Germ cell tumors typically occur in the gonadal regions,characterized by high malignancy and rapid progression.Due to their high sensitivity to chemotherapy,the cure rate is generally high.However,a portion of patients still succumb to chemotherapy resistance and disease progression.The use of immune checkpoint inhibitors has significantly improved the prognosis for various solid tumors,while the immune mechanisms and efficacy of immunotherapy in germ cell tumors remain understudied.Whether relapsed and refractory germ cell tumors can benefit from immune checkpoint inhibitors remains to be investigated.In this review,we summarize the immune-related mechanisms,case reports,and clinical trials of immunotherapy in germ cell tumors to assess the effectiveness of this therapy,providing a reference for future basic research and clinical practice.
Humans ; Neoplasms, Germ Cell and Embryonal/therapy* ; Immune Checkpoint Inhibitors/therapeutic use* ; Immunotherapy ; Testicular Neoplasms/drug therapy* ; Neoplasm Recurrence, Local ; Drug Resistance, Neoplasm

A series of chemotherapeutic drugs that induce DNA damage, such as cisplatin (DDP), are standard clinical treatments for ovarian cancer, testicular cancer, and other diseases that lack effective targeted drug therapy. Drug resistance is one of the main factors limiting their application. Sensitizers can overcome the drug resistance of tumor cells, thereby enhancing the antitumor activity of chemotherapeutic drugs. In this study, we aimed to identify marketable drugs that could be potential chemotherapy sensitizers and explore the underlying mechanisms. We found that the alcohol withdrawal drug disulfiram (DSF) could significantly enhance the antitumor activity of DDP. JC-1 staining, propidium iodide (PI) staining, and western blotting confirmed that the combination of DSF and DDP could enhance the apoptosis of tumor cells. Subsequent RNA sequencing combined with Gene Set Enrichment Analysis (GSEA) pathway enrichment analysis and cell biology studies such as immunofluorescence suggested an underlying mechanism: DSF makes cells more vulnerable to DNA damage by inhibiting the Fanconi anemia (FA) repair pathway, exerting a sensitizing effect to DNA damaging agents including platinum chemotherapy drugs. Thus, our study illustrated the potential mechanism of action of DSF in enhancing the antitumor effect of DDP. This might provide an effective and safe solution for combating DDP resistance in clinical treatment.
Female ; Male ; Humans ; Cisplatin/pharmacology* ; Disulfiram/pharmacology* ; Testicular Neoplasms/drug therapy* ; Fanconi Anemia/drug therapy* ; Alcoholism/drug therapy* ; Drug Resistance, Neoplasm ; Cell Line, Tumor ; Substance Withdrawal Syndrome/drug therapy* ; Apoptosis ; Antineoplastic Agents/therapeutic use* ; Cell Proliferation

