ctDNA guiding adjuvant immunotherapy in urothelial carcinoma.

Minimally invasive approaches to detect residual disease after surgery are needed to identify patients with cancer who are at risk for metastatic relapse. Circulating tumour DNA (ctDNA) holds promise as a biomarker for molecular residual disease and relapse1. We evaluated outcomes in 581 patients who had undergone surgery and were evaluable for ctDNA from a randomized phase III trial of adjuvant atezolizumab versus observation in operable urothelial cancer. This trial did not reach its efficacy end point in the intention-to-treat population. Here we show that ctDNA testing at the start of therapy (cycle 1 day 1) identified 214 (37%) patients who were positive for ctDNA and who had poor prognosis (observation arm hazard ratio = 6.3 (95% confidence interval: 4.45-8.92); P < 0.0001). Notably, patients who were positive for ctDNA had improved disease-free survival and overall survival in the atezolizumab arm versus the observation arm (disease-free survival hazard ratio = 0.58 (95% confidence interval: 0.43-0.79); P = 0.0024, overall survival hazard ratio = 0.59 (95% confidence interval: 0.41-0.86)). No difference in disease-free survival or overall survival between treatment arms was noted for patients who were negative for ctDNA. The rate of ctDNA clearance at week 6 was higher in the atezolizumab arm (18%) than in the observation arm (4%) (P = 0.0204). Transcriptomic analysis of tumours from patients who were positive for ctDNA revealed higher expression levels of cell-cycle and keratin genes. For patients who were positive for ctDNA and who were treated with atezolizumab, non-relapse was associated with immune response signatures and basal-squamous gene features, whereas relapse was associated with angiogenesis and fibroblast TGFß signatures. These data suggest that adjuvant atezolizumab may be associated with improved outcomes compared with observation in patients who are positive for ctDNA and who are at a high risk of relapse. These findings, if validated in other settings, would shift approaches to postoperative cancer care.

Adjunctive Surgery Is Often Without Oncological Benefit at Time of Postchemotherapy Retroperitoneal Lymph Node Dissection.

PURPOSE: Postchemotherapy retroperitoneal lymph node dissection (PC-RPLND) for advanced nonseminomatous germ cell tumors (GCTs) aims to resect all remaining metastatic tissue. Resection of adjacent visceral or vascular organs is commonly performed for complete resection. Resection of organs harboring only necrosis results in relevant overtreatment. The study aimed to describe the frequency of metastatic involvement of resected organs with teratoma or viable cancer and to analyze perioperative complications and relapse-free survival. MATERIALS AND METHODS: In a 2-center study, we reviewed a cohort of 1204 patients who underwent PC-RPLND between 2008 and 2021 and identified 242 (20%) cases of adjunctive surgery during PC-RPLND. We analyzed the removed adjacent structures and the pathohistological presence of GCT elements in the resected organs: viable GCT, teratoma, or necrosis/fibrosis. Surgery-associated complications were reported according to the Clavien-Dindo classification. RESULTS: Viable GCT, teratoma, and necrosis were present in 54 (22%), 94 (39%), and 94 (39%), respectively, of all patients with adjunctive resection of adjacent organs. Vascular resections or reconstructions (n = 112; viable: 23%, teratoma: 41%, necrosis: 36%) were performed most frequently, followed by nephrectomies (n = 77; viable: 29%, teratoma: 39%, necrosis: 33%). Perioperative complications of grade ≥ IIIa occurred in 6.6% of all patients, with no difference between the viable GCT and teratoma/necrosis groups (P = .1). A total of 76 patients have been followed without a relapse for at least 36 months. Median follow-up of the whole cohort was 22 months (quartile 7 and 48). Patients with viable GCT/teratoma in the resected specimens had a significantly increased risk of recurrence by 5 years compared to patients with only necrosis (19% vs 59% vs 81%, P < .001). CONCLUSIONS: This study shows that 33% to 40% of all resections of adjacent organs do not harbor teratoma or viable GCT. This highlights the need for better patient selection for these complex patients.

Bicenter validation of a risk model for the preoperative prediction of extraprostatic extension of localized prostate cancer combining clinical and multiparametric MRI parameters.

