Epithelioid malignant peripheral nerve sheath tumor of the bladder and concomitant urothelial carcinoma: A case report

BACKGROUND Epithelioid malignant peripheral nerve sheath tumor(EMPNST)of the bladder is a rare entity with devastating features.These tumors are thought to originate from malignant transformation of pre-existing schwannomas of pelvic autonomic nerve plexuses,and unlike the conventional malignant peripheral nerve sheath tumor(MPNST),are not associated with neurofibromatosis.The tumor has dis-tinctive morphological,immunohistochemical and molecular features.Addi-tionally,it tends to be more aggressive and have a higher mortality.This is the first case that presents with a synchronous urothelial carcinoma of the bladder and the epithelioid variant of MPNST in the literature.It’s also the second re-ported case of EMPNST originating from the bladder wall.CASE SUMMARY In this case report,we present the detailed clinical course of a 71-year-old patient with EMPNST of the bladder alongside a literature review.CONCLUSION During the management of EMPNST cases,offering aggressive treatment moda-lities to the patient,such as radical cystectomy,is appropriate for the best chance to contain the disease,regardless of the tumor stage and the extent of local disease at initial diagnosis.

Concurrent occurrence of adenocarcinoma and urothelial carcinoma of the prostate gland:A case report

BACKGROUND Adenocarcinoma is the most common subtype of prostate cancer.Prostatic urothelial carcinoma(UC)typically originates from the prostatic urethra.The concurrent occurrence of adenocarcinoma and UC of the prostate gland is uncommon.CASE SUMMARY We present the case of an 82-year-old male patient with simultaneous adenocarcinoma and UC of the prostate gland.The patient underwent a transrectal ultrasound-guided biopsy,and the pathology test revealed UC.Subsequently,transurethral laser prostatectomy was performed,and the pathology test indicated adenocarcinoma of the prostate with a Gleason score of 3+4 and highgrade UC.Therefore,the patient was treated with androgen deprivation therapy,systemic chemotherapy,and immunotherapy.Magnetic resonance imaging performed during follow-up revealed a prostate tumor classified as cT2cN1M0,stage IVA.Therefore,the patient underwent robotic-assisted radical prostatectomy and bilateral pelvic lymph node dissection.The final pathology test of the prostate gland revealed acinar-type adenocarcinoma,Gleason pattern 4+3,pT2N0M0,and high-grade UC.The patient regularly presented to the clinic for postoperative follow-up evaluations.He did not experience any urinary discomfort.CONCLUSION According to our literature review,this is the first reported case of coexisting adenocarcinoma and UC of the prostate gland.

Potential role of transmembrane 9 superfamily member 1 as a biomarker in urothelial cancer

Bladder cancer is a urological tumor with high rates of recurrence despite recent advances in novel therapies.Many proteins involved in the molecular mechanisms are currently an enigma,especially the transmembrane 9 superfamily member 1 which has an unclear function.Wei et al published the function and mechanism of this protein,and showed that it could participate in the proliferation,migration and invasion of tumor cells in bladder cancer,therefore treatments directed against this protein may be beneficial in avoiding this condition.

Conservative management of an early abdominal complication during a Tullio percutaneous endoscopic excision of renal pelvis urothelial carcinoma:A case report

BACKGROUND Upper tract urothelial carcinoma(UTUC)representing only a small fraction of all urothelial tumors.It predominantly affects the renal pelvis in men,often coexisting with bladder carcinoma.UTUC displays a more aggressive genetic profile compared to bladder neoplasms,with the majority of patients presenting with advanced disease.Histologically,about a quarter of UTUC cases exhibit high-grade subtypes,associated with a worse prognosis.Tobacco use and past exposure to aromatic amines are significant risk factors for UTUC.Imaging modalities such as Uro-computed tomography and magnetic resonance imaging play crucial roles in diagnosis.Ureterorenoscopy is vital for direct visualization and biopsy sampling,but its limited sampling capacity presents challenges in determining tumor depth and staging.Traditionally,nephroureterectomy with bladder cuff excision has been the gold-standard treatment for UTUC.Endoscopic conservative treatment has recently emerged as a viable option for selected patients,offering comparable oncological outcomes to radical surgery.Percutaneous access is also feasible for larger intrarenal tumors.CASE SUMMARY We present a case of an 84-year-old woman who underwent percutaneous endoscopic excision of a renal pelvis neoplasm using the Tullio laser.Despite successful tumor removal,the patient experienced a postoperative complication with abdominal fluid leakage.Conservative management effectively resolved the complication.Given the patient's age and refusal for radical surgery,the conservative approach proved to be a valid therapeutic choice.CONCLUSION Overall,UTUC remains a diagnostic and therapeutic challenge due to its rarity.However,advances in endoscopic and percutaneous techniques provide valuable alternatives for selected patients,warranting further exploration in this evolving field.

