diagnosis. We will also discuss the need for central nervous system prophylaxis, how this patient is qualified for prophylaxis, and how central nervous system prophylaxis benefits, harms, or does not affect patients with diffuse large B-cell lymphoma.

Non Hodgkin’s Lymphoma with Right Atrial Intra Cardiac Metastases

Background: Diffuse Large B-Cell Lymphoma (DLBCL) is the most variant of Non-Hodgkin’s Lymphoma (NHL) and also the most common variant with secondary intracardiac masses. Case summary: 7 years old child presented to emergency with acute decompensated cardiac failure, ascites and tender hepatomegaly. 2D echo evaluation was suggestive of large intracardiac mass in the right atrium almost completely obstructing Tricuspid valve orifice, gross pericardial effusion and dilated Inferior Vena Cava (IVC). Emergency tumor excision surgery was performed which revealed 4 × 4 cm pinkish firm mass arising from anterior Tricuspid annulus which was completely excised. Child was extubated on postoperative day (POD) 0 and was on minimal inotropic support. Ascites reduced significantly on POD1 allowing abdominal palpation which revealed a mass in the epigastric region. This prompted evaluation by pediatrician and oncology workup suggestive of increased 18-Flouro Deoxy Glucose (18-FDG) uptake in the mediastinum, abdomen, bilateral proximal thighs, all mediastinal lymph nodal stations, bilateral lung hilar stations 10R, 10L involving all encasing the heart and great vessels with pleural deposits, Celiac trunk, superior Mesenteric Artery (SMA), Portal vein, IVC and abdominal aorta. Histo pathology Examination (HPE) and Immuno Histo Chemistry (IHC) of intracardiac mass revealed DLBCL which is metastatic in nature. Chemotherapy was started as per (French American British Lymphomes Malins B) FAB LMB-96 protocol with the child currently in the Induction phase having poor prognosis and less survival interval. Conclusion: Surgery can be considered a treatment option for metastatic intracardiac masses during emergency scenarios like cardiogenic shock to relieve obstruction along the pathway of blood flow in the heart even though we may not be able to completely excise the tumor surgically.

Expression of P120 Catenin mRNA in Non-Hodgkin's Lymphoma Cell Lines

To investigate p120 catenin mRNA expression in Non-Hodgkin＇s lymphoma （NHL） cell lines （U937, Raji, Jurkat and Molt4） and normal lymphocytes and explore the relationship between p120 catenin and Non-Hodgkin＇s lymphoma, total RNA sample was extracted by using TRIzol and reversely transcripted into cDNA. Polymerase chain reaction was performed to detect mRNA expression of p120 catenin in NHL cell lines U937, Raji, Jurkat and Molt4. Normal lymphocytes were used as control. It was found expressions of p120 catenin 1A and 3A mRNA were high in above-mentioned NHL cell lines, but neither p120 catenin 1A nor 3A was found in normal lymphocytes as shown by RT-PCR. It is concluded that both P120ctnlA and P120ctn3A mRNA transcripts were found in all NHL cell lines U937, Raji, Jurkat and Molt4 but they don＇t exist in normal lymphocytes, suggesting pl20cm possibly is of importance in diagnosis and therapy of lymphoma.

Ultrasound features of primary non-Hodgkin’s lymphoma of the palatine tonsil:A case report

BACKGROUND Lymphomas are the second most common malignancy of the head and neck.In this region,the vast majority of extranodal lymphomas are located in the palatine tonsil,accounting for about 51%.Tonsillar lymphomas are aggressive tumors with intermediate-or high-grade histology.We here report a case of primary non-Hodgkin’s lymphoma of the palatine tonsil and analyze its ultrasound features.CASE SUMMARY A 40-year-old man presented with right palatine tonsil swelling for 2 mo after a cold,accompanied by dysphagia,snoring,and suffocation.He had no sore throat,fever,or history of upper respiratory tract infection or tuberculosis.The patient was generally in good health and denied other diseases.He was diagnosed with acute tonsillitis initially and treated with antibiotics for 7 d.However,there was no improvement with the treatment.Tonsil biopsy and ultrasound-guided biopsy of the biggest lymph node of the right neck showed the typical pathology of non-Hodgkin lymphoma.CONCLUSION Primary lymphoma of the tonsils is rare,and its diagnosis is challenging.Ul-trasound is a useful modality in diagnosing oropharyngeal diseases,and can clearly show the features of this tumor,but the final diagnosis should be estab-lished by histology.

Post-Therapy Profile of BMI-for-Age of Indian Survivors of Pediatric Acute Lymphoblastic Leukemia and Non-Hodgkin’s Lymphoma

Background: Obesity in pediatric ALL survivors is a well recognized late effect. Hence the present study examines the BMI-for-age of Indian childhood ALL and NHL survivors. Method: A retrospective study of 118 ALL/NHL survivors and 138 age sex matched was carried out. From the recorded heights and weights were body mass index (BMI) was computed. The survivor data was compared with 138 controls from the data set collected by investigators previously. Results: 82.8% of patients had BMI-for-age in 5th-84th percentile (healthy) at time of diagnosis and at inclusion in the study. Comparison of BMI of survivors with matched controls was not significant. However, The mean BMI-for-age for younger patients (3 to 12 years) was significantly higher than mean BMI-for-age of matched controls. Distribution of data by time elapsed from therapy was significant. Overweight/obesity was observed among the survivors who were off therapy for two years with increase in after four years post-therapy. Conclusion: Our preliminary study indicates late effects of therapy and points to the need of long term assessment of the survivors, even though majority of them were within the normal weight range.

Low-Dose Involved-Field Radiotherapy in Relapsed Low-Grade Non-Hodgkin's Lymphoma in Elderly Patients (Mansoura University Experience)

Purpose: To assess the response rate, duration of response and prognostic factors affecting response after low-dose involved-field radiotherapy in patients with relapsed low-grade B-cell non-Hodgkin lymphoma. Patients and Methods: Forty-four patients were included. Patients were treated with a total dose of 4 Gy (2 × 2 Gy) using 6 - 15 Mv photon or electron beam. Results: most patients were above age of 60 years (59%) with male predominance. Follicular lymphoma was the most common pathological type;bulky disease (>5 cm) was presented in 61.4%. Patients who received only 2 regimens were 63.7% and 31.8% had >2 involved sites. No treatment related toxicity was observed. The overall response rate was 88.7%;complete response was reached in 59.1% and stable disease in 6.8%, progressive disease in 4.5%. Median time to local progression was 33 months (95% CI 23.70 - 42.29);2-year local progression free survival was 78%. Response rate was found to be dependent on age, number of involved sites and lymph node size but independent on sex, pathological type, number of prior regimens, LDH level and time since diagnosis. Conclusion: Short-course-low dose palliative radiotherapy (2 × 2 Gy) affords an attractive option for treatment of relapsed low-grade non-Hodgkin’s lymphoma due to high response rates. However, these results had to be confirmed in a larger number of patients.

Unusual Case of Idiopathic Membranous Later Developing Non-Hodgkin’s Lymphoma

A 30-year-old male presented to nephrology services as a case of nephrotic syndrome and membranous nephropathy was found on renal biopsy. He was treated for this pathology with steroid and cytotoxic drugs and remained in remission for 3 years and then presented with non Hodgkin’s lymphoma.