Non-pulmonary Visceral Metastases Research Articles

Testicular cancer: new developments, molecular pathology, and current research keynote.

Germ cell tumors (GCTs) are now considered acurable cancer, with a> 95% cure rate in all patients and about 90% cure rate in patients with metastatic disease. The success of physicians in curing the disease is underpinned by multidisciplinary advances. Of relevance in this regard are the nowadays-applied homogeneous terminology based on pathologically better characterized testicular neoplasms and the development of awidely used risk stratification model for metastatic disease introduced by the International Germ Cell Cancer Collaborative Group in 1997 and updated in 2021. Non-pulmonary visceral metastases, high levels of the serum tumor markers alpha-fetoprotein (AFP) and human chorionic gonadotropin (HCG), and primary mediastinal non-seminoma are currently identified as determinants of poor prognosis. In addition, the presence of distinct microRNA profiles between seminomas and non-seminoma GCTs has opened up important perspectives in terms of noninvasive biomarkers that can be used in diagnosis and treatment monitoring.

Comprehensive Assessment of Selected Immune Cell Subpopulations Changes in Chemotherapy-Naïve Germ Cell Tumor Patients.

The pattern of immune cell distribution in testicular germ cell tumors (GCT) significantly differs from the immune environment in normal testicular tissues. The present study aimed to evaluate the role of different leukocyte subpopulation in GCTs. A cohort of 84 chemotherapy-naïve GCT patients was analyzed. Immunophenotyping of peripheral blood leukocyte subpopulations was carried out by flow cytometry. In addition, the data assessing the immunophenotypes and the baseline clinicopathological characteristics of the included subjects were statistically evaluated. Their prognostic value for the assessment of progression-free survival (PFS) and overall survival (OS) was estimated. The percentage of different innate/adaptive immune cell subpopulations was significantly associated with poor risk-related clinical features, including the number of metastatic sites, presence of retroperitoneal, mediastinal, lung, brain and non-pulmonary visceral metastases as well as with the S-stage and International Germ Cell Consensus Classification Group (IGCCCG) risk groups. In univariate analysis, the percentages of neutrophils, eosinophils, dendritic cells type 2, lymphocytes and T cytotoxic cells were significantly associated with PFS, while the neutrophil, non-classical monocyte and lymphocyte percentage were associated with OS. However, all these outcome correlations were not independent of IGCCCG in multivariate analysis. The data indicated a link among different innate/adaptive peripheral immune cell subpopulations in GCT patients. In addition, the association between these subpopulations and tumor characteristics was also investigated. The findings of the present study may contribute to a deeper understanding of the interactions between cancer and innate/adaptive immune response in GCT patients.

Prognostic factors associated with malignant somatic transformation (MST) of germ cell tumors (GCT) in a Mexican cohort: The experience of the Instituto Nacional de Cancerología, Mexico (NCIM).

427 Background: MST is a rare entity defined as the development of somatic non-germ cell malignancies within GCT, its incidence varies between 2.7% and 8.6% of GCT’s. Previously reported favorable prognostic factors include synchronous diagnosis of MST and GCT, absence of non-pulmonary visceral metastases (NPVM) and presence of rhabdomyosarcoma. Methods: Retrospective study to describe prognostic factors of MST in GCT in a Hispanic population. Patients (pts) with diagnosis of MST from 2006 to 2019 were identified from the GCT database of the NCIM. Pts’ characteristics and outcomes were collected from clinical charts and recorded. Overall survival (OS) was performed with the Kaplan Meier (KM) method in the whole cohort and in patients with advanced disease (AD) (stage II and III). Comparisons were calculated with the log-rank test for KM and Chi squared test for categorical factors. Results: Seventy-one pts with MST were included in the overall population (OP). Non-seminoma 95.8%; testicular primary 97.2%; clinical stage (CS) I 32.4%, II 16.3%, III 49.3%; S2-S3 42.3%, 39.6% poor IGCCCG prognosis, 11.3% NPVM. Type of MST: 56.3% rhabdomyosarcoma (RMS), 21.1% spindle cell sarcoma, 12.7% PNET, 9.9% adenocarcinoma. 18.3% more than 1 MST histology. Median follow-up: 43.8 months (m). For the OP, mOS 71.1m (95% CI 80.0 – 119.2). OS for CS I have not been reached (NR). Forty-seven pts with AD were included, mOS 37m (95% CI 9.69 – 64.36). Characteristics associated with prognosis for OS for the OP and the AD cohorts are summarized in table. Pts with AD and RMS had more frequently a synchronous tumor (87.5% vs 58.3%, p=0.02) and absence of surgery for MST (70.8% vs 37.5%, p=.02). Conclusions: As far as we know, this is the largest cohort of hispanic pts with MST. Prognostic factors differed between OP and AD cohorts. Pts with MST and AD have a poor prognosis. Synchronous diagnosis of MST and presence of rhabdomyosarcoma are adverse prognostic factors for AD pts. Further study with a larger population is needed to verify these findings. Univariate analysis for OS.[Table: see text]

