Evaluation of QSAR models for predicting mutagenicity: outcome of the Second Ames/QSAR international challenge project.

Quantitative structure-activity relationship (QSAR) models are powerful in silico tools for predicting the mutagenicity of unstable compounds, impurities and metabolites that are difficult to examine using the Ames test. Ideally, Ames/QSAR models for regulatory use should demonstrate high sensitivity, low false-negative rate and wide coverage of chemical space. To promote superior model development, the Division of Genetics and Mutagenesis, National Institute of Health Sciences, Japan (DGM/NIHS), conducted the Second Ames/QSAR International Challenge Project (2020-2022) as a successor to the First Project (2014-2017), with 21 teams from 11 countries participating. The DGM/NIHS provided a curated training dataset of approximately 12,000 chemicals and a trial dataset of approximately 1,600 chemicals, and each participating team predicted the Ames mutagenicity of each trial chemical using various Ames/QSAR models. The DGM/NIHS then provided the Ames test results for trial chemicals to assist in model improvement. Although overall model performance on the Second Project was not superior to that on the First, models from the eight teams participating in both projects achieved higher sensitivity than models from teams participating in only the Second Project. Thus, these evaluations have facilitated the development of QSAR models.

Commentary on "Prognostic effect of carcinoma in situ in muscle-invasive urothelial carcinoma patients receiving neoadjuvant chemotherapy."

BACKGROUND: Carcinoma in situ (CIS) is a poor prognostic finding in urothelial carcinoma. However, its significance in muscle-invasive urothelial carcinoma (MIUC) treated with neoadjuvant chemotherapy (NAC) is uncertain. We assessed the effect of CIS found in pretreatment transurethral resection of bladder tumor (TURBT) biopsies on the pathologic and clinical outcomes. MATERIALS AND METHODS: Subjects with MIUC treated with NAC before cystectomy were identified. The pathologic complete response (pCR) rates stratified by TURBT CIS status were compared. The secondary analyses included tumor response, progression-free survival (PFS), overall survival (OS), and an exploratory post hoc analysis of patients with pathologic CIS only (pTisN0) at cystectomy. RESULTS: A total of 137 patients with MIUC were identified. TURBT CIS was noted in 30.7% of the patients. The absence of TURBT CIS was associated with a significantly increased pCR rate (23.2% vs. 9.5%; odds ratio = 4.08; 95% CI: 1.19-13.98; P = 0.025). Stage pTisN0 disease was observed in 19.0% of the TURBT CIS patients. TURBT CIS status did not significantly affect the PFS or OS outcomes. Post hoc analysis of the pTisN0 patients revealed prolonged median PFS (104.5 vs. 139.9 months; P = 0.055) and OS (104.5 vs. 152.3 months; P = 0.091) outcomes similar to those for the pCR patients. CONCLUSION: The absence of CIS on pretreatment TURBT in patients with MIUC undergoing NAC was associated with increased pCR rates, with no observed differences in PFS or OS. Isolated CIS at cystectomy was frequently observed, with lengthy PFS and OS durations similar to those for pCR patients. Further studies aimed at understanding the biology and clinical effect of CIS in MIUC are warranted.

Multidisciplinary clinic approach improves overall survival outcomes of patients with metastatic germ-cell tumors.