BACKGROUND: This study aimed to validate a previously published risk model (RM) which combines clinical and multiparametric MRI (mpMRI) parameters to predict extraprostatic extension (EPE) of prostate cancer (PC) prior to radical prostatectomy (RP). MATERIALS AND METHODS: A previously published RM combining clinical with mpMRI parameters including European Society of Urogenital Radiology (ESUR) classification for EPE was retrospectively evaluated in a cohort of two urological university hospitals in Germany. Consecutive patients (n = 205, January 2015 -June 2021) with available preoperative MRI images, clinical information including PSA, prostate volume, ESUR classification for EPE, histopathological results of MRI-fusion biopsy and RP specimen were included. Validation was performed by receiver operating characteristic analysis and calibration plots. The RM's performance was compared to ESUR criteria. RESULTS: Histopathological T3 stage was detected in 43% of the patients (n = 89); 45% at Essen and 42% at Düsseldorf. Discrimination performance between pT2 and pT3 of the RM in the entire cohort was AUC = 0.86 (AUC = 0.88 at site 1 and AUC = 0.85 at site 2). Calibration was good over the entire probability range. The discrimination performance of ESUR classification alone was comparable (AUC = 0.87). CONCLUSIONS: The RM showed good discriminative performance to predict EPE for decision-making for RP as a patient-tailored risk stratification. However, when experienced MRI reading is available, standardized MRI reading with ESUR scoring is comparable regarding information outcome. A main limitation is the potentially limited transferability to other populations because of the high prevalence of EPE in our subgroups.

Mortality from prostate cancer in the years 2007-2021 in North Rhine-Westphalia, Germany.

BACKGROUND: The crude mortality rate and the lifetime mortality risk from prostate cancer in Germany are above international average. However age-standardised mortality and years of life lost per capita from prostate cancer are declining. This study analyses the mortality-related measures for the federal state of North Rhine-Westphalia (NRW) in Germany. METHODS: Based on the cause of death statistics and data from the NRW State Cancer Registry on 45,300 deaths in the years 2007-2021, mortality rates, the lifetime mortality risk from prostate cancer, median age at death and years of life lost are presented. Additionally, the 15 most frequent causes of death of 95,013 patients diagnosed with prostate cancer are reported. RESULTS: With a stable lifetime mortality risk from prostate cancer, age-standardised mortality and years of life lost per capita are decreasing while crude mortality and median age at death are increasing in NRW. Less than half of the patients die from their prostate cancer. Cancers of the urinary bladder and other urinary organs also occur more frequently as a cause of death than it would be expected based on the age-specific risk in the total population. CONCLUSIONS: More people in North Rhine-Westphalia are dying of prostate cancer over time due to demographic ageing alone. At the same time, the age-specific mortality risk has not increased and when patients die of prostate cancer, it is at an increasingly older age. However, there is a statistical association with deaths from cancers of the lower urinary tract in patients diagnosed with prostate cancer, which demands further evaluation.

Discordance of retroperitoneal and thoracic histologic findings in patients with metastatic germ cell tumors at postchemotherapy residual tumor resection.

INTRODUCTION AND OBJECTIVES: Postchemotherapy residual tumor resection (PC-RTR) is an important part of the multimodal treatment for patients with metastatic germ cell tumors. Simultaneous retroperitoneal and thoracic metastases often require consecutive surgical procedures. This study analyzes the histologic findings after abdominal and thoracic surgery in order to tailor the sequence and intensity of surgery. PATIENTS AND METHODS: From a total of 671 PC-RTRs from 2008 to 2021 we analyzed 50 patients with stage III non-seminomatous germ cell tumor (NSGCT) who had undergone both retroperitoneal and thoracic postchemotherapy residual tumor resection after first-line and salvage chemotherapy. RESULTS: All patients included had stage III NSGCT. 39 and 11 patients received first-line and salvage chemotherapy, respectively. 45 (90%) patients received retroperitoneal resection first, followed by thoracic surgery. Three patients (6%) underwent thoracic surgery before retroperitoneal surgery and two patients (4%) underwent simultaneous surgery. Overall, the histology of retroperitoneal and thoracic specimens was discordant in 23% of cases. After first-line chemotherapy, of fourteen patients with necrosis in retroperitoneal histology, four patients had vital carcinoma in lung histology. In patients with teratoma in the retroperitoneum, the thoracic findings were concordant in most cases (78%). When teratomatous elements were also present in the orchiectomy specimen, concordance was 100%. After salvage chemotherapy, the discordance rate was 55%. CONCLUSION: The data presented in this study underline that retroperitoneal residual masses with necrosis cannot reliably predict histologic findings of thoracic specimens. Patients with teratoma in the retroperitoneum have a high likelihood of teratoma in the thoracic specimen.

