Modified retroperitoneal lymph node dissection for post-chemotherapy residual tumour: a long-term update.

OBJECTIVE: To update previously reported outcomes of modified-template post-chemotherapy retroperitoneal lymph node dissection (PC-RPLND) in appropriately selected patients with metastatic non-seminomatous germ cell tumour (NSGCT), as our previous report was criticised for short follow-up and so we now provide a long-term update on this cohort. PATIENTS AND METHODS: In all, 100 patients with normal serum markers after cisplatin-based chemotherapy and residual retroperitoneal tumour underwent modified PC-RPLND between 1991 and 2004. Using a prospectively managed institutional testicular cancer database, long-term follow-up was obtained. RESULTS: As previously reported, 43 patients underwent a right-modified template, 18 patients underwent a full-left-modified template, and 39 patients underwent a left-modified template. The updated long-term median follow-up for the entire cohort is 125 months. Seven patients developed recurrent disease with a median (range) time to recurrence of 11 (6-102) months, and one patient died from recurrent disease in the chest 4 years after surgery. All recurrences were outside the boundaries of a full-bilateral template RPLND, with the most common location of recurrence being the chest. The 5- and 10-year recurrence-free survival rates were 93% and 92%, respectively. The overall survival at 10 years was 99%. CONCLUSIONS: In appropriately selected patients with low-volume disease before and after chemotherapy, a modified template has durable long-term efficacy without risk of in-field recurrences at a median follow-up of 125 months.

Inpatient Experiences with MyChart Bedside.

BACKGROUND: As technology is increasingly being integrated into hospital-based care, it is important to assess patient experiences. The purpose of this project was to conduct an evaluation of inpatient experiences with MyChart® Bedside. MATERIALS AND METHODS: A convenience sample of patients (n = 88) were included in this study, who responded to a Web-based self-reported survey that was embedded within the MyChart Bedside application. RESULTS: The majority of respondents (78%) reported that MyChart Bedside was easy to use. The respondents agreed that MyChart Bedside improved communication with their nurses (74%) and with their physicians (53%), as well as helped them understand their medications (90%) during their inpatient hospitalization. CONCLUSIONS: The study found that the majority of patients were satisfied with MyChart Bedside, and they reported that it helped them learn more about their medications, as well as communicate with their care team.

Outcomes of postchemotherapy retroperitoneal lymph node dissection following high-dose chemotherapy with stem cell transplantation.

BACKGROUND: Characterizing the role of postchemotherapy retroperitoneal lymph node dissection (PC-RPLND) after high-dose chemotherapy (HDCT) has been limited by small sample sizes. This study reports on survival after HDCT with stem cell support and PC-RPLND as well as histologic findings in the retroperitoneum. METHODS: The prospectively maintained testicular cancer database of Indiana University was queried for patients receiving HDCT with stem cell transplantation before PC-RPLND. The cause and date of death were obtained through patient chart review and contact with referring physicians. The Kaplan-Meier method was used to evaluate overall survival (OS). The log-rank test was used for tests of significance. A multivariate, backward, stepwise Cox regression model was built to evaluate predictors of overall mortality. RESULTS: A total of 92 patients were included in the study. In the entire cohort, the retroperitoneal (RP) histology findings at the time of PC-RPLND were necrosis (26%), teratoma (34%), and cancer (38%). Sixty-six patients (72%) harbored either a teratoma or active cancer in the RP specimen at PC-RPLND. The median follow-up for the entire cohort was 80.6 months. A total of 28 patients (30%) died during follow-up. The 5-year OS rate of the entire cohort was 70%. The most significant predictor of death was PC-RPLND performed in the desperation setting with elevated markers. CONCLUSIONS: Despite these patients being heavily pretreated with multiple cycles of chemotherapy, including HDCT, approximately three-fourths were found to have a teratoma and/or active cancer in the retroperitoneum. This underscores the importance of PC-RPLND for rendering patients free of disease and providing a potential for cure.

Reoperative retroperitoneal lymph node dissection for metastatic germ cell tumors: analysis of local recurrence and predictors of survival.