Background: To report our experience utilizing a multidisciplinary clinic (MDC) at Indiana University (IU) since the publication of the International Germ Cell Cancer Collaborative Group (IGCCCG), and to compare our overall survival (OS) to that of the National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) Program. Patients and methods: We conducted a retrospective analysis of all patients with metastatic germ-cell tumor (GCT) seen at IU from 1998 to 2014. A total of 1611 consecutive patients were identified, of whom 704 patients received an initial evaluation by our MDC (including medical oncology, pathology, urology and thoracic surgery) and started first-line chemotherapy at IU. These 704 patients were eligible for analysis. All patients in this cohort were treated with cisplatin-etoposide-based combination chemotherapy. We compared the progression-free survival (PFS) and OS of patients treated at IU with that of the published IGCCCG cohort. OS of the IU testis cancer primary cohort (n = 622) was further compared with the SEER data of 1283 patients labeled with 'distant' disease. The Kaplan-Meier method was used to estimate PFS and OS. Results: With a median follow-up of 4.4 years, patients with good, intermediate, and poor risk disease by IGCCCG criteria treated at IU had 5-year PFS of 90%, 84%, and 54% and 5-year OS of 97%, 92%, and 73%, respectively. The 5-year PFS for all patients in the IU cohort was 79% [95% confidence interval (CI) 76% to 82%]. The 5-year OS for the IU cohort was 90% (95% CI 87% to 92%). IU testis cohort had 5-year OS 94% (95% CI 91% to 96%) versus 75% (95% CI 73% to 78%) for the SEER 'distant' cohort between 2000 and 2014, P-value <0.0001. Conclusion: The MDC approach to GCT at high-volume cancer center associated with improved OS outcomes in this contemporary dataset. OS is significantly higher in the IU cohort compared with the IGCCCG and SEER 'distant' cohort.

Outcome analysis of patients with transformed teratoma to primitive neuroectodermal tumor.

BACKGROUND: The emergence of a primitive neuroectodermal tumor (PNET) within a germ-cell tumor (GCT) is rare. We assess the prognosis and response to treatment. PATIENTS AND METHODS: Eighty-one patients were identified. Selected patients were treated with cyclophosphamide 1200 mg/m(2), doxorubicin 75 mg/m(2), and vincristine 2 mg i.v. alternating with ifosfamide 1.8 g/m(2) x 5 days plus etoposide 100 mg/m(2) x 5 days (CAV/IE). Ewing's sarcoma (EWS) translocation was assessed using a FISH-based method. RESULTS: Median follow-up was 41 months. Seventy-six patients had PNET in the primary tumor or in initial metastasis. Five harbored PNET only at relapse. Twenty-six of 76 underwent primary retroperitoneal lymph node dissection, 13 of whom had retroperitoneal PNET and four are dead of disease (DOD). Fifty of 76 were initially treated with GCT chemotherapy (n = 49) or CAV/IE (n = 1). Twenty-seven of these 50 underwent complete postchemotherapy resection of residual PNET and 17 are DOD. Ten patients received CAV/IE. Eight achieved an objective response, and five are currently alive. One of the 14 specimens examined carried the EWS translocation. CONCLUSIONS: PNET of GCT origin is associated with an adverse outcome. For low-volume disease, surgery is the optimal initial therapy. CAV/IE may have a role in patients with unresectable disease.

Molecular genetic evidence supporting the neoplastic nature of stromal cells in 'fibrosis' after chemotherapy for testicular germ cell tumours.

A residual retroperitoneal mass containing only fibrosis and necrosis is present in 40-52% of patients with advanced testicular germ cell tumours after chemotherapy. The biological nature and genetic characteristics of the stromal cells in these residual masses have not been adequately investigated. Laser-microdissected stromal cells from 27 patients who underwent retroperitoneal lymph node dissection after chemotherapy for metastatic testicular germ cell tumour were analysed. Allelic loss in the stromal cells of fibrosis was present at one or more of the ten microsatellite DNA loci examined in 23 (85%) of the cases. Chromosome arm 12p anomalies, the hallmark of germ cell neoplasia, were present in nine (33%) cases. The high frequency of allelic losses and chromosome arm 12p anomalies in the stromal cells from residual retroperitoneal fibrous masses after chemotherapy for testicular germ cell tumours suggests that the stromal cells are derived from the same tumour progenitor cells as the pre-existing metastatic germ cell tumour.

Biochemical disease-free survival in patients with a high prostate-specific antigen level (20-100 ng/mL) and clinically localized prostate cancer after radical prostatectomy.