[Prostate cancer screening? Only evidence-based, risk-adjusted, and organized!] / Prostatakarzinom-Screening? Nur evidenzbasiert, risikoadaptiert und organisiert!

In view of a recent recommendation of the European Commission to conceptualize novel screening approaches for lung, gastric, and prostate cancer, Germany is also invoked to revise its prostate early detection program. This discussion article provides an overview of new findings on prostate cancer screening, which suggest an organized and risk-adapted screening approach. Based on the German risk-adapted screening trial PROBASE, together with recently published data on organized screening programs in Europe, model projects should be established to determine the specific modalities for a new organized and risk-adapted prostate cancer screening program.

Adherence to a risk-adapted screening strategy for prostate cancer: First results of the PROBASE trial.

PROBASE is a population-based, randomized trial of 46 495 German men recruited at age 45 to compare effects of risk-adapted prostate cancer (PCa) screening starting either immediately at age 45, or at a deferred age of 50 years. Based on prostate-specific antigen (PSA) levels, men are classified into risk groups with different screening intervals: low-risk (<1.5 ng/ml, 5-yearly screening), intermediate-risk (1.5-2.99 ng/ml, 2 yearly), and high risk (>3 ng/ml, recommendation for immediate biopsy). Over the first 6 years of study participation, attendance rates to scheduled screening visits varied from 70.5% to 79.4%, depending on the study arm and risk group allocation, in addition 11.2% to 25.4% of men reported self-initiated PSA tests outside the PROBASE protocol. 38.5% of participants had a history of digital rectal examination or PSA testing prior to recruitment to PROBASE, frequently associated with family history of PCa. These men showed higher rates (33% to 57%, depending on subgroups) of self-initiated PSA testing in-between PROBASE screening rounds. In the high-risk groups (both arms), the biopsy acceptance rate was 64% overall, but was higher among men with screening PSA ≥4 ng/ml (>71%) and with PIRADS ≥3 findings upon multiparameter magnetic resonance imaging (mpMRI) (>72%), compared with men with PSA ≥3 to 4 ng/ml (57%) or PIRADS score ≤ 2 (59%). Overall, PROBASE shows good acceptance of a risk-adapted PCa screening strategy in Germany. Implementation of such a strategy should be accompanied by a well-structured communication, to explain not only the benefits but also the harms of PSA screening.

Characterizing the mutational burden, DNA methylation landscape, and proteome of germ cell tumor-related somatic-type malignancies to identify the tissue-of-origin, mechanisms of therapy resistance, and druggable targets.

BACKGROUND: Germ cell tumors (GCT) might undergo transformation into a somatic-type malignancy (STM), resulting in a cell fate switch to tumors usually found in somatic tissues, such as rhabdomyosarcomas or adenocarcinomas. STM is associated with a poor prognosis, but the molecular and epigenetic mechanisms triggering STM are still enigmatic, the tissue-of-origin is under debate and biomarkers are lacking. METHODS: To address these questions, we characterized a unique cohort of STM tissues on mutational, epigenetic and protein level using modern and high-throughput methods like TSO assays, 850k DNA methylation arrays and mass spectrometry. RESULTS AND CONCLUSIONS: For the first time, we show that based on DNA methylation and proteome data carcinoma-related STM more closely resemble yolk-sac tumors, while sarcoma-related STM resemble teratoma. STM harbor mutations in FGF signaling factors (FGF6/23, FGFR1/4) highlighting the corresponding pathway as a therapeutic target. Furthermore, STM utilize signaling pathways, like AKT, FGF, MAPK, and WNT to mediate molecular functions coping with oxidative stress, toxin transport, DNA helicase activity, apoptosis and the cell cycle. Collectively, these data might explain the high therapy resistance of STM. Finally, we identified putative novel biomarkers secreted by STM, like EFEMP1, MIF, and DNA methylation at specific CpG dinucleotides.

Quantum State Assignment Flows.

