Testicular Lymphoma Research Articles

Phase 2 Study of Abbreviated 3 Cycles of Rituximab Plus CHOP (Cyclophosphamide, Adriamycin, Vincristine, and Prednisolone) Immunochemotherapy in Patients with Completely Excised Stage I or II CD20+ Diffuse Large B-Cell Lymphoma (CISL 12-09)

▪Introduction: Full cycles of R-CHOP chemotherapy or abbreviated chemotherapy followed by radiotherapy are recommended as standard of care for limited stage (LS) diffuse large B-cell lymphoma (DLBCL). There are occasions when lesions are completely excised during the diagnostic surgical resection. In addition, initial surgical resection of the involved area is often performed in the treatment of intestinal lymphomas with LS disease due to obstructive lesions or perforation risk. As to these patients without residual gross lesions, however, the number of cycles of chemotherapy has not so far been questioned and full cycles of chemotherapy are usually performed. Thus, we aimed to investigate the effectiveness of an abbreviated three courses of R-CHOP chemotherapy in patients with completely excised stage I or II CD20+ DLBCL.Methods: This is a multicenter, single arm, phase 2 study designed to evaluate efficacy and safety of 3 cycles of R-CHOP chemotherapy in low risk LS DLBCL. Key inclusion criteria were as follows: pathologically confirmed CD20 positive DLBCL, age >18 years, stage I or II, and complete resection with no residual lesion after surgical resection. Patients with B symptoms, bulky disease, primary breast, testicular or CNS lymphomas were excluded. R-CHOP chemotherapy started within 6 weeks from surgical resection and was repeated every 3 weeks for 3 cycles. Prophylactic G-CSF was not administered. Radiologic tumor assessment was performed at baseline, every 3 months until 2 years, then every 6 months until 5 years after completion of study treatment. The primary endpoint was 2-year disease-free survival (DFS). Secondary endpoints included overall survival and safety. (ClinicalTrials.gov: NCT01279902.)Results: Twenty-three patients were enrolled between Dec 2010 and May 2013. Of these, one was excluded because of ineligibility and the remaining 22 patients were included in the analysis. The median age at diagnosis was 57 years (range, 29-77 years). Fourteen patients had stage 1 disease and the other eight had stage 2. Preoperative LDH level was available in 11 patients and it was elevated in two of them. Thus, preoperative IPI scores could be calculated in those 11 patients; 0 in 8, 1 in one, and 2 in one patients, respectively. Postoperative IPI scores were 0 in 11, 1 in 10 and 2 in one patients. Primary sites included intestine (n=15), cervical lymph nodes (n=4), stomach (n=1), tonsil (n=1) and spleen (n=1). All the 22 patients completed 3 cycles of R-CHOP chemotherapy as planned. With a median follow-up of 39.5 months (95% CI, 29.9-47.1 months), only one patient showed disease progression and died with the estimated 2-year DFS and OS rates of 95.0%. It was the only one patient with IPI of 2 with elevated LDH and age>60 that showed disease progression at 12.7 months. He had a splenic mass and underwent splenectomy followed by 3 cycles of R-CHOP. He underwent one cycle of salvage R-ESHAP chemotherapy but died of rapid disease progression. No grade 3 or 4 non-hematologic toxicities were observed. Neutropenia was the most common grade 3 or 4 hematologic toxicity which was noted in 8 (36.4%) patients. Three patients experienced G3 febrile neutropenia.Conclusions: Three cycles of abbreviated R-CHOP chemoimmunotherapy is an effective and safe therapeutic approach for patients with localized and completely excised DLBCL especially in those with low-risk IPI. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Dose-Adjusted Etoposide, Prednisone, Vincristine, Cyclophosphamide, Doxorubucin and Rituximab (da-EPOCH-R) Vs Rituxan, Cyclophosphamide, Doxorubucin, Vincristine and Prednisone (R-CHOP) As First Line Treatment for Diffuse Large B-Cell Lymphoma (DLBCL)