Objective: To analyze the clinicopathologic characteristics and prognosis of testicular diffuse large B-cell lymphoma (DLBCL) . Methods: A retrospective analysis was performed on 68 patients with testicular DLBCL admitted to Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine from October 2001 to April 2020. The gene mutation profile was evaluated by targeted sequencing (55 lymphoma-related genes) , and prognostic factors were analyzed. Results: A total of 68 patients were included, of whom 45 (66.2% ) had primary testicular DLBCL and 23 (33.8% ) had secondary testicular DLBCL. The proportion of secondary testicular DLBCL patients with Ann Arbor stage Ⅲ-Ⅳ (P<0.001) , elevated LDH (P<0.001) , ECOG score ≥ 2 points (P=0.005) , and IPI score 3-5 points (P<0.001) is higher than that of primary testicular DLBCL patients. Sixty-two (91% ) patients received rituximab in combination with cyclophosphamide, adriamycin, vincristine, and prednisone (R-CHOP) -based first-line regimen, whereas 54 cases (79% ) underwent orchiectomy prior to chemotherapy. Patients with secondary testicular DLBCL had a lower estimated 5-year progression-free survival (PFS) rate (16.5% vs 68.1% , P<0.001) and 5-year overall survival (OS) rate (63.4% vs 74.9% , P=0.008) than those with primary testicular DLBCL, and their complete remission rate (57% vs 91% , P=0.003) was also lower than that of primary testicular DLBCL. The ECOG scores of ≥2 (PFS: P=0.018; OS: P<0.001) , Ann Arbor stages Ⅲ-Ⅳ (PFS: P<0.001; OS: P=0.018) , increased LDH levels (PFS: P=0.015; OS: P=0.006) , and multiple extra-nodal involvements (PFS: P<0.001; OS: P=0.013) were poor prognostic factors in testicular DLBCL. Targeted sequencing data in 20 patients with testicular DLBCL showed that the mutation frequencies of ≥20% were PIM1 (12 cases, 60% ) , MYD88 (11 cases, 55% ) , CD79B (9 cases, 45% ) , CREBBP (5 cases, 25% ) , KMT2D (5 cases, 25% ) , ATM (4 cases, 20% ) , and BTG2 (4 cases, 20% ) . The frequency of mutations in KMT2D in patients with secondary testicular DLBCL was higher than that in patients with primary testicular DLBCL (66.7% vs 7.1% , P=0.014) and was associated with a lower 5-year PFS rate in patients with testicular DLBCL (P=0.019) . Conclusion: Patients with secondary testicular DLBCL had worse PFS and OS than those with primary testicular DLBCL. The ECOG scores of ≥2, Ann Arbor stages Ⅲ-Ⅳ, increased LDH levels, and multiple extra-nodal involvements were poor prognostic factors in testicular DLBCL. PIM1, MYD88, CD79B, CREBBP, KMT2D, ATM, and BTG2 were commonly mutated genes in testicular DLBCL, and the prognosis of patients with KMT2D mutations was poor.
Male ; Adult ; Humans ; Prognosis ; Retrospective Studies ; Myeloid Differentiation Factor 88 ; China/epidemiology* ; Testicular Neoplasms/drug therapy* ; Cyclophosphamide ; Rituximab/therapeutic use* ; Lymphoma, Large B-Cell, Diffuse/drug therapy* ; Prednisone/therapeutic use* ; Doxorubicin/therapeutic use* ; Vincristine/therapeutic use* ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use* ; Immediate-Early Proteins/therapeutic use* ; Tumor Suppressor Proteins

This study aimed to ascertain the current status of Japanese sperm banking for young cancer patients. During 2015, we mailed the directors of 695 institutes where sperm cryopreservation might be performed with questionnaires requesting information on the number of patients, age, precryopreservation chemotherapy, semen analyses results and diagnoses, cryopreservation success rate, and causes of unsuccessful cryopreservation. Of these 695 institutes, 92 had cryopreserved sperm before chemotherapy within the study period. In all, 820 cancer patients (237 testicular, 383 hematological, 46 bone and soft tissue, 20 brain, and 134 other malignancy) consulted the responding institutes for sperm cryopreservation. Except for testicular tumor, the number of patients whose sperm was preserved before cancer treatment was low compared to that of young cancer patients. Approximately 20% of patients with malignancies other than testicular tumor underwent chemotherapy before cryopreservation. The success rate of cryopreservation in hematological malignancy was 82.5%, significantly lower than that of both the testicular cancer (93.6%) and other malignancy groups (95.6%) (P < 0.05). The primary reasons for preservation failure were azoospermia and poor semen quality. Patients with hematological malignancies had a higher rate of unsuccessful cryopreservation compared to those in other groups, possibly due to the large number of patients requesting sperm cryopreservation after chemotherapy induction. In Japan, information regarding sperm banking prior to cancer treatment appears to be lacking. Information regarding sperm preservation before chemotherapy should be provided to all Japanese oncologists.
Adolescent ; Adult ; Age Factors ; Azoospermia ; Cryopreservation ; Drug Therapy ; Humans ; Japan/epidemiology* ; Male ; Middle Aged ; Neoplasms/epidemiology* ; Semen Analysis ; Semen Preservation/methods* ; Sperm Banks/statistics & numerical data* ; Surveys and Questionnaires ; Testicular Neoplasms/epidemiology* ; Treatment Outcome ; Young Adult