Neuroendocrine cancer of the prostate. Two case reports

Background: Neuroendocrine cancer of the prostate can present in diverse clinical pictures, potentially hampering the diagnosis and probably leading to underdiagnosis. Methods: Two cases are presented corresponding respectively to two forms of the disease: de novo neuroendocrine cancer and dedifferenciation of an adenocarcinoma of the prostate to neuroendocrine cancer under long term luteinising hormone releasing hormone (LHRH) agonist treatment. Results: Suspicion of neuroendocrine cancer may be raised in prostate cancer patients presenting either clinical or radiological metastatic progression without prostate specific antigen (PSA) rise, or relatively extended metastatic disease right at diagnosis associated to relatively low PSA, yet any non-pulmonary visceral metastases. Neuroendocrine cancer of the prostate can also turn out to be the origin of an adenocarcinoma of unknown primary. Conclusion: In case these considerations are respected the risk of missing the correct diagnosis of a neuroendocrine cancer of the prostate may be minimised.

Very late recurrence in germ cell tumor of the testis: Lessons and implications.

5030 Background: Up to 30% of patients with germ cell tumor of the testis (TGCT) develop recurrent disease after initial treatment. The majority of recurrences occur in the first 2 years after treatment. Very late recurrence (LR), i.e. > 5 years after initial presentation, occurs in about 1% of patients with TGCT and is associated with poor prognosis. Current guideline does not require follow-up after 5 years to detect LR, except in those presenting with metastatic NSGCT. Methods: We retrospectively reviewed the records of patients from the Genitourinary Medical Oncology clinic at the M. D. Anderson Cancer Center, who developed recurrent disease > 5 years after their initial diagnosis of TGCT. Specifically, we examined the pathology and location of their primary and recurrent tumors, treatments rendered (e.g., surgery, radiotherapy, chemotherapy), and overall survival after LR. Overall survival from the time of LR was estimated using Kaplan-Meier estimates and compared for patient subgroups with log rank tests. Fisher’s exact test was used to compare proportions in patient subgroups. Results: We identified 25 patients who developed LR between July 2007 and August 2020. Age at time of LR: median 46 years (range, 29-61); time of late LR: median 16.1 years (range, 6.8-33.1 years) after diagnosis. Stage at time of diagnosis: I – 5, II-IIIA – 13, IIIB-C – 7. Pathology of primary: nonseminoma with yolk sac tumor or teratoma – 15, nonseminoma without yolk sac tumor or teratoma – 1, not available – 9. Pathology of LR: somatic transformation to carcinoma – 9, somatic transformation to sarcoma – 2, nonseminoma with yolk sac tumor or teratoma – 10, nonseminoma without yolk sac tumor or teratoma – 2, not available – 2. Overall, 5 patients (20%) had LR in retroperitoneum alone, 6 patients (24%) had non-retroperitoneal nodal or pulmonary metastases, and 14 patients (56%) had non-pulmonary visceral metastases. Nine patients (36%) are deceased, ten patients (40%) are alive without evidence of disease (NED), and 6 patients are alive with disease (24%). With a median follow-up of 42 months, 68% of patients are alive 3 years after LR. Patients with prior post-chemotherapy consolidation surgery have longer survival, 80% vs. 53% at 3 years, respectively (p = 0.01). Additionally, at their last follow-up 9/12 vs. 1/13 patients were NED with vs. without prior post-chemotherapy consolidation surgery, respectively (p = 0.001). Conclusions: Patients with LR > 5 years after initial presentation tend to harbor nonseminoma (with yolk sac tumor and or teratoma). Among these patients, a majority who did not undergo surgery to remove residual disease after chemotherapy developed somatic transformation and succumbed to their LR. Further investigation into rates of LR among all patients may be warranted given the poor survival after LR.

Prognostic Value of Apoptosis-Inducing Factor (AIF) in Germ Cell Tumors.