Objectives:To assess the efficacy and safety of da-EPOCH-R as frontline treatment for patients diagnosed with Stage III/IV Diffuse Large B-Cell Lymphoma.Methods:We conducted a retrospective study of newly diagnosed patients with advanced Diffuse Large B-Cell Lymphoma from January 2008 till September 2015, who received frontline da-EPOCH-R or R-CHOP at our Health System. We excluded patients with primary CNS lymphoma, primary testicular lymphoma and patients who received chemotherapy for a prior lymphoma.25 patients who received da-EPOCH-R and 50 patients who received R-CHOP were identified. Da-EPOCH-R regimen consisted of Etoposide 50mg/m2/day, Doxorubucin 10mg/m2/day and Vincristine 0.4mg/m2/day given on Days 1-4, Cyclophosphamide 750mg/m2 on Day 5, Prednisone 60mg/m2 twice a day from Days 1-6 and Rituximab 375mg/m2given on Day 5. On Day 6 G-CSF was administered. Each cycle was given every 21 days for a total of 6 cycles. The dose of Etoposide, Doxorubucin and Cyclophosphamide was adjusted according to standard protocols. All patients on the da-EPOCH arm were on Acyclovir, Ciprofloxacin, Fluconazole and Trimethoprim-Sulfamethoxazole for anti-microbial prophylaxis during their treatment. The use of growth factors and anti-microbial prophylaxis was inconsistent in the R-CHOP arm.Results:When comparing the da-EPOCH-R arm versus the R-CHOP arm, the average age of the patients was 50 years (25-81) vs 60 years (19-84). High-risk IPI was similar in both arms (76% vs 74%). The percentage of non-germinal center type (non-GCB) was equal as well (36% vs 32%). The average number of cycles administered was 5.3 compared to 4.8. There were more dose reductions in the da-EPOCH-R arm (36% vs 24%), however fewer delays and cessations were noted (36% vs 54%).After a median follow up of 29.1 months, the age-adjusted overall survival (77% vs. 69%, p=0.093) and disease-free survival (76% vs. 55% p=0.54) was improved in the da-EPOCH-R arm. In the non-GCB variant da-EPOCH improved overall survival by 77% (p=0.024). The Overall Response Rate was higher in the da-EPOCH-R arm 80% (CR/CRU=64% and PR=16%) vs. 56% (CR/CRU=44% and PR=12%). The relapse rate was lower in the da-EPOCH-R arm (16% vs 28%), and it was lower in the non-GCB patients as well (11% vs 25%). There were more Grade 3-4 neutropenia in the da-EPOCH arm (72% vs 48%), however infectious complications were lower (24% vs 42%). There were fewer unplanned admissions in the da-EPOCH arm (32% vs 60%) and a significantly lower treatment related mortality (12% vs 22%). Other Grade 3-4 toxicities too were lower in the da-EPOCH-R arm (20% vs 30%). Conclusion:Our preliminary results suggest that da-EPOCH-R has a survival benefit especially in the non-GCB subgroup. Our data does show good survival data even for the GCB subtypes. There was a higher response rate, lower relapse rate and no added toxicities in patients who received da-EPOCH-R. A Phase III trial is currently ongoing and will provide us with answers regarding the efficacy and toxicities of this chemotherapy regimen. DisclosuresNo relevant conflicts of interest to declare.

MYD88, CD79B, and CD79A Gene Mutations in CD5-Positive Diffuse Large B-Cell Lymphoma