This paper introduces assignment flows for density matrices as state spaces for representation and analysis of data associated with vertices of an underlying weighted graph. Determining an assignment flow by geometric integration of the defining dynamical system causes an interaction of the non-commuting states across the graph, and the assignment of a pure (rank-one) state to each vertex after convergence. Adopting the Riemannian-Bogoliubov-Kubo-Mori metric from information geometry leads to closed-form local expressions that can be computed efficiently and implemented in a fine-grained parallel manner. Restriction to the submanifold of commuting density matrices recovers the assignment flows for categorical probability distributions, which merely assign labels from a finite set to each data point. As shown for these flows in our prior work, the novel class of quantum state assignment flows can also be characterized as Riemannian gradient flows with respect to a non-local, non-convex potential after proper reparameterization and under mild conditions on the underlying weight function. This weight function generates the parameters of the layers of a neural network corresponding to and generated by each step of the geometric integration scheme. Numerical results indicate and illustrate the potential of the novel approach for data representation and analysis, including the representation of correlations of data across the graph by entanglement and tensorization.

A randomized trial of risk-adapted screening for prostate cancer in young men-Results of the first screening round of the PROBASE trial.

There is no generally accepted screening strategy for prostate cancer (PCa). From February 2014 to December 2019 a randomized trial (PROBASE) recruited 46 642 men at age 45 to determine the efficacy of risk-adapted prostate-specific antigen-based (PSA) screening, starting at either 45 or 50 years. PSA tests are used to classify participants into a low (<1.5 ng/mL), intermediate (1.5-2.99 ng/mL) or high (≥3 ng/mL) risk group. In cases of confirmed PSA values ≥3 ng/mL participants are recommended a prostate biopsy with multiparametric magnetic resonance imaging (mpMRI). Half of the participants (N = 23 341) were offered PSA screening immediately at age 45; the other half (N = 23 301) were offered digital rectal examination (DRE) with delayed PSA screening at age 50. Of 23 301 participants who accepted baseline PSA testing in the immediate screening arm, 89.2% fell into the low, 9.3% into intermediate, and 1.5% (N = 344) into the high risk group. Repeat PSA measurement confirmed high-risk status for 186 men (0.8%), of whom 120 (64.5%) underwent a biopsy. A total of 48 PCas was detected (overall prevalence 0.2%), of which 15 had International Society of Uropathology (ISUP) grade 1, 29 had ISUP 2 and only 4 had ISUP ≥3 cancers. In the delayed screening arm, 23 194 participants were enrolled and 6537 underwent a DRE with 57 suspicious findings, two of which showed PCa (both ISUP 1; detection rate 0.03%). In conclusion, the prevalence of screen-detected aggressive (ISUP ≥3) PCa in 45-year-old men is very low. DRE did not turn out effective for early detection of PCa.

Quality of life after robotic-assisted and laparoscopic radical prostatectomy: Results of a multicenter randomized controlled trial (LAP-01).

BACKGROUND: To explore cross-sectional and longitudinal differences in general health-related and prostate cancer-specific quality of life (QoL) after robotic-assisted (RARP) and laparoscopic (LRP) radical prostatectomy and to analyze predictive variables for QoL outcomes. METHODS: In this multicenter, randomized controlled trial, prostate cancer patients were randomly assigned 3:1 to undergo either RARP or LRP. Patient-reported outcomes were prospectively collected before and 1, 3, 6, 12 months after radical prostatectomy and included QoL as a secondary outcome. Validated questionnaires were used to assess general health-related (EORTC QLQ-C30) and prostate cancer-specific (QLQ-PR25) QoL. Cross-sectional and longitudinal contrasts were analyzed through linear mixed models. Predictive variables for QoL outcomes were identified by general linear modeling. RESULTS: Of 782 randomized patients, QoL was evaluable in 681 patients. In terms of general QoL, the cross-sectional analysis showed only small differences between study arms, whereas longitudinal comparison indicated an advantage of RARP on recovery: RARP patients reported an earlier return to baseline in global health status (3 vs. 6 months) and social functioning (6 vs. 12 months). In role functioning, only the RARP arm regained baseline scores. Regarding prostate-specific QoL, LRP patients experienced more urinary symptoms and reported 3.2 points (95% confidence interval 0.4-6, p = 0.024) higher mean scores at 1-month follow-up and in mean 2.9 points (0.1-5, p = 0.042) higher urinary symptoms scores at 3-month follow-up than RARP patients. There were no other significant differences between treatment groups. Urinary symptoms, sexual activity, and sexual function remained significantly worse compared with baseline at all time points in both arms. CONCLUSIONS: Compared with LRP, the robotic approach led to an earlier return to baseline in several domains of general health-related QoL and better short-term recovery of urinary symptoms. Predictive variables such as the scale-specific baseline status and bilateral nerve-sparing were confirmed.