OBJECTIVE: To examine our experience with radical prostatectomy (RP) in patients with a serum prostate-specific antigen (PSA) level of > 20 ng/mL (who are sometimes considered poor candidates for RP) to determine the outcome and possible predictors of a favourable outcome. PATIENTS AND METHODS: We retrospectively reviewed the medical records of 79 patients who underwent RP with an initial PSA of 20-100 ng/mL. Biochemical disease-free survival (BDFS) was assessed using the Kaplan-Meier method and predictors of treatment outcome examined by uni- and multivariate analysis. Patients excluded from the analysis were 11 (14%) whose surgery was aborted after finding cancerous pelvic nodes and who did not undergo RP; four others with normal nodes during RP who had metastatic tumour on permanent sections; and 14 who had follow-up data for < 2 years. RESULTS: The mean (sd) age of the 50 patients in the final study population was 63 (7) years and the mean PSA 37.9 (16.0) ng/mL. The median (range) follow-up was 54 (24-120) months. The BDFS was 60% at 3 years and 48% at 5 years of follow-up. Two patients developed a local recurrence and eight developed metastatic disease. On logistic regression analysis of factors influencing BDFS, only extracapsular extension of disease was predictive of PSA recurrence; no preoperative factor was significant. When time to PSA recurrence was assessed by Cox regression analysis, again only extracapsular extension was predictive, with no preoperative variable a statistically significant predictor. CONCLUSIONS: Patients with a high serum PSA level (20-100 ng/mL) may be appropriate candidates for RP. While the cancer-free survival is not as good as in patients with a lower PSA, a significant percentage of patients achieve BDFS. No preoperative variables were predictive of disease-free survival or time to PSA recurrence.

Accuracy of predicting long-term prostate specific antigen outcome based on early prostate specific antigen recurrence results after radical prostatectomy.

PURPOSE: We determined how prostate specific antigen (PSA) doubling time changed with time and whether an early measure of doubling time would accurately predict long-term PSA values and clinical outcome in a cohort of patients followed expectantly after radical prostatectomy. MATERIALS AND METHODS: We analyzed data on 121 patients with PSA recurrence after radical retropubic prostatectomy. Group and individual analyses were performed on 60 patients who met study inclusion criteria. PSA doubling time was calculated and a curve was plotted using logarithmic transformation with linear regression and least squares analysis. In analysis 1 patients were placed into 3 subgroups according to doubling time. Doubling time was calculated per subgroup and the slopes of the aggregate curves were compared to determine how doubling time changed with time. In analysis 2 we calculated early doubling time per patient using only the initial 2 detectable PSA values and compared it with eventual doubling time in each using all PSA values. In addition, we analyzed how doubling time correlated with the clinical course. RESULTS: Using the group methodology there was no statistically significant acceleration or deceleration with time in doubling time slope in any of the 3 subgroups. On individual analysis we noted a weak correlation of early with eventual doubling time (correlation coefficient 0.69, p = 0.01). In 88% of patients eventual doubling time was not within 10% of early doubling time. Metastasis developed in 60% of patients with an eventual DT of 0 to 6 months, while 80% with an eventual doubling time of 6 to 12 months had no evidence of local or metastatic disease. No patients with an eventual doubling time of greater than 12 months have had metastatic disease and only 4 (16%) had local recurrence, which was treated with radiation therapy. In 8 of the 14 patients (23%) with local recurrence or metastatic disease early doubling time predicted eventual doubling time. Early doubling time was more rapid and slower than eventual doubling time in 5 and 1, respectively, of the remaining cases, which would have placed them in a different subgroup. CONCLUSIONS: On group analysis PSA doubling time appeared to be constant with time and there was no evidence that it accelerated with time in our dataset of PSA recurrence after radical prostatectomy. On individual analysis early doubling time showed a weak but statistically significant correlation with eventual doubling time. However, there was significant inaccuracy when predicting PSA doubling time based on early PSA values in individuals. Generally early projections of doubling time tend to over predict tumor biological aggressiveness, that is local recurrence or metastasis. A need remains for more accurate predictors of the rate of disease progression at initial PSA recurrence to determine accurately early in the clinical course the patients who may benefit from additional therapy. Currently no patient in our study has died of prostate cancer.

Germ cell tumor associated primitive neuroectodermal tumors.