INTRODUCTIONDiffuse large B-cell lymphoma (DLBCL) is regarded as a clinicopathologically heterogeneous group of lymphomas and is classified as activated B-cell-like (ABC) DLBCL or germinal center B-cell-like (GCB) DLBCL based on the cell-of-origin (COO). Nuclear factor-kappa B (NF-kB) activation is indispensable for ABC DLBCL cell survival. Genes in the NF-kB signaling pathway, such as myeloid differentiation factor 88 (MYD88) and CD79B, are mutated in 20-40% of ABC DLBCLs. CD5 is expressed in approximately 10% of DLBCLs. CD5-positive (CD5+) diffuse large B-cell lymphoma (DLBCL) is characterized by frequent central nervous system (CNS) relapse and a predominant activated B-cell-like nature. Primary DLBCL in sanctuary sites (DLBCL-SS) also shows these features, and more than 70% of the patients exhibit MYD88 (L265P) and CD79B mutations. This study aimed to ascertain the frequencies of MYD88 (L265P), CD79B, and CD79A mutations in CD5+ DLBCL and to determine whether CD5+DLBCL shows the same features as DLBCL-SS in terms of gene mutations.PATIENTS AND METHODSThis study included 40 patients with CD5+DLBCL. All the patients were diagnosed with DLBCL, not otherwise specified, according to the 2008 WHO classification between 1993 and 2014 at Mie University Hospital. CD5 expression in tumor cells was analyzed by immunohistochemistry using frozen sections or by flow cytometry. Mutation analysis was performed by direct sequencing.RESULTSDirect sequencing was successful with samples from all 40 patients with CD5+ DLBCL. The median age was 64 years (range: 15 to 91 years). The COO classification was determined by gene expression profiling (GEP) in 29 patients. In the other 11 patients, the COO was identified by immunohistochemistry according to Hans' criteria. Thirty-six (90%) cases were confirmed as ABC/non-germinal center DLBCL. Two patients fulfilled the criteria for primary testicular DLBCL. One patient had systemic CD5+ DLBCL with bone and brain involvement. None of the other patients had CNS involvement at diagnosis. The MYD88 L265P mutation was identified in 13 (33%) of the cases, and no other MYD88 mutations were found. CD79B mutations were detected in 15 (38%) cases, and 10 of these cases overlapped with the MYD88-mutated group. One of the two patients with testicular involvement had double mutations. The other had MYD88 mutation alone. One patient with brain involvement had double mutations. Only one case (3%) had a CD79A mutation as well as CD79B and MYD88 mutations. The incidence of MYD88 L265P, CD79B, and CD79A mutations in ABC/non-GCB DLBCLs was 13/36 (36%), 14/36 (39%), and 1/36 (3%), respectively. Of the 15 cases with a CD79B mutation, 14 had missense mutations in an immunoreceptor tyrosine-based activation motif (ITAM) domain; all of these mutations occurred in the first tyrosine of the ITAM (Y196H [7/14], Y196S [4/14], Y196N [2/14], and Y196C [1/14]), and two cases showed double mutations (Y196H/H225Y and Y196S/K219R). One case had a 13-base deletion in exon 5 before the first tyrosine of the ITAM. MYD88 and CD79B mutations were associated with localized disease (P = 0.038 and P = 0.003, respectively). Clinical information on first-line treatment was available for 38 patients. Before 2002, anthracycline-containing chemotherapies without rituximab were selected as first-line treatment. Since 2002, CHOP chemotherapy with rituximab (R-CHOP) has predominated. For this reason, 18 patients who were treated with R-CHOP were included in the survival analysis in this study. The COO of these 18 patients was confirmed as ABC/non-GCB DLBCL. Two patients with primary testicular lymphoma and one with CD5+ DLBCL with brain involvement were not included in this cohort of 18 patients. With a median follow-up of 7.1 years, there was no significant difference in overall survival based on MYD88 mutation status (P = 0.98) or CD79B mutation status (P= 0.69).CONCLUSIONSTo the best of our knowledge, this is the first study toreport the frequency of MYD88, CD79B, and CD79A mutations in the largest cohort of CD5+ DLBCLpatients. The incidence of MYD88 and CD79B mutations in CD5+ DLBCL is lower than that in DLBCL-SS, suggesting that CD5+DLBCL is not the same disease as DLBCL-SS. DisclosuresTakeuchi:Chugai: Honoraria. Yamaguchi:Chugai: Honoraria; Eisai: Honoraria; Takeda: Honoraria; Kyowa-Hakko Kirin: Honoraria; Zenyaku: Honoraria. Miyazaki:Eisai: Honoraria; Kyowa Kirin: Honoraria; Chugai: Honoraria. Tawara:Astellas: Honoraria. Katayama:Bristol-Myers Squibb Japan: Honoraria; Alexion Pharmaceuticals: Honoraria; Eisai: Honoraria; Taisho Toyama Pharma: Honoraria; Nippon Shinyaku: Honoraria; Kyowa Hakko Kirin: Honoraria, Research Funding; Astellas: Honoraria, Research Funding; Dainippon Sumitomo Pharma: Honoraria; Chugai: Honoraria, Research Funding; Takeda: Honoraria; Shire: Honoraria; Daiichi Sankyo: Honoraria; Shionogi: Honoraria; Celgene: Honoraria; Pfizer: Honoraria.

In Silico and Functional Characterization of TBL1XR1 as a Tumor Suppressor in Large B-Cell Lymphomas