PURPOSE: To evaluate the clinicopathologic and oncological outcomes of advanced metastatic testicular cancer in Korean men who underwent retroperitoneal lymph node dissection (RPLND) following chemotherapy. MATERIALS AND METHODS: Data of 26 patients with testicular cancer who underwent RPLND after chemotherapy at 2 hospitals in Korea between September 2004 and June 2016 were retrospectively analyzed. Clinical and histopathological variables such as stage of the testicular cancer, age of the patients during surgery, size of the retroperitoneal lymph nodes (RPLNs), histopathological results, duration and complications related to the surgery, cancer recurrence, and mortality were analyzed. RESULTS: During testicular surgery, the T stage was pT1, pT2, and pT3 in 50% (n=13), 26.9% (n=7), and 15.3% (n=4) of the patients, respectively. Mixed germ cell tumor was the most common finding, seen in 73.1% (n=19) of patients. The indications for RPLND were residual lymph nodes after chemotherapy, 84.6% (n=22); and disease progression and remission, 7.7% (n=2). Pathological analysis revealed viable tumors in 19.2% of patients (n=5), necrotic/fibrotic tissue in 42.3% (n=11), and teratoma in 34.6% (n=9). Intraoperative and postoperative complications occurred in 23.1% (n=6) and 19.2% of patients (n=5). The median duration of follow-up was 27.5 months (interquartile range, 1.3–108.2 months); 11.5% (n=3) patients had recurrence, and 3.8% (n=1) died of progressive metastatic testicular cancer. CONCLUSIONS: Viable germ cell tumors were present in 19.2% of patients with testicular cancer who underwent RPLND after chemotherapy. This is the first study of its kind in the Korean population.
Disease Progression ; Drug Therapy ; Follow-Up Studies ; Humans ; Korea ; Lymph Node Excision* ; Lymph Nodes* ; Male ; Mortality ; Neoplasms, Germ Cell and Embryonal ; Postoperative Complications ; Recurrence ; Retrospective Studies ; Teratoma ; Testicular Neoplasms*

OBJECTIVETo investigate the clinicopathological features of testicular malignant Leydig cell tumor (TMLCT) and improve the non-invasive diagnosis of the disease.

METHODSWe retrospectively analyzed the clinicopathological data on a case of TMLCT, detected the circulating tumor cells (CTC) in the peripheral venous blood, and reviewed the related literature.

RESULTSThe patient, a 47-year-old male, underwent radical orchidoepididymectomy under general anesthesia. Postoperative pathology confirmed the lesion to be TMLCT, which was mainly composed of Leydig cells and suspected with vessel carcinoma embolus. Immunohistochemistry showed the tumor cells to be positive for α-inhibin, Ki67, CD30, vimentin, EMA, and PLAP, but negative for CK, CK7, S100, CD10, SMA, Des, AFP, hCG, CEA, CK19, CD117, Oct-4, LCA, CD20, Pax-5, CD3, and CD43. Two CTCs were detected in the peripheral venous blood. The patient received 3 courses of chemotherapy for retroperitoneal multiple lymph nodes metastasis post-operatively. Subsequent CT imaging manifested no obvious reduction of the retroperitoneal lymph nodes and consequently the patient again underwent retroperitoneal lymphadenectomy and cryoablation. At 8 months after treatment, CT examination revealed notably enlarged retroperitoneal lymph nodes with the right adrenal gland evidently invaded.

CONCLUSIONTMLCT is an extremely rare sex-gonad stromal tumor with high malignancy and poor prognosis, and CTCs may be used for its early diagnosis and prognostic prediction.

Biomarkers, Tumor ; metabolism ; Humans ; Immunohistochemistry ; Leydig Cell Tumor ; drug therapy ; pathology ; surgery ; Lymph Node Excision ; Lymphatic Metastasis ; Male ; Middle Aged ; Neoplastic Cells, Circulating ; Prognosis ; Retrospective Studies ; Sex Cord-Gonadal Stromal Tumors ; drug therapy ; pathology ; surgery ; Testicular Neoplasms ; drug therapy ; pathology ; surgery

OBJECTIVETo observe the inhibitory effect of gefitineb on the proliferation and its inducing effect on the apoptosis of mouse I-10 Leydig testicular cancer cells in vitro.

