Intron lariat spliceosomes convert lariats to true circles: implications for intron transposition.

Rare, full-length circular intron RNAs distinct from lariats have been reported in several species, but their biogenesis is not understood. We envisioned and tested a hypothesis for their formation using Saccharomyces cerevisiae, documenting full-length and novel processed circular RNAs from multiple introns. Evidence implicates a previously undescribed catalytic activity of the intron lariat spliceosome (ILS) in which the 3'-OH of the lariat tail (with optional trimming and adenylation by the nuclear 3' processing machinery) attacks the branch, joining the intron 3' end to the 5' splice site in a 3'-5' linked circle. Human U2 and U12 spliceosomes produce analogous full-length and processed circles. Postsplicing catalytic activity of the spliceosome may promote intron transposition during eukaryotic genome evolution.

Intron-lariat spliceosomes convert lariats to true circles: implications for intron transposition.

Rare, full length circular intron RNAs distinct from lariats have been reported in several species, but their biogenesis is not understood. We envision and test a hypothesis for their formation using Saccharomyces cerevisiae, documenting full length and novel processed circular RNAs from multiple introns. Evidence implicates a previously undescribed catalytic activity of the intron-lariat spliceosome (ILS) in which the 3'-OH of the lariat tail (with optional trimming and adenylation by the nuclear 3' processing machinery) attacks the branch, joining the intron 3' end to the 5' splice site in a 3'-5' linked circle. Human U2 and U12 spliceosomes produce analogous full length and processed circles. Post-splicing catalytic activity of the spliceosome may promote intron transposition during eukaryotic genome evolution.

Protein-RNA Networks Regulated by Normal and ALS-Associated Mutant HNRNPA2B1 in the Nervous System.

HnRNPA2B1 encodes an RNA binding protein associated with neurodegeneration. However, its function in the nervous system is unclear. Transcriptome-wide crosslinking and immunoprecipitation in mouse spinal cord discover UAGG motifs enriched within ∼2,500 hnRNP A2/B1 binding sites and an unexpected role for hnRNP A2/B1 in alternative polyadenylation. HnRNP A2/B1 loss results in alternative splicing (AS), including skipping of an exon in amyotrophic lateral sclerosis (ALS)-associated D-amino acid oxidase (DAO) that reduces D-serine metabolism. ALS-associated hnRNP A2/B1 D290V mutant patient fibroblasts and motor neurons differentiated from induced pluripotent stem cells (iPSC-MNs) demonstrate abnormal splicing changes, likely due to increased nuclear-insoluble hnRNP A2/B1. Mutant iPSC-MNs display decreased survival in long-term culture and exhibit hnRNP A2/B1 localization to cytoplasmic granules as well as exacerbated changes in gene expression and splicing upon cellular stress. Our findings provide a cellular resource and reveal RNA networks relevant to neurodegeneration, regulated by normal and mutant hnRNP A2/B1. VIDEO ABSTRACT.

Distinct and shared functions of ALS-associated proteins TDP-43, FUS and TAF15 revealed by multisystem analyses.

The RNA-binding protein (RBP) TAF15 is implicated in amyotrophic lateral sclerosis (ALS). To compare TAF15 function to that of two ALS-associated RBPs, FUS and TDP-43, we integrate CLIP-seq and RNA Bind-N-Seq technologies, and show that TAF15 binds to ∼4,900 RNAs enriched for GGUA motifs in adult mouse brains. TAF15 and FUS exhibit similar binding patterns in introns, are enriched in 3' untranslated regions and alter genes distinct from TDP-43. However, unlike FUS and TDP-43, TAF15 has a minimal role in alternative splicing. In human neural progenitors, TAF15 and FUS affect turnover of their RNA targets. In human stem cell-derived motor neurons, the RNA profile associated with concomitant loss of both TAF15 and FUS resembles that observed in the presence of the ALS-associated mutation FUS R521G, but contrasts with late-stage sporadic ALS patients. Taken together, our findings reveal convergent and divergent roles for FUS, TAF15 and TDP-43 in RNA metabolism.