Postchemotherapy Residual Tumor Resection in Patients with Elevated Tumor Markers.

PURPOSE: The oncologic benefit of postchemotherapy (PC) residual tumor resection (RTR) in patients with germ cell tumors and elevated serum tumor markers (STMs) remains unclear. This analysis was performed to better define patients who benefit from surgery in this setting. MATERIALS AND METHODS: Of 575 PC-RTR procedures (July 2008-July 2019) 153 were performed in patients with elevated STMs (human chorionic gonadotropin [HCG] >2.0 mIU/ml, alpha-fetoprotein [AFP] >7.0 µg/l), including 55 after first line and 98 after second or later line chemotherapy. RESULTS: Viable cancer in the resected specimen was significantly more common in the salvage group than in the first line group (48.98% vs 16.36%, p=0.0001988) and was a predictor of survival in both groups. A preoperative serum level of AFP ≥30 µg/l was a significant predictor of viable cancer in the first line and salvage groups (55.56% [p=0.0157] and 66.67% [p=0.0017], respectively). The overall relapse-free survival rate (22.7% and 50%, p=0.00032) and overall survival rate (37.8% and 65%, p=0.0059) were significantly worse in the salvage group than in the first line group. A preoperative serum level of AFP ≥30 µg/l and viable cancer/teratoma found in the histological examination of the RTR specimens were significant predictors of relapse after first line chemotherapy. Serum AFP ≥30 µg/l and HCG ≥20 mIU/ml were significant factors affecting survival in the first line group. CONCLUSIONS: Patients with AFP serum levels >30 µg/l and HCG ≥20 mIU/ml after first line chemotherapy should receive salvage chemotherapy instead of surgery. After second or later line therapy, the prognosis of patients with elevated markers and surgery is poor regardless of the tumor marker levels. However, 38% of these patients are long-term survivors, which justifies PC-RTR in this setting.

Value of T2 Mapping MRI for Prostate Cancer Detection and Classification.

BACKGROUND: Currently, multi-parametric prostate MRI (mpMRI) consists of a qualitative T2 , diffusion weighted, and dynamic contrast enhanced imaging. Quantification of T2 imaging might further standardize PCa detection and support artificial intelligence solutions. PURPOSE: To evaluate the value of T2 mapping to detect prostate cancer (PCa) and to differentiate PCa aggressiveness. STUDY TYPE: Retrospective single center cohort study. POPULATION: Forty-four consecutive patients (mean age 67 years; median PSA 7.9 ng/mL) with mpMRI and verified PCa by subsequent targeted plus systematic MR/ultrasound (US)-fusion biopsy from February 2019 to December 2019. FIELD STRENGTH/SEQUENCE: Standardized mpMRI at 3 T with an additionally acquired T2 mapping sequence. ASSESSMENT: Primary endpoint was the analysis of quantitative T2 values and contrast differences/ratios (CD/CR) between PCa and benign tissue. Secondary objectives were the correlation between T2 values, ISUP grade, apparent diffusion coefficient (ADC) value, and PI-RADS, and the evaluation of thresholds for differentiating PCa and clinically significant PCa (csPCa). STATISTICAL TESTS: Mann-Whitney test, Spearman's rank (rs ) correlation, receiver operating curves, Youden's index (J), and AUC were performed. Statistical significance was defined as P < 0.05. RESULTS: Median quantitative T2 values were significantly lower for PCa in PZ (85 msec) and PCa in TZ (75 msec) compared to benign PZ (141 msec) or TZ (97 msec) (P < 0.001). CD/CR between PCa and benign PZ (51.2/1.77), respectively TZ (19.8/1.29), differed significantly (P < 0.001). The best T2 -mapping threshold for PCa/csPCa detection was for TZ 81/86 msec (J = 0.929/1.0), and for PZ 110 msec (J = 0.834/0.905). Quantitative T2 values of PCa did not correlate significantly with the ISUP grade (rs  = 0.186; P = 0.226), ADC value (rs  = 0.138; P = 0.372), or PI-RADS (rs  = 0.132; P = 0.392). DATA CONCLUSION: Quantitative T2 values could differentiate PCa in TZ and PZ and might support standardization of mpMRI of the prostate. Different thresholds seem to apply for PZ and TZ lesions. However, in the present study quantitative T2 values were not able to indicate PCa aggressiveness. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 2.