Simple SummaryGerm cell tumors (GCTs) are the most common solid malignancies in young men. GCTs are extraordinary sensitive to chemotherapy and represent a model of curable cancer. However, in a small proportion of patients the disease progresses or relapses despite administration of salvage chemotherapy. Apoptosis is a form of programmed cell death that occurs in multicellular organisms. It is well established that dysregulation of apoptosis plays an important role in pathogenesis of malignant diseases and may be associated with tumor progression and resistance to cytotoxic treatment. This study aimed to evaluate expression of apoptosis inducing factor (AIF) in GCTs. We observed lower AIF expression in GCTs compared to normal testicular tissue. We also showed prognostic significance of AIF in GCTs. AIF downregulation might represent one of the mechanisms of inhibition of apoptosis with subsequent facilitation of cell survival and metastatic dissemination of GCTs and perhaps could serve as a potential therapeutic target. Apoptosis is a strictly regulated process essential for preservation of tissue homeostasis. This study aimed to evaluate expression of apoptosis inducing factor (AIF) in testicular germ cell tumors (GCTs) and to correlate expression patterns with clinicopathological variables. Formalin-fixed and paraffin-embedded specimens of non-neoplastic testicular tissue and GCTs obtained from 216 patients were included in the study. AIF expression was detected by immunohistochemistry, scored by the multiplicative quickscore method (QS). Normal testicular tissue exhibits higher cytoplasmic granular expression of AIF compared to GCTs (mean QS = 12.77 vs. 4.80, p < 0.0001). Among invasive GCTs, mean QS was the highest in embryonal carcinoma, yolk sac tumor and seminoma, lower in teratoma and the lowest in choriocarcinoma. No nuclear translocation of AIF was observed. Nonpulmonary visceral metastases were associated with lower AIF expression. Metastatic GCTs patients with high AIF expression had better overall survival compared to patients with low AIF expression (HR = 0.26, 95% CI 0.11–0.62, p = 0.048). We observed significantly lower AIF expression in GCTs compared to normal testicular tissue, which is an uncommon finding in malignant tumors. AIF downregulation might represent one of the mechanisms of inhibition of apoptosis and promotion of cell survival in GCTs.

ELLA01-1: A study to determine the utility of TP53 mutations as a prognostic biomarker in adenoid cystic carcinoma.

6585 Background: TP53 mutations are reported in 5% of patients with adenoid cystic carcinoma (ACC). Whilst TP53 mutations are associated with adverse clinical outcomes across multiple tumour types, their prognostic significance in ACC is unknown. We sought to determine the utility of TP53 mutations as a prognostic biomarker in a prospective cohort of ACC patients. Methods: From April 2017 to September 2019, 146 patients with ACC were prospectively recruited to an ethically approved study. DNA was extracted from archival FFPE samples and underwent targeted next generation sequencing (Qiagen GeneRead DNAseq Targeted Panel V2 n = 134; Foundation Medicine; n = 12). Clinical, pathological and outcome data were collected on all patients and Kaplan-Meier survival analysis was performed to test for survival differences between TP53 mutated and wild-type ACC. Results: 146 ACC patients (mean age 48 years, range 16-79) underwent DNA extraction and next generation sequencing for TP53 mutations. The primary site was major salivary gland in 47% and minor salivary gland in 48% (other 5%). Analysis was successful in 122/146 patients (84%). Recurrent or metastatic disease was present in 94% (115/122) at study entry. TP53 alterations were identified in 9% (11/122), most frequently within the DNA binding domain (9/11). Non-pulmonary visceral metastases were seen more frequently in TP53 wild-type than in TP53 mutated ACC (44% vs. 10%; p = 0.042), and other clinical parameters were balanced between groups. During follow-up from diagnosis (median follow up 6.6 years), death occurred in 45% of patients with TP53 mutation and in 23% with TP53 wild-type ACC (p = ns). In TP53 mutated ACC, median overall survival was significantly shorter (5.3 vs. 16.3 years), and 10-year survival rate significantly lower (42% vs. 82%) than TP53 wild-type ACC (log-rank p = 0.013). Conclusions: In this cohort of patients with ACC, TP53 mutations were seen with a higher frequency than previously reported. This may be explained by the high frequency of recurrent or metastatic disease at study entry. TP53 mutation was associated with a statistically significant reduction in overall survival in patients with recurrent and metastatic ACC. These findings suggest that stratifying by TP53 status may be of clinical value to inform follow-up strategy in addition to established clinical, pathological and genomic biomarkers.