A randomized, double-blind study of AMG 108 (a fully human monoclonal antibody to IL-1R1) in patients with osteoarthritis of the knee.

INTRODUCTION: AMG 108 is a fully human, immunoglobulin subclass G2 (IgG2) monoclonal antibody that binds the human interleukin-1 (IL-1) receptor type 1, inhibiting the activity of IL-1a and IL-1b. In preclinical studies, IL-1 inhibition was shown to be beneficial in models of osteoarthritis (OA). The purpose of this two-part study was to evaluate the safety and pharmacokinetics (PK; Part A) and clinical effect (Part B) of AMG 108 in a double-blind, placebo-controlled, multiple-dose study in patients with OA of the knee. METHODS: In Part A, patients received placebo or AMG 108 subcutaneously (SC; 75 mg or 300 mg) or intravenously (IV; 100 mg or 300 mg) once every 4 weeks for 12 weeks; in Part B, patients received placebo or 300 mg AMG 108 SC, once every 4 weeks for 12 weeks. The clinical effect of AMG 108 was measured in Part B by using the Western Ontario and McMaster Universities (WOMAC) osteoarthritis index pain score. RESULTS: In Part A, 68 patients were randomized, and 64 received investigational product. In Part B, 160 patients were randomized, and 159 received investigational product. AMG 108 was well tolerated. Most adverse events (AEs), infectious AEs, serious AEs and infections, as well as withdrawals from the study due to AEs occurred at similar rates in both active and placebo groups. One death was reported in an 80-year-old patient (Part A, 300 mg IV AMG 108; due to complications of lobar pneumonia). AMG 108 serum concentration-time profiles exhibited nonlinear PK. The AMG 108 group in Part B had statistically insignificant but numerically greater improvement in pain compared with the placebo group, as shown by the WOMAC pain scores (median change, -63.0 versus -37.0, respectively). CONCLUSIONS: The safety profile of AMG 108 SC and IV was comparable with placebo in patients with OA of the knee. Patients who received AMG 108 showed statistically insignificant but numerically greater improvements in pain; however, minimal, if any, clinical benefit was observed. TRIAL REGISTRATION: This study is registered with ClinicalTrials.gov with the identifier NCT00110942.

Crystal structures of complexes containing domains from two viral internal ribosome entry site (IRES) RNAs bound to the 70S ribosome.

Internal ribosome entry site (IRES) RNAs are elements of viral or cellular mRNAs that bypass steps of canonical eukaryotic cap-dependent translation initiation. Understanding of the structural basis of IRES mechanisms is limited, partially due to a lack of high-resolution structures of IRES RNAs bound to their cellular targets. Prompted by the universal phylogenetic conservation of the ribosomal P site, we solved the crystal structures of proposed P site binding domains from two intergenic region IRES RNAs bound to bacterial 70S ribosomes. The structures show that these IRES domains nearly perfectly mimic a tRNA • mRNA interaction. However, there are clear differences in the global shape and position of this IRES domain in the intersubunit space compared to those of tRNA, supporting a mechanism for IRES action that invokes hybrid state mimicry to drive a noncanonical mode of translocation. These structures suggest how relatively small structured RNAs can manipulate complex biological machines.

Long-term outcome for patients with high volume retroperitoneal teratoma undergoing post-chemotherapy surgery.