Preoperative clinical and radiographic predictors of major vascular surgery in patients with testicular cancer undergoing post-chemotherapy residual tumor resection (PC-RPLND).

PURPOSE: To evaluate the probability to correctly predict major vascular surgery (MVS) in patients undergoing postchemotherapy retroperitoneal lymph node dissection (PC-RPLND) for testicular cancer. METHODS: From a database of 504 RPLNDs performed in 434 patients (2008-2018), 78 patients submitted to PC-RPLND for non-seminoma germ-cell cancer after cisplatin-based chemotherapy with available preoperative CT scans were identified. Second PC-PLNDs (Re-Dos), salvage RPLNDs, or RPLNDs for late-relapse were excluded as well as thoraco-abdominal approaches. Preoperative imaging was reviewed by a urologist and a radiologist blinded to operative details. RESULTS: Of 78 patients, 16 (20.5%) underwent MVS (caval and/or aortic replacement or reconstruction). On univariable analyses, transversal diameter, sagittal diameter, tumor volume, aorta- and cava-tumor contact angle, poor IGCCCG score, clinical stage III and preoperative positive markers were predictors of MVS (all p values ≤ 0.01). At multivariable analyses aorta- (cut-off 64°) and cava-tumor contact angle (cut-off 98°) and poor IGCCCG score represented the three most important predictors of MVS (all p values ≤ 0.05). The model constructed has a PPV 100%, NPV 87% and an accuracy of 88%. CONCLUSIONS: Presence of aorta-tumor contact angle ≥ 64°, cava-tumor contact angle ≥ 98° and poor IGCCCG score identify correctly 9 out of 10 patients requiring MVS at the time of first PC-RPLND.

Late relapsing germ cell tumors with elevated tumor markers.

PURPOSE: Late relapsing germ cell tumors (LR-GCT) are considered a rare distinct biologic entity as their clinical presentation and response to treatment is different to early recurrences. While serum tumor markers (AFP and ß-HCG) play an important role at the time of first diagnosis to correctly classify prognosis and treatment of germ cell tumors, they may not have the same significance in a late relapse situation. PATIENTS AND METHODS: Thirty-seven patients with LR-GCT with elevated serum tumor markers were identified in our database. Twenty-six patients underwent primary surgical resection of the late relapsing tumor. Eleven patients received salvage chemotherapy and a post-chemotherapy residual tumor resection. Serum tumor markers, histological findings and oncological outcome were analyzed. RESULTS: In the histopathological specimen, viable cancer was found in 20 cases (54%) and teratoma was found in 16 cases (43%). In nine cases (24%), a somatic-type malignant transformation was present. In 19 of 37 patients (51.4%), the late relapse specimen presented a histological type of GCT, which was not present in the primary histology. Twenty-two patients (59.5%) were included in follow-up analysis. Mean and median follow-up time was 62.2 and 53 months, respectively. Seventeen patients (77.3%) suffered a relapse or had progressive disease after LR therapy. Five patients (22.7%) have been relapse-free after LR therapy (mean FU 61.6 months). Ten patients died of disease during follow-up (45.5%) and had a mean time from LR to death of 66.4 months. Eleven patients were alive at last follow-up (mean FU 62.2 months). Relapse and survival rate were similar between patients who received primary resection of LR tumor and patients who received salvage chemotherapy followed by surgery. CONCLUSION: Patients with a late relapsing germ cell tumor and elevated markers have a poor prognosis and a high risk for another relapse independent on primary treatment. The histological type and aggressiveness of a late relapsing tumor cannot be predicted with serum tumor marker levels at the time of diagnosis of LR. In up to 54% of cases, primary histology did not coincide with LR histology. Therefore, we propose primary surgical resection of a late relapsing tumor if a complete resection is feasible in order to gain exact histology and tailor further treatment.

Can magnetic resonance imaging replace conventional computerized tomography for follow-up of patients with testicular cancer? A systematic review.