Management Practices of Locally Advanced and Metastatic Urothelial Carcinoma: A Questionnaire-Based Survey among Lebanese Oncologists

Background and Objective: The outcome of locally advanced and metastatic urothelial carcinoma LA/mUC has improved over the past years with a plethora of new treatments and the approval of immune checkpoint inhibitors (ICIs), antibody-drug conjugates, and targeted agents, to identify locally advanced metastatic urothelial carcinoma’s current management practices in Lebanon and the implication of the ongoing economic crisis on the medical practice. Methods: An online questionnaire was used to survey ten Lebanese oncologists from six different hospitals, between July 5 and July 11, 2022, requesting information pertaining to their current clinical practice in the pharmacological treatment of locally advanced metastatic urothelial carcinoma. Key Findings: Cisplatin-based chemotherapy was the most frequently reported initial treatment of locally advanced metastatic urothelial carcinoma. Participants reported using immune checkpoint inhibitors in platinum-ineligible patients and those with PDL1 positive tumors. Also, they would not consider the concomitant use of immunotherapy and chemotherapy in the first-line setting. Participants believed that avelumab maintenance is effective in the absence of progression after first-line platinum-based chemotherapy;they would consider initiating it 2 - 10 weeks after completion of chemotherapy. Conclusions and Clinical Implications: After comparing with current international guidelines, this study shows that Lebanese oncologists follow international guidelines and have deep knowledge of recent clinical trials for the management of locally advanced metastatic urothelial carcinoma, regardless of economic crisis challenges.

Metachronous urothelial carcinoma in the renal pelvis,bladder,and urethra:A case report

BACKGROUND Urothelial carcinoma(UC)is a common malignancy of the urinary system that can occur anywhere from the renal pelvis to the proximal urethra.Most UCs are in the bladder and have multifocal growth.Upper urinary tract UC(UTUC),which occurs in the renal pelvis or ureter,accounts for only 5%to 10%of UCs.CASE SUMMARY In March 2015,a 70-year-old male who initially presented to a local hospital with a complaint of painless hematuria was diagnosed with UTUC of the right renal pelvis.The doctors administered radical nephroureterectomy and bladder cuff excision.Although the doctors recommended intravesical chemotherapy and regular follow-up,he rejected this advice.In December 2016,the patient presented at our hospital with dysuria.We identified UC in the residual bladder and administered radical cystectomy and left cutaneous ureterostomy.In November 2021,he presented again with urethral bleeding.We detected urethral UC as the cause of urethral orifice bleeding and administered radical urethrectomy.Since then,he has visited regularly for 6-mo follow-ups,and was in stable condition as of December 2022.CONCLUSION UTUC is prone to seeding and recurrence.Adjuvant instillation therapy and intense surveillance are crucial for these patients.

Coexistence of urinary tuberculosis and urothelial carcinoma:A case report

BACKGROUND Taiwan has a high prevalence of tuberculosis and urothelial carcinoma.However,the simultaneous occurrence of both disorders in one patient is uncommon.Tuberculosis and urothelial carcinoma share some common risk factors and could demonstrate overlapping clinical manifestations.CASE SUMMARY Herein,we report the case of a patient who presented with fever,persistent hematuria,and pyuria.Chest computed tomography scans revealed a bilateral upper lobes cavitary lesion with fibrosis.Severe hydronephrosis of the right kidney and renal stones and cysts in the left kidney were observed.Initial microbiological testing was negative;however,a polymerase chain reaction assay of the urine confirmed a urinary tuberculosis infection.The patient was started on an anti-tuberculosis regimen.Ureteroscopy performed to resolve obstructive nephropathy revealed the incidental finding of a left middle-third ureteral tumor.Examination after biopsy and transurethral resection of the bladder tumor indicated urothelial carcinoma.The patient underwent laparoscopic nephroureterectomy,with bladder cuff excision for the right kidney and ureter,and holmium laser ablation of the ureteral lesion to preserve the left kidney and ureter.He has remained stable after the procedures.CONCLUSION Although establishing a causal relationship between tuberculosis and cancer is difficult,medical personnel should consider their correlation.