PURPOSE: We determined outcomes in patients with testicular cancer with large volume (greater than 10 cm) retroperitoneal teratoma treated with post-chemotherapy retroperitoneal lymph node dissection. MATERIALS AND METHODS: A retrospective review of our testicular cancer database was performed from 1995 to 2005 to identify patients undergoing post-chemotherapy retroperitoneal lymph node dissection for residual masses larger than 10 cm with final pathological examination revealing teratoma. A total of 99 patients met the study inclusion criteria. RESULTS: A total of 27 patients presented with disease limited to the retroperitoneum, 46 had 2 or 3 disease sites and 26 had 4 or more disease sites. Mean and median hospital stay was 7.3 and 5.0 days, respectively. There were 23 recurrences in 27 locations with the most common being pulmonary in 5, mediastinal in 5 and retroperitoneal in 5. The 2 and 5-year disease-free survival was 86% and 75% with a mean followup of 42 months. The 2-year disease-free survival for patients presenting with retroperitoneal disease only was 86% compared to 79% and 41% for patients presenting with 2 to 3 disease sites and more than 4 disease sites, respectively (p = 0.004). The 2-year disease-free survival was 78% for patients undergoing retroperitoneal lymph node dissection alone, 80% for retroperitoneal lymph node dissection plus 1 or 2 other sites and 40% for retroperitoneal lymph node dissection plus resection of 3 or more disease sites (p = 0.026). CONCLUSIONS: The recurrence rate for resected post-chemotherapy high volume teratoma is 25% at 5 years. The most common sites of recurrence are the lung, mediastinum and retroperitoneum.

Is full bilateral retroperitoneal lymph node dissection always necessary for postchemotherapy residual tumor?

BACKGROUND: Traditionally, postchemotherapy (PC) surgery for metastatic nonseminomatous germ cell tumor (NSGCT) has used a full bilateral retroperitoneal lymph node dissection (RPLND) from the crus of the diaphragm to the bifurcation of the common iliac arteries, from ureter to ureter. With the primary landing zone well defined in low-volume retroperitoneal disease, the authors performed modified dissections in the PC setting in a select population; and, herein, they report disease outcome. METHODS: From 1991 to 2004, a retrospective review of the testicular cancer database at the authors' institution was performed to identify patients with NSGCT, normal serum tumor markers after cisplatin-based chemotherapy, and residual retroperitoneal tumor who underwent modified PC-RPLND. All patients had metastatic disease at initial presentation that was limited to the primary landing zone (left or right). RESULTS: One hundred patients were identified, including 43 who underwent a right modified template, 18 patients who underwent a left full modified template, and 39 patients who underwent a left modified template. Pathology revealed cancer in 2% of patients, teratoma in 62% of patients, and necrosis in 36% of patients. The 2- and 5-year disease-free survival rate was 95%, and the median follow-up was 31.9 months (range, 1-152 months). Four patients developed recurrent disease with a median time to recurrence of 8.25 months (range, 6-11 months). All recurrences were outside the boundaries of a full bilateral RPLND. CONCLUSIONS: Selected patients at PC surgery can be managed with modified PC-RPLND.

Short-term morbidity of primary retroperitoneal lymph node dissection in a contemporary group of patients.

PURPOSE: We defined the blood loss, operative time and short-term morbidity of primary retroperitoneal lymph node dissection in a contemporary series to assess whether laparoscopic retroperitoneal lymph node dissection actually confers the magnitude of benefit claimed. MATERIALS AND METHODS: A retrospective chart review was performed of 75 consecutive patients who underwent primary retroperitoneal lymph node dissection during the 18 months ending May 2005. Two patients were excluded, including 1 who underwent right hemicolectomy for cecal adenocarcinoma and 1 with a pure seminomatous intra-abdominal testicle. RESULTS: Of the 73 patients 69 (94%) underwent unilateral dissection and 60 (82.2%) underwent a nerve sparing procedure. Mean operative time was 132 minutes (range 81 to 246) and mean blood loss was 207 cc (range 50 to 500). Nasogastric tubes were placed in 2 patients (2.7%). Mean time to start clear liquids was 1.0 day. Mean hospital stay was 2.8 days (range 2 to 4). CONCLUSIONS: The short-term morbidity of open retroperitoneal lymph node dissection, including operative time, blood loss and hospital stay, has significantly improved compared to historical controls. Perioperative management has changed with time. Comparing the morbidity of laparoscopic retroperitoneal lymph node dissection to that of historical controls is inappropriate.

Post chemotherapy RPLND in patients with elevated markers: current concepts and clinical outcome.

