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.
Abstract Testicular germ cell tumors represent a biologically unique disease process. These tumors are exquisitely sensitive to platinum-based chemotherapy, can be cured with surgical metastasectomy, ...and are known for the integration of biologic markers to stage and assign risk. Exploring further biologic markers that offer insight into the molecular mechanisms that contribute to disease biology is important. In this review, we attempt to summarize the utility of the current and some future biologic markers for disease monitoring and relapse.
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.
Abstract
We investigated the challenges of conducting IMPACT2, an ongoing randomized study that evaluates molecular testing and targeted therapy (ClinicalTrials.gov: NCT02152254). Patients with ...metastatic cancer underwent tumor profiling and were randomized between the two arms when eligibility criteria were met (Part A). In Part B, patients who declined randomization could choose the study arm. In Part A, 69 (21.8%) of 317 patients were randomized; 78.2% were not randomized because of non-targetable alterations (39.8%), unavailability of clinical trial (21.8%), other reasons (12.6%), or availability of US Food and Drug Administration (FDA)-approved drugs for the indication (4.1%). In Part B, 32 (20.4%) of 157 patients were offered randomization; 16 accepted and 16 selected their treatment arm; 79.0% were not randomized (patient’s/physician’s choice, 29.3%; treatment selection prior to genomic reports, 16.6%; worsening performance status/death, 12.7%; unavailability of clinical trials, 6.4%; other, 6.4%; non-targetable alterations, 5.7%; or availability of FDA-approved drugs for the indication, 1.9%). In conclusion, although randomized controlled trials have been considered the gold standard for drug development, the execution of randomized trials in precision oncology in the advanced metastatic setting is complicated. We encountered various challenges conducting the IMPACT2 study, a large precision oncology trial in patients with diverse solid tumor types. The adaptive design of IMPACT2 enables patient randomization despite the continual FDA approval of targeted therapies, the evolving tumor biomarker landscape, and the plethora of investigational drugs. Outcomes for randomized patients are awaited.
Objective To evaluate the oncologic outcomes of patients with retroperitoneal teratoma only at primary retroperitoneal lymph node dissection (RPLND) who did not receive adjuvant chemotherapy. ...Materials and Methods Between 1979 and 2010, 23 patients with clinical stage (CS) I and II disease underwent primary RPLND at our institution with teratoma only in the retroperitoneum. No patient received adjuvant chemotherapy and the minimum follow-up was 2 years. Results At the initial diagnosis, 13 patients (56.5%) had CS I disease and 10 patients (43.5%) had CS II disease. Pathologic staging demonstrated IIA in 13 patients (56.5%), IIB in 8 patients (34.8%), and IIC in 2 patients (8.7%). The 5-year disease-free survival (DFS) was 100% with a median follow-up of 5.8 years (range, 2.1-25.4). DFS was not significantly different comparing pathologic stage IIA vs IIB/IIC disease ( P = .73). Two patients (14%) developed late relapses. One patient had a pelvic recurrence 11 years after primary RPLND. Final pathology from the pelvic resection demonstrated embryonal carcinoma. He remains disease free after his second surgery. The second patient had a contralateral retroperitoneal recurrence with yolk-sac tumor and teratoma 11 years after primary RPLND. He was treated with chemotherapy followed by postchemotherapy RPLND. Conclusion The relapse rate for patients with teratoma only at primary RPLND is low irrespective of PS. Adjuvant chemotherapy is therefore not recommended in the management of these patients.
Objective To determine survival outcomes in clinical stage I germ cell tumor (GCT) patients requiring retroperitoneal lymph node dissection (RPLND) for late relapse (LR) occurring while on ...surveillance. Methods The Indiana University Testis Cancer Database was queried from 1985 to 2013 to identify all patients who presented with clinical stage I GCT, elected surveillance, relapsed ≥2 years after initial diagnosis, and underwent RPLND in treatment of their LR. Clinical, pathologic, and treatment characteristics were reviewed. Results Twenty-eight patients met inclusion criteria. The mean age at diagnosis was 29.3 years. Testicular primary was pure seminoma in 2, intratubular germ cell neoplasia with scar in 1, nonseminomatous GCT in 24, and unknown in 1 patient. The median time from diagnosis to relapse was 48.5 months (range, 28-321 months). At relapse, serum tumor markers were elevated in 13 patients (46.4%). Nineteen patients were given cisplatin-based chemotherapy at LR. RPLND was initial management of LR in 9. At RPLND, 10, 5, and 13 patients demonstrated fibrosis, teratoma, and viable malignancy, respectively. On the last follow-up, 24 patients (85.7%) were free of disease and 4 patients (14.3%) had died of their disease. Conclusion When examining outcomes among patients undergoing RPLND at LR of GCT, it appears that patients experiencing LR on surveillance have more favorable histology and survival outcomes than previously reported for unselected patients experiencing LR.