PURPOSE: Follow-up protocols for patients with testicular cancer (TC) have significantly reduced the number of cross-sectional imaging studies to reduce radiation exposure. At present, it is unclear whether magnetic resonance imaging (MRI) could replace conventional computerized tomography (CT) imaging. The objective of this study is to summarize the scientific evidence on this topic and to review guideline recommendations with regard to the use of MRI. METHODS: A systematic literature review was performed searching Medline and Cochrane databases for prospective studies on patients with TC in the follow-up care (last search in February 2021). Additionally, guideline recommendations for TC were screened. Data extraction and quality assessment of included studies were performed and used for a descriptive presentation of results. RESULTS: A total of four studies including two ongoing trials were identified. Overall, the scientific evidence of prospective comparative studies is based on 102 patients. Data suggest that abdominal imaging with MRI can replace conventional CT for detection of lymph node metastasis of the retroperitoneum to spare radiation exposure and contrast media application. However, experienced radiologists are needed. Clinical guidelines are aware of the risk of diagnosis-induced secondary malignancy due to CT imaging and some have adapted their recommendations accordingly. Results of the two ongoing trials on 738 patients are expected soon to provide more reliable results on this topic. CONCLUSIONS: There is growing evidence that abdominopelvic MRI imaging can replace CT imaging during follow-up of patients with TC in order to reduce radiation exposure and diagnosis-induced secondary malignancy.

Prognostic factors in patients with clinical stage I nonseminoma-beyond lymphovascular invasion: a systematic review.

OBJECTIVE: To systematically evaluate evidence on prognostic factors for tumor recurrence in clinical stage I nonseminoma patients other than lymphovascular invasion (LVI). METHODS: We performed a systematic literature search in the biomedical databases Medline (via Ovid) and Cochrane Central Register of Controlled Trials (search period January 2010 to February 2021) for full text publications in English and German language, reporting on retro- or prospectively assessed prognostic factors for tumor recurrence in patients with stage I nonseminomatous germ cell tumors. RESULTS: Our literature search yielded eleven studies reporting on 20 potential prognostic factors. Results are based on cohort studies of mostly moderate to low quality. Five out of eight studies found a significant association of embryonal carcinoma (EC) in the primary tumor with relapse. Among the different risk definitions of embryonal carcinoma (presence, predominance, pure), presence of EC alone seems to be sufficient for prognostification. Interesting results were found for rete testis invasion, predominant yolk sac tumor, T-stage and history of cryptorchidism, but the sparse data situation does not justify their clinical use. CONCLUSIONS: No additional factors that meet the prognostic value of LVI, especially when determined by immunohistochemistry, could be identified through our systematic search. The presence of EC might serve as a second, subordinate prognostic factor for clinical use as the data situation is less abundant than the one of LVI. Further efforts are necessary to optimize the use of these two prognostic factors and to evaluate and validate further potential factors with promising preliminary data.

How to classify, diagnose, treat and follow-up extragonadal germ cell tumors? A systematic review of available evidence.

PURPOSE: To present the current evidence and the development of studies in recent years on the management of extragonadal germ cell tumors (EGCT). METHODS: A systematic literature search was conducted in Medline and the Cochrane Library. Studies within the search period (January 2010 to February 2021) that addressed the classification, diagnosis, prognosis, treatment, and follow-up of extragonadal tumors were included. Risk of bias was assessed and relevant data were extracted in evidence tables. RESULTS: The systematic search identified nine studies. Germ cell tumors (GCT) arise predominantly from within the testis, but about 5% of the tumors are primarily located extragonadal. EGCT are localized primarily mediastinal or retroperitoneal in the midline of the body. EGCT patients are classified according to the IGCCCG classification. Consecutively, all mediastinal non-seminomatous EGCT patients belong to the "poor prognosis" group. In contrast mediastinal seminoma and both retroperitoneal seminoma and non-seminoma patients seem to have a similar prognosis as patients with gonadal GCTs and metastasis at theses respective sites. The standard chemotherapy regimen for patients with a EGCT consists of 3-4 cycles (good vs intermediate prognosis) of bleomycin, etoposid, cisplatin (BEP); however, due to their very poor prognosis patients with non-seminomatous mediastinal GCT should receive a dose-intensified or high-dose chemotherapy approach upfront on an individual basis and should thus be referred to expert centers Ifosfamide may be exchanged for bleomycin in cases of additional pulmonary metastasis due to subsequently planned resections. In general patients with non-seminomatous EGCT, residual tumor resection (RTR) should be performed after chemotherapy. CONCLUSION: In general, non-seminomatous EGCT have a poorer prognosis compared to testicular GCT, while seminomatous EGGCT seem to have a similar prognosis to patients with metastatic testicular seminoma. The current insights on EGCT are limited, since all data are mainly based on case series and studies with small patient numbers and non-comparative studies. In general, systemic treatment should be performed like in testicular metastatic GCTs but upfront dose intensification of chemotherapy should be considered for mediastinal non-seminoma patients. Thus, EGCT should be referred to interdisciplinary centers with utmost experience in the treatment of germ cell tumors.