PURPOSE: While reoperative retroperitoneal lymph node dissection results in durable long-term survival, outcomes are comparatively worse than in patients who undergo initial adequate resection. We identified predictors of cancer specific survival and correlated technical aspects of initial resection to local recurrence in patients treated with repeat retroperitoneal lymph node dissection. MATERIALS AND METHODS: We reviewed subsequent data on 203 patients treated with reoperation for recurrent retroperitoneal germ cell tumor after initial retroperitoneal lymph node dissection with local relapse. We used multivariate Cox proportion hazard models for cancer specific survival and multivariate logistic regression for local recurrence. RESULTS: The only 2 factors associated with local recurrence at lymph node dissection were incomplete lumbar vessel division at initial resection (p<0.01) and teratoma histology in the reoperative pathology specimen (p=0.01). Median followup was 73 months. Initial survival analysis including preoperative variables indicated that active cancer at initial operation (p=0.04), increased serum tumor markers (p=0.02), M1b stage (p<0.01) and salvage chemotherapy (p=0.01) were independent predictors of worse cancer specific survival. After introducing the final pathological data from reoperation into the final multivariate model only active cancer at reoperation (p<0.01), M1b stage (p=0.01) and salvage chemotherapy before reoperation (p=0.02) retained the association with worse oncologic outcomes. CONCLUSIONS: Tumor biology and inadequate surgical technique (incomplete lumbar ligation) are associated with local recurrence after initial retroperitoneal lymph node dissection. Decreased cancer specific survival is expected in this population, mostly driven by active cancer in the final pathology specimen.

Management of germ cell tumors with somatic type malignancy: pathological features, prognostic factors and survival outcomes.

PURPOSE: Germ cell tumors with somatic type malignancy are rare, occurring in approximately 2.7% to 8.6% of germ cell tumor cases. Prognostic factors and optimal management remain poorly defined. MATERIALS AND METHODS: The Indiana University testis cancer database was queried from 1979 to 2011 for patients demonstrating germ cell tumor with somatic type malignancy at orchiectomy or subsequent resection. Patients with transformation to primitive neuroectodermal tumor only were excluded from study due to distinct management. Chart review, pathological review and survival analysis were performed. RESULTS: A total of 121 patients met the study inclusion criteria. The most common somatic type malignancy histologies were sarcoma (59), carcinoma (31) and sarcomatoid yolk sac tumor (17). Of these patients 32 demonstrated somatic type malignancy at germ cell tumor diagnosis. For those with delayed identification, median time from germ cell tumor to somatic type malignancy diagnosis was 33 months. This interval was longest for carcinomas (108 months). At a median followup of 71 months, 5-year cancer specific survival was 64%. Predictors of poorer cancer specific survival included somatic type malignancy diagnosed at late relapse (p = 0.017), referral to Indiana University for reoperative retroperitoneal lymph node dissection (p = 0.026) and grade (p = 0.026). None of these factors maintained prognostic significance on multivariate analysis. Somatic type malignancy histology subtype, stage, risk category and number of resections were not predictive of cancer specific survival. CONCLUSIONS: Germ cell tumor with somatic type malignancy is associated with poorer cancer specific survival than traditional germ cell tumor. Established prognostic factors for germ cell tumor lose predictive value in the setting of somatic type malignancy. Aggressive and serial resections are often necessary to optimize cancer specific survival. Tumor grade is an important prognostic factor in sarcomas and sarcomatoid yolk sac tumors.

Survival analysis of pure seminoma at post-chemotherapy retroperitoneal lymph node dissection.

PURPOSE: Viable seminoma encountered at post-chemotherapy retroperitoneal lymph node dissection for pure testicular seminoma is rare due to the chemosensitivity of this germ cell tumor. In this study we define the natural history of viable seminoma at post-chemotherapy retroperitoneal lymph node dissection. MATERIALS AND METHODS: The Indiana University testis cancer database was queried from 1988 to 2011 to identify all patients with primary testicular or retroperitoneal pure seminoma and who were found to have pure seminoma at post-chemotherapy retroperitoneal lymph node dissection. Clinical characteristics were reviewed and survival analysis was performed. RESULTS: A total of 36 patients met the study inclusion criteria. All patients received standard first line cisplatin based chemotherapy and 17 received salvage chemotherapy. The decision to proceed to retroperitoneal lymph node dissection was based on enlarging retroperitoneal mass and/or positron emission positivity in the majority of cases. Seven patients had undergone previous retroperitoneal lymph node dissection. Additional surgical procedures were required in 19 patients to achieve a complete resection. The 5-year cancer specific survival rate was 54%. However, only 9 of 36 patients remained continuously free of disease and of these patients 4 received adjuvant chemotherapy. Mean time from post-chemotherapy retroperitoneal lymph node dissection to death was 6.9 months. Second line chemotherapy, reoperative retroperitoneal lymph node dissection and earlier era of treatment were associated with poorer cancer specific survival. CONCLUSIONS: A total of 36 patients with pure seminoma were found to have viable pure seminoma at post-chemotherapy retroperitoneal lymph node dissection. While 5-year cancer specific survival was 54%, these surgeries are technically demanding and only a minority of patients achieves a durable cure from surgery alone.