Large B-cell lymphomas (LBCL) exhibit multiple genetic alterations, often in specific combinations. However, little is known about the biologic consequences of these concurrent genetic features. We recently characterized the comprehensive molecular signatures of two LBCL subtypes that exclusively involve extranodal disease sites, primary central nervous system lymphoma (PCNSL) and primary testicular lymphoma (PTL). In contrast to systemic diffuse large B-cell lymphomas (DLBCLs) or most activated B-cell (ABC)-type DLBCLs, the majority of PCNSLs and PTLs exhibit oncogenic Toll-like receptor (TLR) signaling (MYD88L265P activating mutations), often with concurrent B-cell receptor (BCR) activation (CD79BY196mut) and/or additional mutations or inactivating rearrangements of TBL1XR1 (Chapuy and Roemer et al, Blood 2016; 127:869-81).TBL1XR1 is a component of the NCoR/SMRT co-repressor complex that modulates TLR/MYD88 signaling by increasing the clearance of NCoR/SMRT transcriptional co-repressors from certain TLR/MYD88 target genes. However, the functional consequences of somatic mutations in TBL1XR1 (TBL1XR1mut) or reduced TBL1XR1wt expression in LBCLs remain to be defined. For these reasons, we performed in silico modeling of the identified TBL1XR1mut and functionally characterized TBL1XR1mut and decreased TBL1XR1wt expression in model LBCL systems.First, we evaluated the frequency and types of TBL1XR1mut in our local series of PCNSLs and 151 primary DLBCLs (102 local and 49 previously published) for which we had whole exome sequenceing data. Thirty-six percent of PCNSLs and 6% of DLBCLs in this series exhibit TBL1XR1mut, over half of which occur in the context of MYD88 and/or CD79B mutations. In these PCNSLs and DLBCLs, we identifed 13 different non-synonymous TBL1XR1 mutations. All identified non-overlapping TBL1XR1 mutations were in the WD40 propellar domains, which are critical for protein-protein interactions. To gain insights into the structural consequences of TBL1XR1mut, we overlayed these alterations onto the TBL1XR1 protein crystal structure, modeled the corresponding mutations in silico and assessed protein stability changes. Eighty percent of the TBL1XR1mut resulted in significant destabilization of the mutant protein (ΔΔGibbsFreeEnergy median: 9.78 kcal/mol, range: 1.91 - 28.31). We found that mutations often perturbed the 3D protein structure by abrogating critical polar interactions (representative example TBL1XR1wt vs. TBL1XR1H390R in Figure 1). These in silico modeling data suggest that genetic perturbations of TBL1XR1mut disrupt the function of the encoded protein.For that reason, we modeled reduced TBL1XR1wt expression in informative DLBCL cell lines with or without concurrent CD79B/MYD88 mutations (TMD8 and OCI-Ly1, respectively) by genetically depleting endogenous TBL1XR1 alleles with CRISPR/Cas9. All of the resulting LBCL cell lines with loss of either one or two TBL1XR1 alleles exhibited significantly increased proliferation in comparison to the parental controls. We next assessed the role of TBL1XR1mut by generating HA-tagged versions of each identified TBL1XR1 mutation with site-directed mutagenesis. Viral particles of TBL1XR1mut constructs and the TBL1XR1wt control were used to reconstitute mutant and wild type protein in the TBL1XR1-/- Ly1 cell line. Reconstitution with each TBL1XR1mut significantly enhanced LBCL proliferation, in comparison to TBL1XR1wt.Taken together, these in silico and experimental data suggest that TBL1XR1mut in PCNSL and DLBCL are inactivating events and establish TBL1XR1 as a tumor suppressor in these diseases. Additional analysis of potential interactions between perturbed TBL1XR1 and MYD88/CD79B are underway. [Display omitted] DisclosuresRodig:Bristol-Myers Squibb: Honoraria, Research Funding; Perkin Elmer: Membership on an entity's Board of Directors or advisory committees.

Primary Testicular Lymphoma:a Single Center Experience and Literature Review

Background: Primary testicular lymphoma (PTL), a rare and aggressive lymphoma mainly affecting the elderly, makes up 1-2% of Non-Hodgkin's lymphomas (NHL). Diffuse large B cell lymphoma (DLBCL) is the most common histological type of PTL. At present, comprehensive management is used for the treatment of PTL, such as operation, chemotherapy and radiotherapy. Although there are multiple treatment methods for PTL, its prognosis is very poor.Materials and Methods: We retrospectively studied clinical data of 28 patients who were 10 to 82 years old and were diagnosed with PTL between March 2006 and November 2014.The clinical data included clinical characteristic, staging, treatment and outcomes. All of the patients received therapy [rituximab, CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone), intrathecal prophylaxis, or irradiation for the contralateral testis] after orchiectomy. The therapeutic effects were evaluated as complete response (CR), partial response (PR), progressive disease (PD) and stable disease (SD). The prognostic evaluation was based on age, lactic dehydrogenase (LDH), Eastern Cooperative Oncology Group Performance Status (ECOG PS) and staging.Results: The main clinical features of the 28 patients were shown in Table 1. All patients had testicular mass. Nine patients achieved complete response (CR), 8 patients had partial response (PR), and progressive disease (PD) occurred in 3 patients after 13, 12 and 20 months after treatment, respectively(Table 2). Eight patients died. The median overall survival (OS) was 19.6 months and the median progression-free survival (PFS) was 19.4months(Figure 1,2).Conclusion: PTL is a highly aggressive disease. Although there are multiple treatment methods for PTL, it readily recurs and its prognosis is very poor. From this study, we can see that age, LDH, ECOG PS and staging are the main factors to affect PFS and OS of the patients with PTL(Table 3). [Display omitted] [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Nivolumab (Anti-PD1) Therapy for Relapsed/ Refractory Primary Central Nervous System Lymphoma and Primary Testicular Lymphoma