METHODSWe treated I-10 Leydig testicular cancer cells of mice with gefitineb at 0, 1.25, 2.5, 5, 10, 20, and 40 µmol/L. Then we determined the inhibitory effect of gefitineb on the growth of the cells by MTT, detected their early and late apoptosis by Annexin V-FITC/propidium iodide double staining and Hoechst 33258 nuclear staining, respectively, and observed the expressions of apoptosis-related proteins Bcl-2, Bax and caspase 3/9 by Western blot.

RESULTSCompared with the blank control group, gefitineb significantly inhibited the proliferation of the I-10 cells at 10 and 20 µmol/L (P < 0.05). The survival rate of the cells was (32.4 ± 2.8)% (P < 0.01) and their early and late apoptosis rates were (26.7 ± 4.2)% and (59.33 ± 10.2)% in the 40 µmol/L group, significantly different from those in the control (P < 0.05 and P <0.01). In comparison with the blank control group, gefitineb at 10, 20, and 40 µmol/L increased the expression of pro-apoptotic protein Bax by (41.9 ± 7.1), (60.1 ± 9.8), and (69.0 ± 11.3)% (all P < 0.05), decreased that of apoptosis-inhibitory protein Bcl-2 by (50.3 ± 8.9), (63.9 ± 6.9), and (88.7 ± 13.9)% (all P < 0.05), and elevated that of the cleft proteins caspase-3 by (69.0 ± 6.9)% (P < 0.05), (71.5 ± 8.1)% (P < 0.05), and (110.9 ± 14.2)% (P < 0.01) and caspase-9 by (51.8 ± 4.9), (54.7 ± 6.7), and (43.8 ± 11.8)% (all P < 0.05).

CONCLUSIONGefitineb can increase the cytotoxicity of I-10 Leydig testicular cancer cells of mice and induce their apoptosis via the mitochondria-mediated apoptosis signaling pathway.

Animals ; Antineoplastic Agents ; pharmacology ; Apoptosis ; drug effects ; Apoptosis Regulatory Proteins ; metabolism ; Caspase 3 ; metabolism ; Caspase 9 ; metabolism ; Cell Proliferation ; drug effects ; Cell Survival ; Leydig Cell Tumor ; drug therapy ; metabolism ; pathology ; Male ; Mice ; Neoplasm Proteins ; metabolism ; Neoplasms, Germ Cell and Embryonal ; drug therapy ; metabolism ; pathology ; Quinazolines ; pharmacology ; Testicular Neoplasms ; drug therapy ; metabolism ; pathology ; bcl-2-Associated X Protein ; metabolism

PURPOSE: This study evaluated the demographics and semen parameters of males with cancer who banked their sperm prior to chemotherapy. MATERIALS AND METHODS: This is a retrospective study of 66 cases referred for sperm banking prior to initiation of chemotherapy over a 15-year period (1999~2014). Patients who had previously received cancer treatment including chemotherapy or radiotherapy were not included in this study. RESULTS: We studied a total of 66 cancer patients referred for cryopreservation of sperm prior to chemotherapy. The mean age of the patients at the time of banking was 32.0+/-7.9 years (range, 19~58 years). The types of cancer were testicular cancer (31 cases, 47.0%), non-Hodgkin's disease (10 cases, 15.1%), Hodgkin's disease (5 cases, 7.6%), leukemia (8 cases, 12.1%), gastrointestinal malignancy (5 cases, 7.6%), and musculoskeletal malignancy (5 cases, 7.6%). There were significant differences in sperm concentration and viability among the various types of cancer, but no significant difference in semen volume or sperm motility and morphology. CONCLUSIONS: In this study we found that sperm quality could decrease even before chemotherapy. Because chemotherapy can also negatively affect spermatogenesis, sperm cryopreservation prior to treatment should be strongly recommended for cancer patients of reproductive age.
Cryopreservation* ; Demography ; Drug Therapy* ; Hodgkin Disease ; Humans ; Infertility, Male ; Korea ; Leukemia ; Male ; Radiotherapy ; Retrospective Studies ; Semen ; Semen Analysis* ; Sperm Banks ; Sperm Motility ; Spermatogenesis ; Spermatozoa* ; Testicular Neoplasms