Clinical and pathological features predictive of nephrectomy at post-chemotherapy retroperitoneal lymph node dissection.

PURPOSE: We determined the clinical and pathological features associated with nephrectomy at post-chemotherapy retroperitoneal lymph node dissection. MATERIALS AND METHODS: We retrospectively reviewed the testis cancer database from 1980 to 2007 to identify all patients treated with post-chemotherapy retroperitoneal lymph node dissection. Patients with pure seminoma and nongerm cell histology were excluded from study. A total of 1,807 patients were identified, of whom 17 without recorded mass size were excluded from further study. Pathological and clinical variables were assessed by bivariate analysis. Multivariate logistic regression was used to determine predictors of nephrectomy at post-chemotherapy retroperitoneal lymph node dissection. RESULTS: The overall incidence of nephrectomy at post-chemotherapy retroperitoneal lymph node dissection was 14.8% (265 of 1,790 cases). The incidence of nephrectomy was 17.0%, 18.9%, 13.6% and 8.0% in 1980 to 1988 (group 1), 1989 to 1997 (group 2), 1998 to 2002 (group 3) and 2002 to 2007 (group 4) (p = 0.0001). The nephrectomy rate for tumors less than 2, 2 to 5, 5 to 10 and greater than 10 cm was 6.0%, 5.8%, 13.9% and 31.9%, respectively (p = 0.0001). The incidence of nephrectomy based on retroperitoneal histology was 10.3% for fibrosis, 14.5% for teratoma and 20.4% for cancer (p = 0.0001). The strongest predictor of nephrectomy at post-chemotherapy retroperitoneal lymph node dissection was retroperitoneal mass size greater than 10 cm (OR 9.30, 95% CI 3.8-22.7). CONCLUSIONS: The incidence of nephrectomy at post-chemotherapy retroperitoneal lymph node dissection has decreased in the last 3 decades. A higher incidence was observed in patients with larger volume tumors, those who received salvage chemotherapy, those with a left primary testicular tumor and those with increased markers at post-chemotherapy surgery.

Incidence, histology and management of intraluminal thrombus at post-chemotherapy retroperitoneal lymph node dissection.

PURPOSE: We determined the incidence, histology and management of intraluminal thrombus in a large group of patients treated with post-chemotherapy retroperitoneal lymph node dissection. MATERIALS AND METHODS: We queried the testicular cancer database at our institution from January 1990 to June 2010. Tumor resection en bloc with major vascular structures and/or thrombectomy at post-chemotherapy retroperitoneal lymph node dissection was done in 240 patients, of whom 89 had a total of 98 intraluminal thrombi involving major vasculature. RESULTS: The site of the 98 thrombi was the inferior vena cava (72), aorta (1) and renal vein (20). Management of the 72 vena caval thrombi included cavectomy (36), partial cavectomy (9) and thrombectomy (27). For the 20 renal vein thrombi management included nephrectomy (18) and thrombectomy (2). The single aortic thrombus was managed by aortic resection and replacement. Pathological evaluation revealed bland thrombi in 31 cases, necrosis in 23, teratoma in 28, active germ cell cancer in 12 and sarcoma in 4. In 40 patients a total of 71 additional procedures were required, including nephrectomy in 32, liver resection in 6, bowel resection in 7, thoracotomy in 6, vertebral resection in 3, orchiectomy in 11, and duodenal repair, ureteroureterotomy, stent removal, cholecystectomy, appendectomy and paraspinal tumor removal in 1 each. There were 17 Clavien III or worse complications in a total of 11 patients, including 2 deaths. Average estimated blood loss was 1,165 ml (range 200 to 7,000) and average hospital stay was 9.3 days (range 2 to 70). CONCLUSIONS: The incidence of intraluminal thrombus at post-chemotherapy retroperitoneal lymph node dissection is 5.8%. Cancer pathology was observed in 44.9% of cases. Surgeons who perform post-chemotherapy retroperitoneal lymph node dissection should be well versed in vascular techniques with respect to the major vasculature.