PURPOSE: This retrospective review was done to assess the prognosis and response in patients presenting with primitive neuroectodermal tumor admixed with germ cell tumor. MATERIALS AND METHODS: Of the 40 patients treated at our institution from 1984 to 1999, 15 had initial stage I and 25 had initial metastatic disease. Median followup after the diagnosis was 25 months (range 4 to 142). RESULTS: Of the 40 patients 15 presented with clinical stage I disease, including 9 treated with retroperitoneal lymph node dissection and 6 who elected surveillance. Seven of the 9 patients had normal lymph nodes and all continuously had no evidence of disease. Two of the 9 patients had lymph nodes involved with teratoma with or without primitive neuroectodermal tumor. Retroperitoneal relapse in 5 of the 6 patients on surveillance was treated with cisplatin based chemotherapy followed by post-chemotherapy retroperitoneal lymph node dissection. Residual primitive neuroectodermal tumor was noted in 4 of the 5 patients and only 3 of 6 are currently without disease at a median followup of 17 months (range 15 to 69). A total of 25 patients presented with metastatic disease, of whom 23 underwent cisplatin based chemotherapy. Only 3 patients achieved complete remission with chemotherapy alone and 2 of the 3 subsequently relapsed. Of the remaining 20 patients 16 underwent post-chemotherapy retroperitoneal lymph node dissection, including 11 with primitive neuroectodermal tumor in the resected specimen. Two of these 11 patients have continuously had no evidence of disease, while an additional 3 currently have no evidence of disease after further therapy. Teratoma was present in the resected specimen in 5 of 16 patients, of whom 2 have continuously had no evidence of disease, while an additional 2 currently have no evidence of disease after further surgical resection. Therefore, 11 of 25 patients who presented with metastatic disease currently have no evidence of disease at a median followup of 19 months (range 2 to 111). CONCLUSIONS: Primitive neuroectodermal tumor in the orchiectomy specimen has adverse prognostic significance. This condition in the retroperitoneum is potentially curable by retroperitoneal lymph node dissection but rarely eradicated by chemotherapy. Therefore, we recommend retroperitoneal lymph node dissection for all clinical stage I cases with primitive neuroectodermal tumor in the orchiectomy specimen. Patients who present with metastatic primitive neuroectodermal tumor should be treated aggressively with surgical resection as an integral part of the therapeutic strategy.

Aortic replacement during post-chemotherapy retroperitoneal lymph node dissection.

PURPOSE: We reviewed the records of 15 patients with metastatic germ cell cancer who underwent aortic resection and replacement during post-chemotherapy retroperitoneal lymph node dissection to determine the morbidity and the therapeutic benefit. MATERIALS AND METHODS: Between 1970 and 1998, 1,250 patients underwent post-chemotherapy retroperitoneal lymph node dissection. Our retrospective review revealed that 15 patients underwent aortic replacement at that operation. RESULTS: In addition to aortic replacement 11 patients underwent 15 additional procedures, including nephrectomy in 7, vena caval resection in 3, pulmonary resection in 1, small bowel resection in 2, 1 hepatic resection in 1 and L4 vertebrectomy in 1. No patient had necrosis as the only pathological condition. Three patients (20%) had teratoma and 12 (80%) had viable tumor in the retroperitoneal specimen. All 4 patients who underwent post-chemotherapy retroperitoneal lymph node dissection and aortic replacement after induction chemotherapy alone have no evidence of disease. Only 1 of the 11 patients who received salvage chemotherapy with or without previous post-chemotherapy retroperitoneal lymph node dissection have no evidence of disease. Overall 33% of the patients have no evidence of disease. There were no graft related complications. CONCLUSIONS: Aortic resection at post-chemotherapy retroperitoneal lymph node dissection is justified based on therapeutic benefit and morbidity.

Vertical rectus muscle augmented transposition in Duane syndrome.