Elevated serum tumor markers after cisplatin-based chemotherapy usually contraindicate surgery because of the presence of active germ-cell elements; however, some patients have undergone PCRPLND with curative intent. We evaluated the role of surgery to resect retroperitoneal-only marker positive tumor. Residual germ-cell cancer was identified in 50% of patients with elevated tumor markers with one third alive at 5 years; 5-year survival with residual teratoma or necrosis was 77.5% and 85.7%, respectively. Predictors of retroperitoneal teratoma or fibrosis included declining tumor makers at surgery, betaHCG < 100, and first-line chemotherapy. Predictors of death included rising preoperative betaHCG, elevated AFP, redo RPLND, and active germ-cell cancer in the resected specimen. Select patients with elevated tumor markers after chemotherapy are cured with surgery.

Retroperitoneal lymph node dissection in testicular cancer.

With long-term survival in excess of 90% across all stages, testicular cancer has come to represent the model for successful multidisciplinary cancer care. Retroperitoneal lymph node dissection (RPLND) remains an integral component of testis cancer management strategies for both early- and advanced-stage disease. Commensurate with improvements made in clinical staging and in our understanding of the natural history of testis cancer, lymphatic spread, and neuroanatomy, considerable modifications in the technique and template of RPLND have taken place. The morbidity of primary RPLND and postchemotherapy RPLND is low when performed by experienced surgeons. This article reviews the evolution, role, and technique of RPLND in contemporary practice.

Significance of primary tumor size and preorchiectomy serum tumor marker level in predicting pathologic stage at retroperitoneal lymph node dissection in clinical Stage A nonseminomatous germ cell tumors.

OBJECTIVES: To determine whether the size of the primary tumor and degree of preorchiectomy serum alpha-fetoprotein (AFP) and beta-human chorionic gonadotropin (beta-hCG) elevation predict for retroperitoneal pathologic findings in patients with clinical Stage A nonseminomatous germ cell tumor undergoing primary retroperitoneal lymph node dissection. METHODS: The testicular cancer database was queried to identify patients with clinical Stage A nonseminomatous germ cell tumor with normalization of serum tumor markers after orchiectomy who had undergone retroperitoneal lymph node dissection. A total of 779 patients were identified. The preorchiectomy serum tumor marker level was recorded and categorized into the following subsets: AFP: less than 20 (normal), 20 to 100, 100 to 1000, and more than 1000 ng/dL; and beta-hCG: less than 5.0 (normal), 5 to 100, 100 to 1000, and more than 1000. The association between AFP, beta-hCG, and primary tumor size and retroperitoneal pathologic findings was determined. RESULTS: The retroperitoneal pathologic examination revealed metastatic disease in 207 patients (26.6%). The preorchiectomy serum beta-hCG level, as a categorical variable, was not predictive of positive retroperitoneal pathologic findings (P = 0.187). The preorchiectomy serum AFP did predict for positive retroperitoneal pathologic findings, with lower serum AFP levels associated with a greater incidence of retroperitoneal metastasis (P <0.001). The primary tumor size was not predictive of positive retroperitoneal pathologic findings (P = 0.113). CONCLUSIONS: Neither the primary tumor size nor the preorchiectomy beta-hCG level was predictive of retroperitoneal metastases. However, a normal preorchiectomy AFP level was associated with a greater incidence of retroperitoneal metastases.

Does the presence of extranodal extension in pathological stage B1 nonseminomatous germ cell tumor necessitate adjuvant chemotherapy?