Molecular genetic evidence supporting the neoplastic nature of fibrous stroma in testicular teratoma.

Testicular teratoma typically consists of heterogeneous mixtures of diverse epithelial and stromal components. The biological nature and genetic characteristics of the fibrous stroma of testicular teratomas have not been thoroughly investigated. Chromosome 12p abnormalities are the hallmark genetic alterations of germ cell tumors. We studied chromosome 12p abnormalities in the fibrous stroma and other components of pure testicular teratomas from 32 patients using interphase fluorescence in situ hybridization. Overall, 72% (23/32) of pure testicular teratomas had chromosome 12p abnormalities. Isochromosome 12p or 12p overrepresentation independent of isochromosome 12p was detected in the fibrous stroma in 53% (17/32) and 41% (13/32) of cases, respectively. Among the 17 cases positive for isochromosome 12p, 8 (47%) also had 12p overrepresentation. In 31% (10/32) cases, the fibrous stroma showed neither 12p overrepresentation nor isochromosome 12p. Isochromosome 12p and 12p overrepresentation were identified, respectively, in the gastrointestinal-type epithelium of 14/23 (61%) and 15/23 (65%) cases; in the respiratory-type epithelium of 41% (7/17) and 41% (7/17) cases; in the squamous epithelium of 62% (8/13) and 54% (7/13) cases; and in the cartilage of 63% (5/8) and 38% (3/8) cases. Concordant chromosomal 12p abnormalities were observed between the fibrous stroma and epithelial elements of testicular teratomas. Our results indicate that the fibrous stroma of testicular teratomas frequently has genetic abnormalities similar to those of the epithelial components. Concordant chromosome 12p alterations between the fibrous stroma and epithelial elements provide further evidence that both epithelial and fibrous components of teratoma are derived from a common progenitor.

Pyridyl aminothiazoles as potent Chk1 inhibitors: optimization of cellular activity.

Translation of significant biochemical activity of pyridyl aminothiazole class of Chk1 inhibitors into functional CEA potency required analysis and adjustment of both physical properties and kinase selectivity profile of the series. The steps toward optimization of cellular potency included elimination of CDK7 activity, reduction of molecular weight and polar surface area and increase in lipophilicity of the molecules in the series.

Effective siRNA delivery and target mRNA degradation using an amphipathic peptide to facilitate pH-dependent endosomal escape.

Effective delivery of siRNA (small interfering RNA) into the cells requires the translocation of siRNA into the cytosol. One potential delivery strategy uses cell-delivery peptides that facilitate this step. In the present paper, we describe the characterization of an amphipathic peptide that mediates the uptake of non-covalently bound siRNA into cells and its subsequent release into the cytosol. Biophysical characterization of peptide and peptide/siRNA mixtures at neutral and lysosomal (acidic) pH suggested the formation of α-helical structure only in endosomes and lysosomes. Surprisingly, even though the peptide enhanced the uptake of siRNA into cells, no direct interaction between siRNA and peptide was observed at neutral pH by isothermal titration calorimetry. Importantly, we show that peptide-mediated siRNA uptake occurred through endocytosis and, by applying novel endosomal-escape assays and cell-fractionation techniques, we demonstrated a pH-dependent alteration in endosome and lysosome integrity and subsequent release of siRNA and other cargo into the cytosol. These results indicate a peptide-mediated siRNA delivery through a pH-dependent and conformation-specific interaction with cellular membranes and not with the cargo.

Ejaculatory status and fertility rates after primary retroperitoneal lymph node dissection.

PURPOSE: We determined the incidence of antegrade emission after primary retroperitoneal lymph node dissection in a large contemporary cohort. Our secondary purpose was to evaluate the fertility rate in this population. MATERIALS AND METHODS: We queried the testicular cancer database at our institution from January 1, 2000 to December 31, 2005 and identified all 280 patients who underwent primary retroperitoneal lymph node dissection. Of these patients we contacted 176, and questioned them about ejaculatory and fertility status at 3 to 9 years of followup. RESULTS: Of 176 patients who underwent primary retroperitoneal lymph node dissection 171 (97%) reported preserved antegrade emission. Of the 135 men who underwent a nerve sparing procedure 134 (99%) could ejaculate, as could 33 of 37 (89%) who underwent nonnerve sparing surgery. An attempt to father children was reported by 64 men, of whom 47 (73.4%) were successful. Three other patients fathered children via in vitro fertilization. CONCLUSIONS: Most men who undergo modern primary retroperitoneal lymph node dissection maintain antegrade emission and ejaculation.