ObjectiveEstimations of the treatment effect on overall survival (OS) may be influenced by post-progression therapies (PPTs). It is unclear how often OS analyses account for PPT effects. The purpose ...of this cross-sectional analysis was to determine the prevalence of OS analyses accounting for PPT effects in phase III oncology trials.Methods and analysisWe screened two-arm, superiority design, phase III, randomised, oncology trials reporting OS from ClinicalTrials.gov. The primary outcome was the frequency of OS analyses adjusting for PPT confounding. Logistic regressions computed ORs for the association between trial-level covariates and the outcome.ResultsA total of 334 phase III trials enrolling 265 310 patients were included, with publications between 2004 and 2020. PPTs were reported in 47% of trials (157 of 334), and an analysis accounting for PPTs was performed in only 12% of trials (N=41). PPT adjustments were often prespecified (N=23, 56%), and appeared to be more likely in cross-over studies (OR 5.04, 95% CI 2.42 to 10.38) and studies with discordant surrogate-OS findings (OR 2.26, 95% CI 1.16 to 4.38). In key subgroup analyses, PPT analyses were infrequent, including 8% of trials among those studying locoregional/first-line therapy and 11% of trials among those powered for OS.ConclusionsAlthough time on PPTs is an important component of OS, PPTs are rarely considered in OS analyses, which may introduce confounding on estimates of the treatment effect on OS. PPTs and methods to account for their effects on OS estimates should be considered at the time of trial design and reporting.
There are an estimated 60,000 new cases of ductal carcinoma in situ (DCIS) each year. A lack of understanding in DCIS pathobiology has led to overtreatment of more than half of patients. We profiled ...the temporal molecular changes during DCIS transition to invasive ductal carcinoma (IDC) using in vivo DCIS progression models. These studies identified B cell lymphoma-9 (BCL9) as a potential molecular driver of early invasion. BCL9 is a newly found co-activator of Wnt-stimulated β-catenin-mediated transcription. BCL9 has been shown to promote progression of multiple myeloma and colon carcinoma. However BCL9 role in breast cancer had not been previously recognized.
Microarray and RNA sequencing were utilized to characterize the sequential changes in mRNA expression during DCIS invasive transition. BCL9-shRNA knockdown was performed to assess the role of BCL9 in in vivo invasion, epithelial-mesenchymal transition (EMT) and canonical Wnt-signaling. Immunofluorescence of 28 patient samples was used to assess a correlation between the expression of BCL9 and biomarkers of high risk DCIS. The cancer genome atlas data were analyzed to assess the status of BCL9 gene alterations in breast cancers.
Analysis of BCL9, by RNA and protein showed BCL9 up-regulation to be associated with DCIS transition to IDC. Analysis of patient DCIS revealed a significant correlation between high nuclear BCL9 and pathologic characteristics associated with DCIS recurrence: Estrogen receptor (ER) and progesterone receptor (PR) negative, high nuclear grade, and high human epidermal growth factor receptor2 (HER2). In vivo silencing of BCL9 resulted in the inhibition of DCIS invasion and reversal of EMT. Analysis of the TCGA data showed BCL9 to be altered in 26 % of breast cancers. This is a significant alteration when compared to HER2 (ERBB2) gene (19 %) and estrogen receptor (ESR1) gene (8 %). A significantly higher proportion of basal like invasive breast cancers compared to luminal breast cancers showed BCL9 amplification.
BCL9 is a molecular driver of DCIS invasive progression and may predispose to the development of basal like invasive breast cancers. As such, BCL9 has the potential to serve as a biomarker of high risk DCIS and as a therapeutic target for prevention of IDC.
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