PURPOSE: The presence of extranodal extension identified at primary retroperitoneal lymph node dissection has been associated with an increased risk of disease recurrence, and as such these patients are sometimes treated with adjuvant chemotherapy. We decided to evaluate the significance of extranodal extension on disease-free survival in patients with pathological stage B nonseminomatous germ cell tumor who did not receive adjuvant chemotherapy. MATERIALS AND METHODS: A retrospective review of our testicular cancer database was performed to identify all patients with clinical stage A nonseminomatous germ cell tumor who underwent primary retroperitoneal lymph node dissection and were found to have retroperitoneal metastasis with 5 or fewer involved nodes and no metastatic node larger than 2 cm. No patient received adjuvant chemotherapy, and all had a minimum followup of 24 months. A single pathologist (LC), who was blinded to clinical outcome, reviewed the retroperitoneal nodal package to identify the presence or absence of extranodal extension, defined as cancer perforating through the lymph node capsule into perinodal tissue. RESULTS: A total of 80 patients were identified with a median followup 48 months, and a 2 and 5-year disease-free survival of 75%. Extranodal extension was present in 23 patients and absent in 57 patients with a median followup of 54 and 44 months, respectively. The 5-year disease-free survival for patients with and without extranodal extension was 74% and 75%, respectively (p=0.67). CONCLUSIONS: We were unable to detect any prognostic significance of extranodal extension in patients found to have retroperitoneal metastasis at primary retroperitoneal lymph node dissection.

Pathologic findings and therapeutic outcome of desperation post-chemotherapy retroperitoneal lymph node dissection in advanced germ cell cancer.

Increased serum tumor markers after cisplatin-based chemotherapy have usually been considered a contraindication to surgery because of the presence of persistent active germ cell elements. However, a select population of patients with elevated serum tumor markers have undergone post-chemotherapy retroperitoneal lymph node dissection (RPLND) with curative intent. We evaluated the role of surgery to resect retroperitoneal-only marker positive tumor. Long-term survival was observed in 50% of patients. Residual germ cell cancer was identified in 50% of patients, with a third alive at 5 years with no observed benefit from adjuvant chemotherapy. Select patients with increased tumor markers after chemotherapy are cured with surgery.

Outcome analysis for patients with elevated serum tumor markers at postchemotherapy retroperitoneal lymph node dissection.

PURPOSE: To evaluate the therapeutic benefit of postchemotherapy retroperitoneal lymph node dissection (PCRPLND) in patients with persistently elevated serum tumor markers. PATIENTS AND METHODS: One hundred fourteen patients with metastatic germ cell cancer with elevated serum tumor markers after first-line (50 patients) or second-line chemotherapy (64 patients) who underwent PCRPLND between 1977 and 2000 with a minimum follow-up of 2-years were included in this retrospective study. RESULTS: The 5-year overall survival was 53.9%. Sixty-one patients (53.5%) are alive with a medium follow-up of 72 months. Fifty-three patients died of disease, with a medium time to death of 8.0 months. Mean preoperative serum alpha-fetoprotein (AFP) and beta-human chorionic gonadotropin (betaHCG) levels were 483 ng/mL and 555 mU/mL, respectively, with no difference in 5-year survival (P = .2). Retroperitoneal pathology revealed germ cell cancer in 53.5% of patients, teratoma in 34.2% of patients, and fibrosis in 12.2% of patients, with 5-year survival rates of 31.4%, 77.5%, and 85.7%, respectively (P < .0001). Predictors of retroperitoneal pathology included an increasing serum AFP or betaHCG, betaHCG more than 100 ng/mL, redo retroperitoneal lymph node dissection (RPLND), and second-line chemotherapy. Poor prognostic variables by multivariable analysis included betaHCG status, serum AFP level, redo RPLND, and germ cell cancer in the resected specimen. CONCLUSION: A subset of patients with elevated serum tumor markers after chemotherapy is curable with surgery. The prognostic factors predictive of outcome in this analysis include an increasing betaHCG, serum AFP level, redo RPLND, and germ cell cancer in the resected specimen. These factors, along with clinical and surgical experience, should aid in determining the appropriate integration of surgery and chemotherapy in this population.

Does the histology of nodal metastasis predict systemic relapse after retroperitoneal lymph node dissection in pathological stage B1 germ cell tumors?