Background: Primary central nervous system lymphoma (PCNSL) and primary testicular lymphoma (PTL) are rare and aggressive extranodal non-Hodgkin lymphomas with shared molecular features and a poor prognosis. PCNSL is currently treated with high-dose methotrexate (HD-MTX) based induction chemotherapy. Younger patients who are healthy and eligible for consolidation treatment are considered for whole brain radiation (WBRT) or high-dose chemotherapy with autologous stem-cell transplant (ASCT). Despite this, nearly 50% of patients with PCNSL relapse within 2 years of diagnosis and one third of patients have primary refractory disease. PTL is treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP). However, almost 50% of patients with PTL progress after induction treatment, frequently with CNS or contralateral testicular involvement. Treatment options are limited for patients with recurrent and refractory PCNSL or PTL, and the majority of patients ultimately die of their disease.We recently identified frequent 9p24.1/ PD-L1(CD274)/ PD-L2 (PDCD1LG2) copy number alterations and additional translocations in PCNSL and PTL (Chapuy and Roemer et al Blood 2016; 127:869-81). These genetic alterations are associated with increased expression of the programmed cell death protein 1 (PD-1) ligands, PD-L1 and PD-L2. Activation of PD-1 signaling by PD-L1 or PD-L2 binding leads to a reversible state of T-cell "exhaustion" characterized by decreased T-cell receptor signaling, reduced T-cell proliferation and survival, perturbed metabolism and altered transcription factor expression. The activity of PD-1 blockade in other lymphomas with 9p24.1 alterations such as classical Hodgkin's lymphoma prompted us to test the efficacy of this approach in PCNSL and PTL.Patients and Methods: We treated 5 patients with recurrent/refractory PCNSL and PTL with off-label Nivolumab, a humanized IgG4 monoclonal antibody checkpoint inhibitor that targets PD-1 and blocks binding by PD-L1 or PD-L2. Median age was 64 (range, 54-85) years with a median Karnofsky Performance Score (KPS) of 70 (40-80) %. Four patients had multiply recurrent disease (3 patients with PCNSL and 1 patient with PTL and CNS relapse); 1 patient had primary refractory PCNSL. All patients had been treated with standard of care treatments and had no other available options. Prior therapies included HD-MTX based chemotherapy, pemetrexed, high-dose cytarabine, WBRT and thiotepa-based chemotherapy followed by ASCT. All patients signed informed consent and were treated with nivolumab at 3mg/kg intravenously every 2 weeks. Only 1 patient received corticosteroids (dexamethasone 2mg daily) during initial nivolumab treatment; steroids were rapidly tapered and discontinued in 4 weeks. Additionally, 1 patient received 3 doses of rituximab and 2 others received WBRT.All patients had objective radiographic responses to treatment with nivolumab, including 4 complete responses and 1 partial response. The patient with CNS relapse from PTL had complete radiographic resolution of CNS abnormalities with persistent intraocular disease that required vitrectomy. All responses were confirmed at repeat restaging. The median number of nivolumab treatments to objective radiographic response was 3 (range, 2-4). The 4 patients who were symptomatic at the initiation of nivolumab therapy had complete or near-complete resolution of neurologic signs/symptoms and a marked improvement in KPS. All patients are alive and remain progression-free at this time. Four patients continue to receive treatment. The median progression-free survival is 9 (range, 7-11) months.Conclusion: Our pilot series indicates that nivolumab is active in primary refractory and relapsed/refractory PCNSL and PTL with CNS relapse. Based on our preclinical molecular data and these pilot clinical results, a multi-institutional phase 2 open-label, single-arm trial of nivolumab in recurrent and refractory PCNSL and PTL patients (CA209-647) is scheduled to open shortly. DisclosuresLaCasce:Forty Seven: Consultancy; Seattle Genetics: Consultancy. Armand:Infinity Pharmaceuticals: Consultancy; Merck: Consultancy, Research Funding; Pfizer: Research Funding; Roche: Research Funding; Sequenta Inc: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding. Shipp:Bayer: Research Funding; Merck, Gilead, Takeda: Other: Scientific Advisory Board; Cell Signaling: Honoraria; Bristol-Myers Squibb: Consultancy, Research Funding.

354P Survival trends of primary testicular diffuse large B-cell lymphoma: A population-based study

354P Survival trends of primary testicular diffuse large B-cell lymphoma: A population-based study

354P Survival trends of primary testicular diffuse large B-cell lymphoma: A population-based study

354P Survival trends of primary testicular diffuse large B-cell lymphoma: A population-based study

Radiation Therapy Improves Outcomes in Patients With Primary Testicular Diffuse Large B-cell Lymphoma

Radiation Therapy Improves Outcomes in Patients With Primary Testicular Diffuse Large B-cell Lymphoma

Prophylactic Scrotal And Contralateral Testicular Radiation Therapy Prevents Local Relapses in Primary Testicular Lymphomas