INTRODUCTION: Reduction or elimination of face turn and esotropia in the primary position while maintaining the largest possible diplopia-free field are the major surgical goals in Duane syndrome with esotropia. Unsatisfactory postoperative results may occur because of limitation in adduction, poor abduction, or induced vertical deviations. Recent reports have shown enhanced results from rectus muscle transposition techniques when a lateral posterior augmentation fixation is placed. METHODS: Preoperative and postoperative data of 2 groups of subjects who had Duane syndrome with esotropia in primary position and markedly reduced abduction were comparatively analyzed. Group A consisted of subjects who had transposition of both vertical rectus muscles to the lateral rectus muscle with a posterior lateral augmentation suture placed in each transposed muscle. Group B subjects had transposition of both vertical rectus muscles to the lateral rectus muscle without the posterior lateral augmentation suture. RESULTS: A total of 32 subjects in group A and 22 subjects in group B were analyzed. In group A, anomalous head position improved 19.1 degrees +/- 10.3 degrees compared with group B subjects who improved 10.6 degrees +/- 5.8 degrees (P <.05). In group A, esotropia in primary position improved 16.4 +/- 9.2 PD compared with group B subjects who improved 8.5 +/- 6.9 PD (P <.05). CONCLUSIONS: Subjects with Duane syndrome and esotropia in primary position who had undergone augmented transposition of the vertical rectus muscles obtained improved head position and better alignment in primary position and had a reduction in the incidence of reoperation for undercorrection when compared with similar patients who had undergone vertical rectus muscle transposition without posterior lateral augmentation sutures.

Altered expression of Ape1/ref-1 in germ cell tumors and overexpression in NT2 cells confers resistance to bleomycin and radiation.

The human AP endonuclease (Ape1 or ref-1) DNA base excision repair (BER) enzyme is a multifunctional protein that has an impact on a wide variety of important cellular functions including oxidative signaling, transcription factor regulation, and cell cycle control. It acts on mutagenic AP (baseless) sites in DNA as a critical member of the DNA BER repair pathway. Moreover, Ape1/ref-1 stimulates the DNA-binding activity of transcription factors (Fos-Jun, nuclear factor-kappaB, Myb, ATF/cyclic AMP-responsive element binding protein family, HIF-1alpha, HLF, PAX, and p53) through a redox mechanism and thus represents a novel component of signal transduction processes that regulate eukaryotic gene expression. Ape1/ref-1 has also been shown to be closely linked to apoptosis associated with thioredoxin, and altered levels of Ape1/ref-1 have been found in some cancers. In a pilot study, we have examined Ape1/ref-1 expression by immunohistochemistry in sections of germ cell tumors (GCTs) from 10 patients with testicular cancer of various histologies including seminomas, yolk sac tumors, and malignant teratomas. Ape1/ref-1 was expressed at relatively high levels in the tumor cells of nearly all sections. We hypothesized that elevated expression of Ape1/ref-1 is responsible in part for the resistance to therapeutic agents. To answer this hypothesis, we overexpressed the Ape1/ref-1 cDNA in the GCT cell line NT2/D1 using retroviral gene transduction with the vector LAPESN. Using an oligonucleotide cleavage assay and immunohistochemistry to assess Ape1/ref-1 repair activity and expression, respectively, we found that the repair activity and relative Ape1/ref-1 expression in GCT cell lines are directly related. NT2/D1 cells transduced with Ape1/ref-1 exhibited 2-fold higher AP endonuclease activity in the oligonucleotide cleavage assay, and this was reflected in a 2-3-fold increase in protection against bleomycin. Lesser protection was observed with gamma-irradiation. We conclude that: (a) Ape1/ref-1 is expressed at relatively high levels in some GCTs; (b) elevated expression of Ape1/ref-1 in testicular cancer cell lines results in resistance to certain therapeutic agents; and (c) Ape1/ref-1 expression in GCT cell lines determined by immunohistochemistry and repair activity assays parallels the level of protection from bleomycin. We further hypothesize that elevated Ape1/ref-1 levels observed in human testicular cancer may be related to their relative resistance to therapy and may serve as a diagnostic marker for refractory disease. To our knowledge, this is the first example of overexpressing Ape1/ref-1 in a mammalian system resulting in enhanced protection to DNA-damaging agents.

Validation of a prediction model and its predictors for the histology of residual masses in nonseminomatous testicular cancer.