Testicular germ cell tumours' clinical stage I: comparison of surveillance with adjuvant treatment strategies regarding recurrence rates and overall survival-a systematic review.

PURPOSE: Testicular germ cell tumours (GCTs) represent the most common malignancy in young adult males with two thirds of all cases presenting with clinical stage I (CSI). Active surveillance is the management modality mostly favoured by current guidelines. This systematic review assesses the treatment results in CSI patients concerning recurrence rate and overall survival in non-seminoma (NS) and pure seminoma (SE) resulting from surveillance in comparison to adjuvant strategies. METHODS/SYSTEMATIC REVIEW: We performed a systematic literature review confining the search to most recent studies published 2010-2021 that reported direct comparisons of surveillance to adjuvant management. We searched Medline and the Cochrane Library with additional hand-searching of reference lists to identify relevant studies. Data extraction and quality assessment of included studies were performed with stratification for histology (NS vs. SE) and treatment modalities. The results were tabulated and evaluated with descriptive statistical methods. RESULTS: Thirty-four studies met the inclusion criteria. In NS patients relapse rates were 12 to 37%, 0 to 10%, and 0 to 11.8% for surveillance, chemotherapy and for retroperitoneal lymph node dissection (RPLND) while overall survival rates were 90.7-100%, 91.7-100%, and 97-99.1%, respectively. In SE CSI, relapse rates were 0-22.3%, 0-5%, and 0-12.5% for surveillance, radiotherapy, chemotherapy, while overall survival rates were 84.1-98.7%, 83.5-100%, and 92.3-100%, respectively. CONCLUSION: In both histologic subgroups, active surveillance offers almost identical overall survival as adjuvant management strategies, however, at the expense of higher relapse rates. Each of the management strategies in CSI GCT patients have specific merits and shared-decision-making is advised to tailor treatment.

First-line salvage treatment options for germ cell tumor patients failing stage-adapted primary treatment : A comprehensive review compiled by the German Testicular Cancer Study Group.

PURPOSE: In this review, we summarize and discuss contemporary treatment standards and possible selection criteria for decision making after failure of adjuvant or first-line cisplatin-based chemotherapy for primarily localized or metastatic germ cell tumors. METHODS: This work is based on a systematic literature search conducted for the elaboration of the first German clinical practice guideline to identify prospective clinical trials and retrospective comparative studies published between Jan 2010 and Feb 2021. Study end points of interest were progression-free (PFS) and overall survival (OS), relapse rate (RR), and/or safety. RESULTS: Relapses of clinical stage I (CS I) patients irrespective of prior adjuvant treatment after orchiectomy are treated stage adapted in accordance for primary metastatic patients. Surgical approaches for sole retroperitoneal relapses are investigated in ongoing clinical trials. The appropriate salvage chemotherapy for metastatic patients progressing or relapsing after first-line cisplatin-based chemotherapy is still a matter of controversy. Conventional cisplatin-based chemotherapy is the international guideline-endorsed standard of care, but based on retrospective data high-dose chemotherapy and subsequent autologous stem cell transplantation may offer a 10-15% survival benefit for all patients. Secondary complete surgical resection of all visible residual masses irrespective of size is paramount for treatment success. CONCLUSIONS: Patients relapsing after definite treatment of locoregional disease are to be treated by stage-adapted first-line standard therapy for metastatic disease. Patients with primary advanced/metastatic disease failing one line of cisplatin-based combination chemotherapy should be referred to GCT expert centers. Dose intensity is a matter of ongoing debate, but sequential high-dose chemotherapy seems to improve patients' survival.