Primary testicular lymphoma is a rare form of extranodal lymphoma typically expressing B-cell markers. The contralateral testis and the central nervous system are common localizations of relapses. The purpose was to evaluate the benefit of prophylactic scrotal radiation therapy (RT). Patients with primary testicular lymphoma were identified from the institutional electronic database, by submitting keywords in a search engine. Eligibility was limited to adults (age > 18 years), and diffuse large B cells subtype. Patient’s clinical data were retrospectively reviewed. Survivals were estimated using the Kaplan-Meier method and compared using log-rank tests. Forty-eight patients were included. The majority of the patients had localized disease (Ann-Arbor stage I-II, 85.4%). Orchiectomy was performed in all cases. Their mean age at diagnosis was 61.4±14.4 years. Median follow-up was 67.7 months (range 5.6-317.2). No patient presented with B symptoms and no central nervous system involvement was documented at diagnosis. International prognostic indexes were 0 in 31.3% of the patients, 1 in 45.8%, 2 or 3 in 10.4% and 4 in one patient (2.1%). Anthracycline-based chemotherapy was administered to 81% of patients, 29.1% had rituximab associated. Prophylactic intrathecal injections of methotrexate were administered to 48% of patients. Scrotal irradiation was given to 37.5% of patients, following chemotherapy. The target volumes comprised the scrotum and contralateral testis. The mean dose was 33.3±.2.9 Gy (range: 30-36). No local relapse was reported among the patients who received scrotal radiotherapy whereas 8 failures (16.7%) where observed in those who did not. The 5-year local control rates were 100% and 81.9% respectively, in the groups of patients with and without prophylactic RT (n=30, and n=18, P=0.034). In the subgroup of patients with stage I-II diseases (n=41), 5-year local control rates were 100% in those who received RT (n=15) and 80.4% in the remaining ones (n=26, P=0.05). Prophylactic scrotal and contralateral testicular RT is effective in preventing local relapses in primary testicular lymphoma.

Fertility preservation in males with cancer: 16-year monocentric experience of sperm banking and post-thaw reproductive outcomes.

Anticancer treatments can impair male fertility. Cryopreservation of semen is an efficient procedure for fertility preservation. The aim of this study was to evaluate pre-freeze semen parameters among the various types of cancer, post-thaw sperm viability and reproductive outcome of samples used for assisted reproductive treatment (ART). This study included 721 men with cancer that had their semen cryopreserved in our bank in 1999-2015. Semen analysis and cryopreservation were performed before the start of antineoplastic treatment, according to the World Health Organization recommendations, European Commission and Italian law. Among the 721 patient, 196 had seminoma of the testis, 173 Hodgkin's lymphoma, 108 mixed testicular tumors, 89 germ cell tumors, 67 other tumors, 46 hematological tumors, and 42 non-Hodgkin's lymphoma. The mean age of patients was significantly lower in Hodgkin's lymphoma compared to other tumors. Statistically significant lower volume, sperm count and number of straws stored were observed respectively in Hodgkin's lymphoma, mixed testicular tumor and hematological tumors. Nineteen patients used their frozen semen for 20 ART cycles. After thawing a significant reduction of motility and vitality was recorded. A lower fertilization rate was observed in patients affected by testicular tumor and lymphoma (35.42% and 50%) compared with other cancers (71.43%). No significant differences were observed in terms of cleavage and implantation rates. A total of five pregnancies and seven healthy newborns were achieved. Fertility preservation before gonadotoxic therapy is of great importance to patients with cancer and must be indicate before the start of treatment.

The clinical characteristics and outcomes of 16 Burkitt' s lymphoma with testicular involvement

目的总结伴有睾丸侵犯的儿童伯基特淋巴瘤的临床特征，以及应用大剂量甲氨蝶呤（HD-MDX，5~8 g/m2）等联合化疗取代睾丸放疗的临床疗效及预后。方法收集16例伴有睾丸侵犯的伯基特淋巴瘤患儿资料，分析其临床特征，按前瞻性方案设计及分层。全部患儿进入高危组分层治疗，并定期追踪随访。方案采用北京儿童医院淋巴瘤治疗方案中的NHL-BCH-2009-成熟B细胞淋巴瘤方案（来自改良的LMB-89方案联合利妥昔单抗治疗）。结果137例伯基特淋巴瘤患儿中伴睾丸侵犯的患儿16例（11.7%）。16例患儿均为Ⅳ期，中位发病年龄为6.5（2.25~13.5）岁。16例患儿中8例存在骨髓侵犯（其中5例已达白血病期），9例存在中枢神经系统受累（其中5例为中枢神经系统白血病，4例为颅内或脊髓占位）；5例为双侧睾丸侵犯，11例为单侧睾丸侵犯；1例病初存在近期EBV感染（EBV-IgM+）。中位随访时间为31.8(0.5~79.0）个月，16例患儿中死亡2例（1例因早期化疗合并症放弃治疗死亡，1例于早期停药后复发死亡）；1例停药2年8个月后出现膀胱部位肿瘤复发，经治疗目前处于完全缓解；13例无事件生存，无睾丸复发。3年总生存率为87.5%，3年无事件生存率为72.9%。追踪其中>10岁患儿（3例）的睾酮水平，均在正常范围。结论对于伴有睾丸侵犯的伯基特淋巴瘤患儿，为减少放疗的远期不良反应、保留睾丸功能，应用HD-MTX等联合化疗取代睾丸放疗，疗效好，不增加睾丸复发率，性腺功能正常，但远期不良反应及睾丸功能仍有待观察。