Increased levels of XPA might be the basis of cisplatin resistance in germ cell tumours

BackgroundGerm cell tumours (GCTs) represent a highly curable malignity as they respond well to cisplatin (CDDP)-based chemotherapy. Nevertheless, a small proportion of GCT patients relapse or do not respond to therapy. As this might be caused by an increased capacity to repair CDDP-induced DNA damage, identification of DNA repair biomarkers predicting inadequate or aberrant response to CDDP, and thus poor prognosis for GCT patients, poses a challenge. The objective of this study is to examine the expression levels of the key nucleotide excision repair (NER) factors, XPA, ERCC1 and XPF, in GCT patients and cell lines.MethodsTwo hundred seven GCT patients’ specimens with sufficient follow-up clinical-pathological data and pairwise combinations of CDDP-resistant and -sensitive GCT cell lines were included. Immunohistochemistry was used to detect the ERCC1, XPF and XPA protein expression levels in GCT patients’ specimen and Western blot and qRT-PCR examined the protein and mRNA expression levels in GCT cell lines.ResultsGCT patients with low XPA expression had significantly better overall survival than patients with high expression (hazard ratio = 0.38, 95% confidence interval: 0.12–1.23, p = 0.0228). In addition, XPA expression was increased in the non-seminomatous histological subtype, IGCCCG poor prognosis group, increasing S stage, as well as the presence of lung, liver and non-pulmonary visceral metastases. Importantly, a correlation between inadequate or aberrant CDDP response and XPA expression found in GCT patients was also seen in GCT cell lines.ConclusionsXPA expression is an additional independent prognostic biomarker for stratifying GCT patients, allowing for improvements in decision-making on treatment for those at high risk of refractoriness or relapse. In addition, it could represent a novel therapeutic target in GCTs.

982P - Two-weekly accelerated BEP (aBEP) regimen as induction chemotherapy (CT) in intermediate and poor prognosis patients (pts) with nonseminomatous germ cell tumours (NSGCT): Final results of phase II trial

BackgroundThree-weekly BEP has been a standard of CT of advanced NSGCT for last two decades. We performed a phase II study to assess the efficacy and toxicity of two-weekly aBEP regimen in the first line treatment of NSGCT. Here we report final efficacy and safety results. MethodsCT-naïve NSGCT pts with intermediate or poor prognosis (IGCCCG) received aBEP as follows: cisplatin 20mg/m2 days 1-5, etoposide 100mg/m2 days 1-5, bleomycin 30IU days 1,3,5 with G-CSF support 300mcg days 6-10. Four cycles of aBEP were administered every 2 weeks. The primary endpoint was the progression free rate. ResultsFrom 2010 to 2014, 67 pts were treated. Intermediate and poor prognosis according IGCCCG had 35 (59%) and 32 (41%) of pts, respectively. In poor prognostic group mediastinal primary tumor had 11 (34%) pts, nonpulmonary visceral metastases - 16 (50%) pts. All pts were assessed for toxicity, which included (grade 3/4, per patient) neutropenia 72%, febrile neutropenia 26%, thrombocytopenia 18%, non-neutropenic infection 3%, anemia 31%. There were no toxic deaths. Dose reduction of cisplatin, etoposide and bleomycin were done on 16 (6.4%), 22 (8.9%) and 19 (7.7%) of 247 cycles, respectively. Median number of cycles was 4 (3-5). Two pts could not receive 4-th cycle due to toxicity. Median duration of treatment (from the first to the last doses of CT) was 7.4 (6.7-10.4) weeks. Totally 44 (72%) pts were able to start 4-th cycle of aBEP by day 50 (<1 week of delay). Median time of f.-up was 74 (5-108) months. Five-years PFS and OS were 88% and 85% (intermediate risk), 63% and 53% (poor risk). There were a trend to improvement of OS in poor risk group over 3-weekly BEP regimen in our center (n=79, 5-y OS 45%, p=0.09). ConclusionsTwo-weekly BEP regimen can be safely administered to NSGCT pts with intermediate and poor prognosis. Promising efficacy of aBEP warrants confirmation in ongoing randomized trial. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