Is retroperitoneal histology predictive of liver histology at concurrent post-chemotherapy retroperitoneal lymph node dissection and hepatic resection?

PURPOSE: We identified factors predicting liver histology in patients with nonseminomatous germ cell tumor undergoing concurrent post-chemotherapy retroperitoneal lymph node dissection and liver resection. MATERIALS AND METHODS: We reviewed the Indiana University testis cancer database to identify all patients with nonseminomatous germ cell tumor and liver metastasis who underwent post-chemotherapy retroperitoneal lymph node dissection and liver resection between 1976 and 2006. RESULTS: A total of 59 patients met study inclusion criteria. Necrosis, teratoma and cancer were identified in 31%, 46% and 24% of retroperitoneal specimens, and in 73%, 17% and 10% of liver specimens, respectively. Concordance between retroperitoneal and liver histology was 49% overall, including 94% for necrosis, 26% for teratoma and 36% for cancer. Liver necrosis alone was found in 94%, 70% and 50% of patients with retroperitoneal necrosis, teratoma and cancer, respectively. CONCLUSIONS: The overall rate of histological discordance between retroperitoneal and liver histology was 51% with 73% of all liver specimens containing necrosis only. Retroperitoneal necrosis is highly predictive of hepatic necrosis (94%). Management for liver lesions at post-chemotherapy retroperitoneal lymph node dissection must be individualized. Observation may be warranted for liver lesions requiring complicated hepatic surgery regardless of retroperitoneal pathology.

Radical prostatectomy as initial monotherapy for patients with pathologically confirmed high-grade prostate cancer.

OBJECTIVE: To report the long-term outcome of high-grade prostate cancer treated with radical prostatectomy (RP) as initial monotherapy, analyse the effect of clinical and pathological variables on survival, and report cancer-related symptoms. PATIENTS AND METHODS: A retrospective chart review was conducted to identify patients with Gleason 8-10 prostate cancer found on pathological review in men undergoing RP as initial therapy for clinically localized disease between 1988 and 2005. Kaplan-Meier analysis was used to calculate event-free survival. Univariable and multivariable analyses were used to assess the effects of clinical and pathological variables on prostate-specific antigen (PSA) recurrence. RESULTS: After excluding 20 patients, 119 were identified with pathologically confirmed high-grade cancers at the time of RP. The overall median (interquartile range) follow-up was 73 (41-113) months. Twenty-four (20%) patients had organ-confined cancer, 60 (50%) had specimen-confined cancer, and 14 (12%) had nodal metastasis. Kaplan-Meier analysis showed overall survival rates at 5 and 10 years, respectively, of 90% and 75%, cancer-specific survival of 92% and 82%, and a PSA recurrence-free follow-up at 5 years of 31%. Using univariable analysis, preoperative PSA level, pathological Gleason score, pathological stage, surgical margin status and tumour volume were found to significantly affect the PSA recurrence-free follow-up. No variables were significant on multivariable analysis. Cancer-related symptoms were reported by only 14 patients, with a median time from surgery to first symptom of 43 months. CONCLUSION: High-grade prostate cancer can be treated with RP as initial monotherapy with an acceptable 10-year cancer-specific survival (82%). The PSA recurrence-free follow-up is poor (31% at 5 years). However, few patients progress to symptomatic recurrence after PSA relapse within the first 5 years.

Epidermal growth factor receptor protein expression and gene amplification in the chemorefractory metastatic embryonal carcinoma.

Testicular cancer is the most common cancer in young male patients. The combination of cisplatin-based chemotherapy and surgery has resulted in high cure rates. However, a small percentage of patients have cancers that are refractory to chemotherapy; treatment options for these patients are limited, and their prognosis is generally poor. Further studies are needed to explore the molecular pathogenesis pathways and potential targets of therapy for this group of highly aggressive tumors. We analyzed 21 patients who presented with metastatic embryonal carcinoma, were treated with chemotherapy, and subsequently underwent retroperitoneal lymph node dissection. Immunostaining for epidermal growth factor receptor (EGFR) was performed on paraffin-embedded tissue sections containing tumor from these specimens, using the avidin-biotin-peroxidase method. EGFR gene amplification was performed by interphase fluorescence in situ hybridization (FISH). Immunohistochemically, 9 of 21 cases (43%) demonstrated positive EGFR staining; 12 of 21 cases (57%) had absent or very limited EGFR expression. FISH revealed EGFR amplification in 1 case (5%), polysomy in 15 of 21 cases (71%), and normal disomy pattern in 5 of 21 cases (24%). A significant correlation between EGFR protein expression level and its chromosome polysomy/amplification was established (P=0.02). Our study showed that EGFR protein is frequently expressed in a subset of patients with chemorefractory metastatic embryonal carcinoma. EGFR chromosomal polysomy/amplification may be one of the mechanisms that cause increased EGFR protein expression, and could potentially be used as indication for anti-EGFR therapy.