PURPOSE: We evaluated the prognostic significance of the histology of metastatic lymph nodes to predict postoperative relapse in pathological stage B1 nonseminomatous germ cell tumor (NSGCT). MATERIALS AND METHODS: A retrospective review of the testicular cancer database was performed to identify all patients with clinical stage A NSGCT who underwent primary retroperitoneal lymph node dissection and were found to have pathological stage B1 disease. No patient received adjuvant chemotherapy and minimal followup was 24 months. RESULTS: A total of 118 patients were identified with a 5-year disease-free survival (DFS) of 68% and a median followup of 43 months. Embryonal cell carcinoma was identified in 92 of 118 (77%) surgical specimens, which was significantly greater than the presence of teratoma (22%), seminoma (16%) and yolk sac (14.4%, p < or = 0.001) with no difference in 5-year DFS comparing the presence or absence of each histology. Solitary histology was noted in 88 of 118 patients (74.5%). Embryonal cell carcinoma was the most common single histology identified at surgery at 64 of 88 (73%), with the incidence of seminoma, teratoma and yolk sac being 12.5%, 9.0% and 5.5%, respectively (p < or = 0.001). There was no statistical difference in DFS for each of the solitary histological subtypes (p=0.67). Recurrence rates were similar for pure embryonal cell carcinoma (69%), mixed embryonal cell carcinoma (63%) and no embryonal cell carcinoma (73%) in the retroperitoneum (p=0.63). CONCLUSIONS: Retroperitoneal histology does not appear to predict outcome in patients with pathological stage B1 NSGCT.

Impact of the number of positive lymph nodes on disease-free survival in patients with pathological stage B1 nonseminomatous germ cell tumor.

PURPOSE: The prognostic significance of the number of metastatic lymph nodes detected at surgery on survival is well documented for breast and colon cancer, and it has recently been reported in bladder cancer. We tested this hypothesis in patients with pathological stage B1 nonseminomatous germ cell tumor (NSGCT). MATERIAL AND METHODS: This series included 118 patients with pathological stage B1 NSGCT (5 or fewer positive lymph nodes) at primary retroperitoneal lymph node dissection who did not receive adjuvant chemotherapy at a followup of greater than 24 months. RESULTS: Five-year disease-free survival (DFS) was 68% at a median followup of 43 months. Median followup in patients without recurrence was 67.4 months and median time to recurrence was 5.0 months. The mean and median number of positive lymph nodes was 2.0. Five-year DFS for 1 or 2 and 3 to 5 positive lymph nodes was 72% and 59%, respectively (p = 0.0847). Five-year DFS for lymph node density less or greater than 0.05 was 75% and 66%, respectively (p = 0.261). Neither the number of positive lymph nodes (continuous and categorical p = 0.201 and 0.271) or the ratio of the number of positive lymph nodes to the total number resected (continuous and categorical p = 0.415 and 0.998, respectively) predicted recurrence. CONCLUSIONS: Primary retroperitoneal lymph node dissection is curative in patients with pathological stage B1 NSGCT and DFS does not seem to be influenced by the number or the ratio of positive lymph nodes resected. This information may be helpful in limiting adjuvant chemotherapy in patients otherwise cured by surgery.

Complications of post-chemotherapy retroperitoneal lymph node dissection for testis cancer.

PURPOSE: Post-chemotherapy retroperitoneal lymph node dissection (PC RPLND) is a tool in the management of testis cancer. Our impression has been that the short-term morbidity of standard PC RPLND has diminished with time. Therefore, we attempted to verify this hypothesis by evaluating the morbidity of the procedure in 2 comparable groups of patients from 2 different periods. MATERIALS AND METHODS: We compared 150 patients who underwent post-chemotherapy RPLND between July 2000 and July 2002 to 79 patients who underwent the same procedure between 1990 to 1992. All patients had clinical stage II-III testis cancer and had received 3 to 4 courses of standard platinum based chemotherapy before surgery. We compared surgical morbidity and postoperative complications in both groups. We also assessed a number of factors (patient characteristics, mass size, pathological features and surgical aspects) that could impact the rate of complications. RESULTS: The 2 groups were comparable regarding preoperative clinical stage, patient characteristics and postoperative pathological findings. PC RPLND procedures were performed using the same technique. Compared to patients in the 1990 to 1992 group, the patients from the 2000 to 2002 group had fewer intraoperative complications and additional procedures (44 [29.3%] of 150 versus 41 [51.9%] of 79, p = 0.0008), a trend toward a lower postoperative complication rate (10 [6.7%] compared to 11 [13.9%], p = 0.07) and shorter hospital stay (average 5.6 versus 8.4 days [p <0.0001]). CONCLUSIONS: With time morbidity and hospital stay after standard PC RPLND have decreased. This finding probably reflects differences in patterns of care rather than changes in surgical technique. Therefore, comparing newer surgical techniques to historical controls is inappropriate since differences may not actually represent the technical advances of the newer procedure.