903O - Redefining the IGCCCG classification in advanced non-seminoma

BackgroundThe International Germ Cell Cancer Collaborative Group (IGCCCG) has been the reference classification for assessing prognosis in men with advanced non-seminomatous germ-cell tumors (NSGCT) for more than 20 years and it relied on 5202 cases treated between 1975 and 1990. MethodsAn international consortium (30 centers/groups) contributed data on 9530 advanced NSGCT patients treated with cisplatin/etoposide based first line chemotherapy between 1990 and 2013 in prospective cohorts or clinical trials. Updated 5-year progression-free (PFS) and overall survival (OS) rates were calculated. A subset of 4874 patients with complete information on components of IGCCCG, age and lung metastases were split into training (3536) and validation sets (1338). Prognostic factors for PFS were identified in the training set (alpha=0.05) by Cox model, including (transformed) continuous factors and interactions. ResultsCompared to the 1997 IGCCCG figures, the contemporary 5-year PFS was unchanged for good and intermediate, but significantly improved for poor risk patients; whereas 5-year OS was substantially better for all risk groups (Table). The subgroup with complete data was unbiased. Besides traditional IGCCCG components, we identified older age and lung metastases as negative determinants of PFS. A nomogram including AFP, HCG (both continuous), LDH>2.5xnormal, mediastinal primary, non-pulmonary visceral metastases, age (linear) and lung metastases, with several interactions was built. Its c-index was 0.745 in the training set compared to 0.701 for the 1997 IGCCCG.Table903OTable5-year PFS IGCCCG 19975-year PFS contemporary5-year OS IGCCCG 19975-year OS contemporaryGood89 (87 – 91%)90 (89 - 91%)91 (89 - 93%)96 (95 - 97%)Intermediate75 (71 – 79%)78 (76 - 80%)79 (75 - 83%)89 (88 - 91%)Poor41 (35 – 47%)54 (52 - 56%)48 (42 - 54%)67 (65 - 69%) ConclusionsIn this modern series, PFS improved for poor risk patients, while OS improved in all IGCCCG risk groups. A new prognostic model including older age and presence of lung metastases as additional negative factors is proposed. Independent validation and comparison to the IGCCCG 1997 are being conducted and will tell if the model can identify patient subgroups who may require intensified treatment. Legal entity responsible for the studyThe International Germ Cell Cancer Collaborative Group (IGCCCG). FundingSwiss Cancer Foundation. DisclosureS. Gillessen: Advisory / Consultancy: AAA International, Active Biotech, Amgen, Astellas Pharma, Bayer, Bristol-Myers Squibb, CellSearch, Clovis, CureVac, Dendreon, ESSA Pharmaceuticals, Ferring, Innocrin Pharmaceuticals, Janssen Cilag, MaxiVAX SA, Millennium, Nectar, Novartis, Orion, Pfizer,; Licensing / Royalties: Co-inventor on patent application (WO 2009138392 A1) for a method for biomarker discover (granted in China, Europe, Japan and the US). R. de Wit: Honoraria (self): Merck, Sanofi, Bayer, Janssen, Roche and Clovis. R.A. Huddart: Honoraria (self): Janssen; Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: MSD; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy: Bristol-Myers Squibb; Research grant / Funding (self): CRUK; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Nektar. All other authors have declared no conflicts of interest.

Neuroendocrine Cancer of the Prostate.

Neuroendocrine cancer of the prostate is considered to be a rare entity with bad prognosis and limited therapeutic options. We performed a prospective analysis of the patients treated in our hospital for prostate cancer between 1st January 2015 and 31rd December 2018. Neuroendocrine phenomena were tested by immunohistochemistry and laboratory chemistry on the request of the clinicians in the cases when a positive diagnosis was suspected. Clinical tableaux of high suspicion of neuroendocrine cancer included radiological progression of a metastatic disease without PSA rise, relatively extended metastatic disease associated to a low PSA, disease with non-pulmonary visceral metastases. 10 patients were diagnosed with neuroendocrine tumour out of 521 prostate cancers. Half of the patients had a survival over a year. 3 patients received 3 lines of efficacious palliative chemotherapy. 1 patient underwent prostatectomy after neoadjuvant chemotherapy for a localised disease. The incidence of neuroendocrine tumours among prostate cancer patients was higher than expected. Some of the patients had a relatively good outcome.

622 - Non-pulmonary visceral metastases are associated with poor survival in post-chemotherapy retroperitoneal lymph node dissection (RPLND) for non-seminomatous germ cell tumours (NSGCT) of the testis

622 - Non-pulmonary visceral metastases are associated with poor survival in post-chemotherapy retroperitoneal lymph node dissection (RPLND) for non-seminomatous germ cell tumours (NSGCT) of the testis

Emerging Prognostic Biomarkers in Testicular Germ Cell Tumors: Looking Beyond Established Practice.

Testicular germ cell tumors are unique among solid cancers. Historically, this disease was deadly if progressed beyond the stage I. The implementation of cisplatin-based chemotherapy regimens has drastically changed the clinical outcome of metastatic testicular cancer. Several biomarkers were established to refine the prognosis by International Germ Cell Collaborative Group in 1997. Among these, the most significant were primary tumor site; metastatic sites, such as non-pulmonary visceral metastases; and the amplitude of serum tumor markers α-fetoprotein, β-chorionic gonadotropin, and lactate dehydrogenase. Since then, oncology has experienced discoveries of various molecular biomarkers to further refine the prognosis and treatment of malignancies. However, the ability to predict the prognosis and treatment response in germ cell tumors did not improve for many years. Clinical trials with novel targeting agents that were conducted in refractory germ cell tumor patients have proven to have negative outcomes. With the recent advances and developments, novel biomarkers emerge in the field of germ cell tumor oncology. This review article aims to summarize the current knowledge in the research of novel prognostic biomarkers in testicular germ cell tumors.