Use of ileum as ureteral replacement in urological reconstruction.

PURPOSE: We reviewed indications and outcomes in patients undergoing ileal ureter replacement for ureteral reconstruction. MATERIALS AND METHODS: Between December 1989 and September 2007, 105 patients underwent ileal ureter replacement, of whom 14 were excluded from study due to incomplete data. The remaining 91 patients (99 renal units) comprised the study cohort. RESULTS: Mean patient age was 46.8 years and mean followup was 36.0 months. Indications for an ileal ureter were stricture following genitourinary surgery in 29 cases (31.9%), radiation induced stricture in 17 (18.7%), nonurological surgery iatrogenic injury in 16 (17.6%) and retroperitoneal fibrosis in 11 (12.1%). Only 4 patients (4.4%) had primary ureteral cancer. Long-term complications included anastomotic stricture in 3 patients (3.3%) and fistula in 6 (6.6%). Serum creatinine decreased or remained stable in 68 patients (74.7%) and hyperchloremic metabolic acidosis developed in 3. No patient complained of excessive urinary mucous production. CONCLUSIONS: In 68.1% of patients indications for an ileal ureter included radiation induced stricture or iatrogenic injury. The ileal ureter is a reasonable option for long-term ureteral reconstruction with preserved renal function in carefully selected patients.

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.

Results of retroperitoneal lymph node dissection after chemotherapy in patients with pure seminoma in the orchidectomy specimen but elevated serum alpha-fetoprotein.

OBJECTIVE: To determine the incidence of necrosis, teratoma, and active cancer in specimens at retroperitoneal lymph node dissection (RPLND) after chemotherapy in patients who presented with a pure seminoma primary tumour and an elevated serum alpha-fetoprotein (AFP) level at diagnosis who underwent surgery. PATIENTS AND METHODS: A retrospective review of the Indiana University testis cancer database from 1980 to 2004 was performed to identify all patients with metastasic germ cell cancer, pure seminoma in the orchidectomy specimen, and an elevated AFP level. In all, 42 patients were identified; two with nonseminomatous germ cell cancer in the contralateral testicle were excluded. RESULTS: RPLND pathology in the 40 patients showed necrosis in 13 (32.5%), teratoma in 12 (30%), and cancer in 15 (37.5%). The histological subtype of the 15 cancer specimens at RPLND was pure seminoma in two, embryonal in three, yolk sac in seven, variant in one, and mixed elements in two (one with seminoma and yolk sac, and one with embryonal and variant). In all, 20 patients presented with a serum AFP level of <1000 microg/mL with nine (45%) having teratoma only in the retroperitoneum in contrast to 20 patients with an AFP level of >1000 microg/mL with three (15%) having teratoma only in the retroperitoneum (P = 0.04). The level of serum AFP did not predict for active cancer in the retroperitoneum (P = 0.5). CONCLUSIONS: RPLND in patients after chemotherapy who presented with pure seminoma in the orchidectomy specimen and an elevated AFP do not have a high probability of finding necrosis only in the RPLND specimen. In fact, the prevalence of persistent cancer is higher compared with the general group of patients that have RPLND after chemotherapy.

Development of thioquinazolinones, allosteric Chk1 kinase inhibitors.

A high throughput screening campaign was designed to identify allosteric inhibitors of Chk1 kinase by testing compounds at high concentration. Activity was then observed at K(m) for ATP and at near-physiological concentrations of ATP. This strategy led to the discovery of a non-ATP competitive thioquinazolinone series which was optimized for potency and stability. An X-ray crystal structure for the complex of our best inhibitor bound to Chk1 was solved, indicating that it binds to an allosteric site approximately 13A from the ATP binding site. Preliminary data is presented for several of these compounds.