PURPOSE: We validated a prediction model for histology of residual retroperitoneal masses, either benign or tumor, in patients treated with chemotherapy for metastatic nonseminomatous testicular cancer. MATERIALS AND METHODS: We studied 276 patients treated with chemotherapy before retroperitoneal lymph node dissection at Indiana University Medical Center between 1985 and 1999. A previously developed prediction model was modified to provide predictions for the Indiana population based on 5 predictors. For these predictors, including teratomatous elements in the primary tumor, pre-chemotherapy tumor markers (alpha-fetoprotein and human chorionic gonadotropin), size of the residual mass and reduction in mass size, univariate and multivariate odds ratios were determined. The modified model was evaluated by calculating the concordance statistic and studying model reliability. RESULTS: All odds ratios from univariate and multivariate analyses were in the expected directions. The modified model had good discriminative ability (concordance statistic 0.79). However, the predicted probabilities for benign tissue were generally too high due to the low prevalence of benign tissue (76 of 276 cases or 28%). CONCLUSIONS: This study confirms the predictive ability of formerly identified predictors for the histology of residual retroperitoneal masses in testicular cancer. However, the previously developed prognostic model must be adjusted for the local overall ratio of benign versus tumor histology to provide reliable predictions in the Indiana population.

Early-stage testis cancer.

The treatment of low-stage testis cancer (defined as clinical stage I or low-volume clinical stage II disease) varies, depending on whether or not the orchiectomy specimen reveals seminoma or nonseminoma. Treatments for clinical stage I seminoma include radiotherapy to the retroperitoneum, surveillance, or two courses of carboplatin chemotherapy. Until the results of an ongoing randomized study comparing radiotherapy with two courses of carboplatin are known, standard accepted treatments currently include radiotherapy or surveillance. In nonbulky clinical stage II seminoma, therapeutic options include radiotherapy or cisplatin-based chemotherapy. For clinical stage I nonseminoma, equivalent short-term survival rates are obtained with either nerve-sparing retroperitoneal lymph node dissection (RPLND), surveillance, or two courses of BEP (bleomycin, etoposide, and platinum) chemotherapy. However, minimization of toxicity of treatment would argue that the two preferred treatments in clinical stage I nonseminoma are nerve-sparing RPLND or surveillance. For low- volume clinical stage II nonseminoma, options include three courses of BEP or primary RPLND. The overall chance for cure is essentially the same for either of these options. Therefore, in each clinical stage of early-stage testis cancer, therapeutic options exist that, based upon current data, are therapeutically equivalent in the short term. Therefore, the ultimate choice of therapy is also dependent upon the short- and long-term toxicity of therapy and the likelihood of late recurrence of disease.

Breast cancer and pregnancy.

A diagnosis of breast cancer during pregnancy or the postpartum period is an unfortunate occurrence. Hormonal factors appear to play an important role early on in the development of breast cancer; however, pregnancy itself does not clearly influence the outcome of an established breast cancer. Diagnosis can be challenging in a pregnant woman and delays in diagnosis are common. Treatment decisions must take into consideration not only toxicity to the mother, but short- and long-term consequences for the fetus as well. Other special considerations with pregnancy-associated breast cancer include the timing of delivery, the potential for nursing, and concerns for future fertility. In general, management of pregnancy associated breast cancer follows the same principals as in non-pregnant patients of similar age. With thoughtful application of available therapies, outcome can be optimized for both the mother and her child.

Clinical stage I pure yolk sac tumor of the testis in adults has different clinical behavior than juvenile yolk sac tumor.

PURPOSE: We evaluated the clinical behavior of clinical stage I pure yolk sac tumor of the testis in adults to determine whether the behavior of this entity is different than that of clinical stage 1 nonseminoma. MATERIALS AND METHODS: We searched the testis cancer database at our institution for adults with clinical stage I pure yolk sac tumor of the testis who underwent retroperitoneal lymph node dissection. We identified 12 such patients and reviewed the database and hospital charts to determine clinical behavior. RESULTS: Disease was pathological stage I in 8 of the 12 patients (66%), including 1 with recurrence after retroperitoneal lymph node dissection. Disease was pathological stage II in 14 patients (33%), including 1 who remains disease-free after electing adjuvant bleomycin, etoposide and cisplatin. Of the 3 patients who elected observation after retroperitoneal lymph node dissection only 1 has had recurrence, while 2 (66%) were cured by retroperitoneal lymph node dissection only. CONCLUSIONS: Contrary to juvenile yolk sac tumor, which has a strong tendency toward hematogenous metastasis, the behavior of clinical stage I adult pure yolk sac tumor is similar to that of all other stage I nonseminomas in adulthood.