913P - The prognostic value of DNA damage level in peripheral blood lymphocytes in germ cell cancer patients

Background: Germ cell tumors (GCTs) are extraordinarily sensitive to cisplatin (CDDP)-based chemotherapy. DNA damage represents one of the most important factors contributing to the toxic effects of CDDP-based chemotherapy. Previously, in a pilot study, we observed prognostic value of the DNA damage level in peripheral blood lymphocytes (PBLs) from chemo-naïve GCT patients. This study was aimed to validate the prognostic value of the DNA damage level in PBL in chemo-naïve, as well as chemotherapy pre-treated GCT patients. Methods: PBLs isolated from 123 GCT patients (101 chemotherapy-naïve and 22 chemotherapy pre-treated) baseline and before 2nd cycle of chemotherapy were included into this prospective study. The DNA damage levels in PBLs were evaluated by the Comet assay and scored as percentage of DNA in tail by the Metafer-MetaCyte analyzing software. The DNA damage level in PBL was categorized as ‘low’ or ‘high’ according to the cut-off level of the mean. Results: The mean ± SEM (standard error of the mean) of the endogenous DNA damage level was 5.25 ± 0.64. Chemotherapy-naïve patients with “low” DNA damage levels at baseline had significantly better progression-free survival (PFS) (hazard ratio [HR] = 0.05 95%CI (0.02 – 0.17), P = 0.0001) and overall survival (OS) (HR = 0.00, P = 0.0002, no death occurred in patients with “low” DNA damage level) compared to patients with “high” DNA damage levels. In multivariate analysis, prognostic value of the DNA damage level in PBL was significantly associated with PFS and OS independently of IGCCCG risk group. Moreover, there was significant correlation between the DNA damage level and response to treatment, non-pulmonary visceral metastases, number of metastatic sites, presence of mediastinal lymph nodes metastases and serum tumor markers level. There was no prognostic value of DNA damage level in PBL before 2nd cycle of chemotherapy and/or in pre-treated GCTs. Conclusions: These data suggest that the DNA damage levels in PBLs of GCT patients are a novel prognostic marker timely identifying patients with poor outcome. We hypothesize that altered DNA damage level in PBLs could be induced by GCTs similarly to cancer-related immunosuppression and is abolished by administration of chemotherapy. Legal entity responsible for the study: Michal Mego. Funding: VEGA 1/0043/18, APVV-15-0086. Disclosure: All authors have declared no conflicts of interest.

Prognostic Factors and Treatment Results After Bleomycin, Etoposide, and Cisplatin in Germ Cell Cancer: A Population-based Study

BackgroundFirst-line treatment for patients with disseminated germ cell cancer (GCC) is bleomycin, etoposide, and cisplatin (BEP). A prognostic classification of patients receiving chemotherapy was published by the International Germ Cell Cancer Collaborative Group (IGCCCG) in 1997, but only a small proportion of the patients received BEP. ObjectiveTo estimate survival probabilities after BEP, evaluate the IGCCCG prognostic classification, and propose new prognostic factors for outcome. Design, setting, and participantsOf a Danish population-based cohort of GCC patients (1984–2007), 1889 received first-line BEP, with median follow-up of 15 yr. Covariates evaluated as prognostic factors were age, year of treatment, primary site, non-pulmonary visceral metastases, pulmonary metastases, and tumor markers. Outcome measurements and statistical analysisOutcomes measured were 5-yr progression-free survival (PFS), 5-yr disease-specific survival (DSS), and 5-yr overall survival (OS) as calculated using the Kaplan-Meier method and the Cox proportional hazards model. Results and limitationsThe 5-yr PFS, DSS, and OS were 87%, 95%, and 93%, respectively, for patients with seminomatous GCC (SGCC) and good prognosis. For nonseminomatous GCC (NSGCC) with good, intermediate, and poor prognosis, the 5-yr probabilities were 90%, 76%, and 55% for PFS; 97%, 87%, and 66% for DSS; and 95%, 85%, and 64% for OS, respectively. For SGCC patients, new adverse prognostic factors not included in the IGCCCG classification were higher age and lactate dehydrogenase ≥1.5 times the upper limit of normal. For NSGCC patients, higher age and pulmonary metastases were additional adverse prognostic factors. Treatment in earlier years was associated with higher mortality. Limitations include the small number of patients in the prognostic groups, and the inability to adjust for performance status and comorbidity. ConclusionsOur study reveals improved survival for disseminated GCC throughout the study period. We propose new prognostic factors for outcome for validation in larger cohorts of patients. Patient summaryIn this study of testicular cancer patients, we evaluated prognostic factors for outcome and calculated survival after standard chemotherapy. We find that survival has improved over the years and we propose new prognostic factors for outcome for validation in larger patient cohorts.