Histology in mixed germ cell tumors. Is there a favorite pairing?

PURPOSE: Mixed germ cell tumors account for approximately 30% to 50% of testicular tumors. To our knowledge a systematic review with statistical analysis of the associations of histological subtypes in mixed germ cell tumors has not been done previously. It was our impression that such associations exist. Delineating concordant histological types may provide insight into the ontogeny of testicular tumors and also have important clinical implications. MATERIALS AND METHODS: We retrospectively reviewed the testis cancer data base at our institution. The primary tumor of orchiectomy specimens was examined in 2589 patients. Of these patients mixed histology was noted in 1765 (68.2%). ORs were calculated for all possible combinations of teratoma, embryonal carcinoma, yolk sac tumor, choriocarcinoma and seminoma. In addition, we evaluated the association of various histological types with teratoma at post-chemotherapy retroperitoneal lymph node dissection. RESULTS: Of 10 possible combinations of histological types in the primary tumor, positive correlations were noted in 4. The strongest correlation was found between teratoma and yolk sac tumor (OR 2.58, p <0.001). Teratoma or yolk sac tumor in the testis was associated with teratoma in the pathology specimen at post-chemotherapy retroperitoneal lymph node dissection. CONCLUSIONS: The strongest associations of histological subtypes in mixed germ cell tumors were seen between yolk sac tumor and teratoma. Similar associations are seen in late relapse and in some cases of prepubertal tumors. Further study of these associations may prove valuable in understanding the biology and clinical behavior of germ cell tumors.

Does retroperitoneal lymph node dissection have a curative role for patients with sex cord-stromal testicular tumors?

BACKGROUND: Sex cord-stromal tumors account for < 5% of all adult testicular tumors, and 10% are malignant. Due to the limited reported experience, there is no agreement on the best management, especially in patients who have tumors with malignant pathologic features or who present with metastatic disease. The authors attempt to evaluate the role of retroperitoneal lymph node dissection (RPLND) in the management of patients with these malignant sex cord-stromal tumors. METHODS: Reviewing the Indiana University testis cancer registry revealed 17 patients who underwent RPLND for sex cord-stromal tumors. Pathology was reviewed for features suggestive of malignancy. The data examined included clinical and pathologic stage, surgical procedure, additional therapy received, and outcome. RESULTS: Pathology included Leydig tumors in six patients, Sertoli tumors in four patients, sex cord-stromal tumors in five patients, a granulosa cell tumor in one patient, and a poorly differentiated non-germ cell tumor in one patient. Nine patients had histologic features suggestive of malignancy. Clinical stage at surgery was Stage I in nine patients and Stage IIA-IIIA in eight patients. Patients underwent modified or bilateral RPLND. Nine patients had pathologic Stage I tumors, and the remaining eight patients and had pathologic Stage IIB-IIIA tumors. Follow-up ranged from 8 months to 11 years. Of the eight patients with Stage II-III disease, six patients eventually died of metastatic disease despite additional radiotherapy and/or chemotherapy. CONCLUSIONS: Sex cord-stromal tumors have a potentially aggressive malignant behavior that is difficult to predict based on clinical and pathologic features. Although the therapeutic role of RPLND in patients with small-volume metastatic retroperitoneal tumors is unclear, RPLND remains an option to be performed immediately after orchiectomy, especially in patients who have tumors with malignant features and/or small-volume metastatic disease.