Expression of OCT4 and SALL4 in Diffuse Large B-cell Lymphoma: An Analysis of 145 Consecutive Cases and Testicular Lymphomas.

OCT4 and SALL4 are transcription factors within a complex network that functions to maintain pluripotency in primitive stem cells and germ cells. Nuclear expression of OCT4 is widely cited as sensitive and specific for primary and metastatic germ cell tumors and is commonly used in the diagnosis of central nervous system (CNS) germinomas. Studies have failed to systematically examine the expression of OCT4 or SALL4 in diffuse large B-cell lymphoma (DLBCL), although this entity enters the morphologic differential diagnosis of some germ cell tumors. A retrospective review was conducted on 145 consecutive cases of DLBCL and testicular lymphoma to evaluate the prevalence of OCT4 and SALL4 expression. Nuclear OCT4 expression was present in 2/11 (18%) testicular DLBCLs and 6/134 (4.5%) nontesticular DLBCLs. Most OCT4 cases demonstrated moderate to strong expression in >50% of neoplastic cells. Rare, weak nuclear SALL4 expression was detected in only 3 nontesticular DLBCLs. Within the extratesticular DLBCL group, 2/6 (33%) primary CNS DLBCLs expressed nuclear OCT4. In addition, OCT4 DLBCL showed an overall predilection toward non-germinal center B-cell phenotype (7/8; 88%) and had a higher than expected rate of CD5 coexpression (4/8, 50%). These results are cautionary against using OCT4 as a sole marker of germ cell differentiation in testicular and extratesticular sites, especially in the CNS. The apparent associations of OCT4 expression with primary CNS DLBCL, non-germinal center B-cell phenotype, and CD5 coexpression raise the question of whether OCT4 expression in DLBCL may reflect more aggressive biology.

Straight Vessel Pattern and Rapid Filling Time: Characteristic Findings on Contrast-Enhanced Sonography of Testicular Lymphoma.

Six patients with 7 lesions that were histologically confirmed as primary testicular lymphoma were preoperatively investigated with a standardized sonographic protocol including contrast-enhanced sonography. Duplex and contrast-enhanced sonography showed marked hypervascularization in all 7 lesions. On contrast-enhanced sonography, the filling time of lymphomatous lesions was significantly shorter than the filling time of a size-matched sample of 10 patients with seminomas (P < .0001). The sonographic hallmarks of testicular lymphoma in our case series were as follows: (1) sharply demarcated homogeneous hypoechoic testicular lesions with marked hypervascularization; (2) a rapid (<7 seconds) filling time of contrast bubbles; and (3) a straight and parallel course of intralesional vessels on contrast-enhanced sonography.

The comparison of sperm quality of cryopreservation between patients with testicular cancer and lymphoma

The comparison of sperm quality of cryopreservation between patients with testicular cancer and lymphoma

Testicular Lymphoma: Clinical and Imaging Features

Testicular Lymphoma: Clinical and Imaging Features

Sphingosine-1-phosphate receptor 1 as a prognostic biomarker and therapeutic target for patients with primary testicular diffuse large B-cell lymphoma.

Sphingosine-1-phosphate (S1P) is a potent lipid mediator that is produced during the metabolism of sphingolipid by sphingosine kinase. S1P has been implicated in the migration and trafficking of lymphocytes and several lymphoid malignancies through S1P receptors. Moreover, the overexpression of sphingosine-1-phosphate receptor 1 (S1PR1) has been correlated with the constitutive activation of signal transducer and activator of transcription (STAT)3 and poor prognosis of diffuse large B-cell lymphoma (DLBCL). Thus, in this study, we examined the expression of S1PR1 in 198 DLBCL samples collected from nodal and various extranodal sites and sub-classified formalin-fixed paraffin-embedded tissue samples into germinal centre B-cell-like (GCB) and non-GCB subgroups using immunohistochemistry. These analyses showed S1PR1 overexpression in 15·7% of all cases with DLBCL and in 54·2% of 24 cases with primary testicular (PT)-DLBCL; S1PR1 expression correlated with S1PR1mRNA expression and STAT3 phosphorylation in fresh samples. Analyses of data from a single institution suggested that S1PR1 overexpression was an independent negative prognostic marker in 68 patients with DLBCL of clinical stages I and II. The present high prevalence of S1PR1 overexpression warrants the consideration of PT-DLBCL as a distinct disease subtype and suggests the potential of the S1P/S1PR1 axis as a therapeutic target.