If a testicular cancer patient has a mass in the retroperitoneum, a metastasis is often the first suspicion, probably leading to improper diagnosis and overtreatment. Here we report a case of retroperitoneal schwannoma mimicking metastatic seminoma. A 29-year-old man, who had a history of seminoma, presented with a single retroperitoneal mass suspected to be a metastasis. Because the patient refused radiotherapy, 3 cycles of cisplatin, etoposide, and bleomycin were offered. Post-chemotherapy computed tomography scan revealed persistence of the retroperitoneal mass, with no change in tumor size or characteristics. Subsequently, retroperitoneal lymph node dissection was performed. The dissected tissue contained negative lymph nodes but a single mass in the attached fat. Pathology revealed retroperitoneal schwannoma, which was confirmed by immunohistochemistry. Thus, clinicians should be aware of retroperitoneal schwannoma and its distinction from metastatic seminoma to avoid misdiagnosis and ensure proper treatment.
Adult ; Antibiotics, Antineoplastic ; therapeutic use ; Antineoplastic Agents ; therapeutic use ; Antineoplastic Agents, Phytogenic ; therapeutic use ; Bleomycin ; therapeutic use ; Cisplatin ; therapeutic use ; Diagnostic Errors ; Etoposide ; therapeutic use ; Humans ; Lymph Node Excision ; Lymph Nodes ; pathology ; Lymphatic Metastasis ; Male ; Neoplasms, Multiple Primary ; Neurilemmoma ; diagnostic imaging ; drug therapy ; pathology ; Radiography ; Retroperitoneal Neoplasms ; diagnostic imaging ; drug therapy ; pathology ; secondary ; Retroperitoneal Space ; Seminoma ; secondary ; surgery ; Testicular Neoplasms ; surgery

OBJECTIVETo investigate the clinicopathologic features, immunophenotype, diagnosis and differential diagnosis, and prognostic factors of testicular diffuse large B-cell lymphoma (DLBCL).

METHODSThe clinical and pathologic profiles of 58 cases of testicular DLBCL were investigated.Immunohistochemical stainings and EBER1/2 in situ hybridization were performed on formalin fixed tissues.

RESULTSThe average age of the patients was 62.1 years, and the median age was 65 years. The course of disease was short in most of the cases. Clinical stages at diagnosis were mainly stage I or II (87.9%, 51/58). Forty eight patients (82.8%) had unilateral testis involvement. Inguinal lymphadenopathy was observed in 12 (20.7%) patients and the other organs were seldom involved. Morphologically, centroblast-like neoplastic cells infiltrated interstitial tissue of testis diffusely and invaded into seminiferous tubules. Tunica albuginea and vessels were involved in 14 (24.1%) and 10 (17.2%) patients, respectively. Immunophenotype analysis showed predominant non-GCB type of DLBCL (48/58, 82.8%) by Hans classification. No EBV infection was detected. Follow-up data were available in 48 (82.8%) patients. Twenty eight patients (58.3%) died of the disease. One-year, 3-year, and 5-year overall survivals were 55.7%, 31.6% and 27.6%, respectively. Age (older than 60 years), B-symptoms, high serum level of LDH, advanced Ann Arbor stage as well as lack of combination of therapy were associated with a poor prognosis.

CONCLUSIONSThis large series of testicular DLBCL mainly present with local disease at diagnosis. Most cases show non-GCB immunophenotype. Despite early clinical stage at presentation, the prognosis is poor. Combined chemotherapy postoperation may prolong survival of the patients.

Adolescent ; Adult ; Aged ; Aged, 80 and over ; Antineoplastic Combined Chemotherapy Protocols ; therapeutic use ; Child ; Cyclophosphamide ; therapeutic use ; Doxorubicin ; therapeutic use ; Follow-Up Studies ; Humans ; Immunophenotyping ; Interferon Regulatory Factors ; metabolism ; Lactate Dehydrogenases ; metabolism ; Lymphatic Metastasis ; Lymphoma, Large B-Cell, Diffuse ; drug therapy ; immunology ; pathology ; surgery ; Male ; Middle Aged ; Neoplasm Staging ; Neprilysin ; metabolism ; Orchiectomy ; Prednisone ; therapeutic use ; Proto-Oncogene Proteins c-bcl-6 ; metabolism ; Survival Rate ; Testicular Neoplasms ; drug therapy ; immunology ; pathology ; surgery ; Vincristine ; therapeutic use ; Young Adult