Rapid and objective CT scan prognostic scoring identifies metastatic patients with long-term clinical benefit on anti-PD-1/-L1 therapy

BackgroundDrugs targeting programmed death receptor-1 (PD-1) and its ligand PD-L1 have shown activity in multiple malignancies. Considering their novel mechanism of action, whether traditional prognostic scores also apply to patients treated with these drugs is unknown. We investigated whether a baseline 3-point (pt) computed tomography (CT) scan (PS3-CT) score and a 7-pt prognostic (PS7) score allowed identifying long-term survivors on anti-PD-1/-L1 therapy. Materials and methodsWe reviewed 251 consecutive patients enrolled in phase I trials evaluating anti-PD-1/-L1 agents between 26th December 2011 and 7th September 2015. PS3-CT was calculated using high tumour burden (TB1D-RECIST > 9 cm), low skeletal muscle index (SMI < 53 cm2 m−2) and non-pulmonary visceral metastases (NPVM) (1 pt each). PS7 was calculated by adding lower performance status, decreased serum albumin, increased serum lactate dehydrogenase and more than two distant metastases (1 pt each). Effect on overall survival (OS) of each parameter was tested using Kaplan–Meier and multivariable Cox analyses. ResultsPS3-CT was a significant independent predictor of OS (hazard ratio [HR] = 1.39 [95% confidence interval {CI} = 1.07–1.81], p = 0.01) when compared to the Royal Marsden Hospital, Barbot and American Joint Committee on Cancer scores. High TB (n = 78), low SMI (n = 55) and NPVM (n = 146) were associated with poorer survival (p < 0.01). High TB and low SMI were independent predictors of OS (respective HR of death: 2.00 [95% CI = 1.38–2.88], p < 0.01 and 1.75 [95% CI = 1.15–2.66], p < 0.01). PS7 was a significant predictor of OS (HR = 1.40 [95% CI = 1.25–1.56], p < 0.01). ConclusionObjective and rapid-risk scoring based on three CT scan parameters allows identifying patients with prolonged OS on anti-PD-1/-L1 therapy, independently from conventional clinical–biological prognostic scores.

Prognostic value of programmed-death-1 receptor (PD-1) and its ligand 1 (PD-L1) in testicular germ cell tumors

Testicular germ cell tumors (TGCTs) belong to the most chemosensitive solid tumors; however, a small proportion of patients fail to be cured with cisplatin-based chemotherapy. Inhibitors of PD-1/PD-L1 pathways represent a new class of promising drugs in anticancer therapy. The aim of this study was to evaluate expression and prognostic value of PD-1 and PD-L1 in TGCTs. Surgical specimens from 140 patients with TGCTs (131 with primary testicular tumor and 9 with extragonadal GCTs) were included into the translational study. PD-1 and PD-L1 expression was detected in the tumor tissue by immunohistochemistry using monoclonal antibodies, scored by the multiplicative quickscore (QS) method, compared with their expression in normal testicular tissue and correlated with clinicopathological characteristics and clinical outcome. None of the GCTs exhibited PD-1 protein, although expression of PD-L1 was significantly higher in GCTs in comparison with normal testicular tissue (mean QS = 5.29 versus 0.32, P < 0.0001). Choriocarcinomas exhibit the highest level of PD-L1 with decreasing positivity in embryonal carcinoma, teratoma, yolk sac tumor and seminoma. PD-L1 expression was associated with poor prognostic features, including ≥3 metastatic sites, increased serum tumor markers and/or non-pulmonary visceral metastases. Patients with low PD-L1 expression had significantly better progression-free survival [hazard ratio (HR) = 0.40, 95% confidence interval (CI) 0.16-1.01, P = 0.008] and overall survival (HR = 0.43, 95% CI 0.15-1.23, P = 0.040) compared with patients with high PD-L1 expression. In this translational study, we showed, for the first time, the prognostic value of PD-L1 expression in TGCTs and our data imply that the PD-1/PD-L1 pathway could be a novel therapeutic target in TGCTs.

Treatment outcome of patients with intermediate- and poor-prognosis metastatic testicular cancer in the 2000s: A multicenter experience in Japan.