Primary testicular lymphoma—A single center experience and review of literature

ObjectiveThe purpose of this study is to evaluate the clinical characteristics, pathology, treatment outcomes, and survival of primary testicular lymphoma (PTL) patients treated at our hospital after 1990. Related literature was reviewed. Materials and methodsWe retrospectively enrolled patients diagnosed with PTL between January 1990 and September 2013 in our institute. Clinical features, pathology, and overall survival were analyzed. Results24 patients were enrolled. They had a mean age at diagnosis of 65.0 years (range 10–84 y), mean follow-up duration 57.0 months (range 3–182 mo), and median overall survival of 38 months (range 4.0–184.7 mo). The most common pathology subtype was diffuse large B-cell lymphoma (n = 21, 87.5%). Fourteen patients (58.3%) achieved complete remission of disease and five patients (20.8%) achieved partial remission after treatment. Three patients had a relapse of disease after complete remission: one in the brain parenchyma, one in the pelvis soft tissue and omentum, and one in the left pyriform muscle. Three patients had metastasis after partial remission of disease: two in the brain parenchyma and one in the cauda equina. By univariate analysis, the factors significantly associated with superior overall survival were primary tumor diameter < 7.5 cm, serum lactate dehydrogenase ≤ 250 U/L, Ann-Arbor Stage IE/II, and International Prognostic Index (IPI) ≤ 1 (p < 0.05). Rituximab-containing treatment did not show overall survival benefits in our series. By multivariate analysis, IPI ≤ 1 showed statistical significance (p = 0.019), suggesting a potential prognostic value of IPI in evaluating PTL patients. ConclusionsThe overall survival of PTL patients is poor, especially those with extensive disease (Stage III/IV). The IPI have a prognostic role in PTL. The use of rituximab in the treatment regimen of PTL does not seem to improve survival in our series.

Targetable genetic features of primary testicular and primary central nervous system lymphomas

AbstractPrimary central nervous system lymphomas (PCNSLs) and primary testicular lymphomas (PTLs) are extranodal large B-cell lymphomas (LBCLs) with inferior responses to current empiric treatment regimens. To identify targetable genetic features of PCNSL and PTL, we characterized their recurrent somatic mutations, chromosomal rearrangements, copy number alterations (CNAs), and associated driver genes, and compared these comprehensive genetic signatures to those of diffuse LBCL and primary mediastinal large B-cell lymphoma (PMBL). These studies identify unique combinations of genetic alterations in discrete LBCL subtypes and subtype-selective bases for targeted therapy. PCNSLs and PTLs frequently exhibit genomic instability, and near-uniform, often biallelic, CDKN2A loss with rare TP53 mutations. PCNSLs and PTLs also use multiple genetic mechanisms to target key genes and pathways and exhibit near-uniform oncogenic Toll-like receptor signaling as a result of MYD88 mutation and/or NFKBIZ amplification, frequent concurrent B-cell receptor pathway activation, and deregulation of BCL6. Of great interest, PCNSLs and PTLs also have frequent 9p24.1/PD-L1/PD-L2 CNAs and additional translocations of these loci, structural bases of immune evasion that are shared with PMBL.

Reproduction and marriage among male survivors of cancer in childhood, adolescence and young adulthood: a national cohort study.

Background:Increased survival after cancer in young age has made long-term follow-up studies of high external validity important. In this national cohort study, we explored the impact of cancer in young age on reproduction and marital status in male survivors.Methods:Hazard ratios (HRs) and relative risks (RRs) of reproductive and marital outcomes were studied for male survivors of cancer in young age (<25 years) and cancer-free male comparisons, born during 1965–1985, by linking compulsory national registries in Norway.Results:Male cancer survivors (n=2687) had reduced paternity (HR: 0.72, 95% confidence interval (CI): 0.68–0.76). This was most apparent in survivors of testicular cancer, brain tumours, lymphoma, leukemia and bone tumours, and when diagnosed with cancer before 15 years of age. Male cancer survivors were more likely to avail of assisted reproduction (RR: 3.32, 95% CI: 2.68–4.11). There was no increased risk of perinatal death, congenital malformations, being small for gestational age, of low birth weight or preterm birth in their first offspring. Male cancer survivors were less likely to marry (HR: 0.93, 95% CI: 0.86–1.00), in particular brain tumour survivors.Conclusions:In this national cohort study, we demonstrated reduced paternity and increased use of assisted reproduction among male cancer survivors, but no adverse outcome for their first offspring at birth.