Characterization and predictors of prostate specific antigen progression rates after radical retropubic prostatectomy.

PURPOSE: Detectable serum prostate specific antigen (PSA) after radical prostatectomy indicates recurrent disease and treatment failure. We characterized PSA recurrence after prostatectomy and identified predictors of rapid PSA progression. MATERIALS AND METHODS: We retrospectively reviewed the medical records of 165 patients with detectable PSA after radical prostatectomy to characterize the rate of PSA increase and correlate this rate with the possible predictors of rapid PSA progression known at prostatectomy. RESULTS: For a median of 48 months postoperatively we followed 142 patients with PSA recurrence after radical prostatectomy who received no immediate adjuvant therapy. PSA doubling time was less than 6, greater than 6, 12, 18 and 24 months in 46%, 54%, 18%, 11% and 9% of cases, while time to PSA 50 ng./ml. was greater than 5, 10, 15 and 20 years in 69%, 34%, 22% and 9%, respectively. Univariate and multivariate analyses revealed that rapid PSA doubling time was associated with Gleason secondary grade, Gleason score and time to initial detectable PSA (p = 0.019, 0.031 and 0.0001, and p = 0.043, 0.045 and 0.0001, respectively). CONCLUSIONS: PSA recurrence progresses at a greatly variable rate and many recurrences progress slowly with a long doubling time. Gleason secondary grade and score appear to be predictive of rapid PSA progression. No other pathological features were predictive of rapid PSA progression.

Risk of systemic metastases in clinical stage I nonseminoma germ cell testis tumor managed by retroperitoneal lymph node dissection.

PURPOSE: We assess the risk of systemic recurrence after retroperitoneal lymph node dissection for clinical stage I nonseminoma germ cell testis tumor based on predominance of embryonal carcinoma and/or vascular invasion in the orchiectomy specimen. MATERIALS AND METHODS: A total of 292 cases of clinical stage I nonseminoma germ cell testis tumor treated with retroperitoneal lymph node dissection from 1990 to 1995 were identified from the Indiana University database. A minimum of 2 years of followup was required for study entry. Review of the written pathological reports classified tumors as embryonal carcinoma predominant, when it was present at a level greater than any other histology, nonpredominant, when it was present but not as the main histological subtype, and absent. Vascular invasion was categorized as present or absent. RESULTS: Of the 292 cases 226 (77. 4%) were pathological stage I and relapse rate after retroperitoneal lymph node dissection was 10.2%. Vascular invasion and embryonal carcinoma predominance in the orchiectomy specimen were predictors of relapse in this group. None of the 35 pathological stage II cases treated with adjuvant chemotherapy had relapse, whereas relapse occurred in 7 of 31 pathological stage II cases (22.6%) not treated with adjuvant chemotherapy. CONCLUSIONS: Pathological stage I cases with predominant embryonal carcinoma and/or vascular invasion in the orchiectomy specimen have a higher probability of systemic recurrence after retroperitoneal lymph node dissection. Dissection alone still has a major therapeutic impact (77%) in patients with clinical stage I, pathological stage II nonseminoma germ cell testis tumor.

Retroperitoneal lymph node dissection for the management of clinical stage I nonseminoma.

PURPOSE: We review the rationale for the use of retroperitoneal lymph node dissection for clinical stage I nonseminomatous testis cancer. MATERIALS AND METHODS: The published literature regarding the alternative treatments for clinical stage I nonseminoma was reviewed as well as the personal experience of the authors to define the role of retroperitoneal lymph node dissection. RESULTS: Retroperitoneal lymph node dissection alone is curative in 50% to 75% of patients with pathological stage II disease. The only significant long-term morbidity is a 1% chance of small bowel obstruction. If recurrence develops after retroperitoneal lymph node dissection, it is virtually always curable with cisplatin based chemotherapy. CONCLUSIONS: Retroperitoneal lymph node dissection retains a therapeutic and staging capability in these patients. The probability for cure, short and long-term morbidity, and minimal need for long-term followup in these patients indicates that retroperitoneal lymph node dissection continues to be standard therapy for clinical stage I nonseminoma.