397 Background: As a risk classification system of metastatic germ cell tumors, the International Germ Cell Consensus (IGCC) classification was proposed in 1997 and has received broad approval. We aimed to clarify the significance of the IGCC classification in the 2000s especially in intermediate and poor-prognosis patients in Japan. Methods: We analyzed 118 patients with intermediate- and poor-prognosis metastatic non-seminomatous germ cell testicular cancer treated at five university hospitals in Japan between 2000 and 2010. Data were collected on age, levels of serum AFP, HCG and LDH, lung metastases, spread to non-pulmonary visceral metastases (NPVM) and on treatment details (first, second and third-line chemotherapy and post-chemotherapy surgery) and survival data. Results: The median age at diagnosis was 31 years (range, 2-54 years). The median follow-up period of all patients was 57 months. Sixty-eight patients were classified as poor prognosis, having LDH elevation in 14 (21%), AFP in 13 (19%), HCG in 27 (40%), presence of NPVM in 44 (65%). As first line chemotherapy, 93 (79%) were treated by BEP (bleomycin, etoposide and cisplatin)-containing regimen. Of 118 patients, 75 (64%) received second-line chemotherapy, in which the most frequently used regimen was taxane-containing regimen, including TIP (paclitaxel, ifosfamide and cisplatin), TIN (paxlitaxel, ifosfamide and nedaplatin) and DIN (docetaxel, ifosfamide and nedaplatin). Third-line chemotherapy was carried out in 33 patients (28%). Eighty-nine patients (75%) underwent post-chemotherapy surgery. The 5-year overall survivals for intermediate (n=50) and poor (n=68) prognosis was 89% and 83% (P=0.23), respectively. In poor prognosis patients, patients with more than 2 poor-prognostic factors had significantly worse survival than those with only one prognostic factor (72% vs 91%, P=0.01). Conclusions: There was a trend of increase in survival for any risk groups and, in particular, large increase in survival for patients with a poor prognosis. Further classification of poor-prognosis patients into two subgroups has a potential to identify a patient group with very poor-prognosis.

Impact of extrascrotal symptoms on treatment outcome in patients with nonseminomatous germ cell tumor with intermediate or poor prognosis.

384 Background: The International Germ Cell Consensus (IGCC) classification is based on primary tumor localization, presence of non-pulmonary visceral metastases, and serum tumor marker levels, not the general condition of patients. The present study aimed to identify novel prognostic factors for nonseminomatous germ cell tumors (NSGCTs) with IGCC intermediate or poor prognosis. Methods: We retrospectively analyzed 399 patients with germ cell tumors (GCT) treated at Tohoku University Hospital between 1979 and 2011. Of these, 52 and 61 patients with NSGCTs were classified as having intermediate and poor prognosis, respectively. Several clinical parameters were reviewed, including age, IGCC prognosis group, kind of induction chemotherapy, and extra-scrotal symptoms at presentation. Extra-scrotal symptoms were defined as symptoms other than scrotal swelling, such as abdominal pain, lumbago, and dyspnea. Survival was estimated using the Kaplan-Meier method. A Cox proportional hazards model was used to assess potential predictors of outcome. Results: The median age of the 113 patients was 30. Median length of follow-up was 57 months. At presentation, 12 (23%) patients with intermediate prognosis and 32 (52%) patients with poor prognosis had extra-scrotal symptoms. In the intermediate prognosis group, the five year overall survival (OS) of patients with extra-scrotal symptoms was significantly worse than that of patients without symptoms (95% vs. 63%, p= 0.0008), but there was no significant difference in five year OS between patients with and without extra-scrotal symptoms in the poor prognosis group (60% vs. 66%, p= 0.265). On multivariate analysis, the presence of extra-scrotal symptoms (hazard ratio [HR] = 2.48, p= 0.0184) and induction chemotherapy not including etoposide (HR = 12.0, p&lt; 0.0001) were independent predictors of inferior OS. Conclusions: The presence of extra-scrotal symptoms was associated with inferior OS, particularly in patients with intermediate prognosis. Intermediate-prognosis patients with extra-scrotal symptoms should be recognized as having poor prognosis.

Protocol for the Examination of Specimens From Pediatric and Adult Patients With Extragonadal Germ Cell Tumors

The College of American Pathologists offers these protocols to assist pathologists in providing clinically useful and relevant information when reporting results of surgical specimen examinations. The College regards the reporting elements in the ‘‘Surgical Pathology Cancer Case Summary (Checklist)’’ portion of the protocols as essential elements of the pathology report. However, the manner in which these elements are reported is at the discretion of each specific pathologist, taking into account clinician preferences, institutional policies, and individual practice. The College developed these protocols as an educational tool to assist pathologists in the useful reporting of relevant information. It did not issue the protocols for use in litigation, reimbursement, or other contexts. Nevertheless, the College recognizes that the protocols might be used by hospitals, attorneys, payers, and others. Indeed, effective January 1, 2004, the Commission on Cancer of the American College of Surgeons mandated the use of the checklist elements of the protocols as part of its Cancer Program Standards for Approved Cancer Programs. Therefore, it becomes even more important for pathologists to familiarize themselves with these documents. At the same time, the College cautions that use of the protocols other than for their intended educational purpose may involve additional considerations that are beyond the scope of these documents.