Bladder preservation in complicated invasive urothelial carcinoma following treatment with cisplatin/gemcitabine plus tislelizumab:A case report

BACKGROUND Invasive urothelial carcinoma(UC)with squamous and glandular differentiation is a highly malignant and complicated pathological subtype,and the standard care is radical cystectomy(RC).However,urinary diversion after RC significantly reduces patient quality of life,thus bladder-sparing therapy has become a research hotspot in this field.Recently,five immune checkpoint inhibitors have been approved for systemic therapy of locally advanced or metastatic bladder cancer by the Food and Drug Administration,but the efficacy of immunotherapy combined with chemotherapy for invasive UC is still unknown,especially for pathological subtypes with squamous and glandular differentiation.CASE SUMMARY We report the case of a 60-year-old male who complained of repetitive painless gross hematuria and was diagnosed with muscle-invasive bladder cancer with squamous and glandular differentiation,defined as cT3N1M0 according to the American Joint Committee on Cancer,who had a strong desire to preserve the bladder.Immunohistochemical staining revealed that programmed cell deathligand 1(PD-L1)expression in the tumor was positive.Thus,a transurethral resection to maximize removal of the bladder tumor was performed under cystoscopy,and the patient subsequently received a combination of chemotherapy(cisplatin/gemcitabine)and immunotherapy(tislelizumab)treatment.No tumor recurrence in the bladder was observed following pathological and imaging examination after 2 cycles and 4 cycles of treatment,respectively.The patient achieved bladder preservation and has been tumor-free for more than two years.CONCLUSION This case shows that the combination of chemotherapy and immunotherapy might be an effective and safe treatment strategy for PD-L1 expression positive UC with divergent histologic differentiation.

Prognostic value of platelet-to-lymphocyte ratio in upper tract urothelial carcinoma patients treated with radical nephroureterectomy:A metaanalysis

Objective:To evaluate the prognostic value of platelet-to-lymphocyte ratio(PLR)in upper tract urothelial carcinoma(UTUC)patients treated with radical nephroureterectomy.Methods:This study was pre-registered in PROSPERO(No.CRD42020186645).Two reviewers independently performed a comprehensive literature search on PubMed,Web of Science,EMBASE,Cochrane Library databases,China Biology Medicine disc(CBM),Wanfang database,and China National Knowledge Infrastructure(CNKI)from inception to May 2021 for prospective or retrospective cohort studies evaluating the prognostic value of PLR.Literature was analyzed with inclusion and exclusion criteria.Data and other useful clinicopathological features were extracted and analyzed with fixed or random-effect models when applicable.Heterogeneity was assessed on the basis of Cochran’s Q test and I2 statistic.Publication bias was assessed with funnel plots and precisely assessed by Egger's tests.Results:A total of ten studies involving 3287 UTUC patients were included.Meta-analysis showed that elevated preoperative PLR was associated with worse overall survival(HR=1.51,95%CI 1.17-1.94,P=0.001),cancer specific survival(HR=1.52,95%CI 1.21-1.90,P<0.001),disease free survival(HR=1.32,95%CI 1.12-1.56,P=0.001),and progression free survival(HR=1.88,95%CI 1.41-2.52,P<0.001).Furthermore,the sensitivity analyses validated the stability and reliability of the results.Conclusion:The present meta-analysis demonstrates a significant association between elevated preoperative PLR and poor prognosis of UTUC patients treated with radical nephroureterectomy.Hence,PLR could be helpful as a potential prognostic biomarker to guide clinical decision-making and select individualized treatment strategies for UTUC patients.However,more prospective and large-scale trials are needed to provide more evidence.

Hyperprogression after anti-programmed death-1 therapy in a patient with urothelial bladder carcinoma:A case report

BACKGROUND Immune checkpoint inhibitors,including programmed death-ligand 1(PD-L1)and programmed death-1(PD-1)have recently been approved to treat locally advanced and metastatic urothelial carcinoma(UC).However,some patients experience rapid tumor progression rather than any clinical benefit from anti-PDL1/PD-1 therapy.CASE SUMMARY A 73-year-old woman with bladder UC showed the progression of multiple metastases after surgery and chemotherapy for over 12 mo.The patient could not tolerate further chemotherapy.Next-generation sequencing was performed,and the results indicated that the tumor mutational burden was 6.4 mutations/Mb.The patient received the anti-PD-L1 agent toripalimab combined with albuminbound paclitaxel.Compared with the baseline staging before immunotherapy,the patient had a treatment failure time of<2 mo,an increase in tumor burden of>50%,and a>2-fold increase in progression,indicating hyperprogression.CONCLUSION Selecting patients most likely to respond to treatment with immunotherapeutic agents remains challenging.For older patients with advanced UC who have already exhausted multi-line chemotherapy options,immunotherapy should be used prudently if no effective biomarker is available.Further studies are required to clarify the causes and mechanisms of hyperprogression.

Research progress in genomics associated with prognosis of upper tract urothelial carcinoma

Upper tract urothelial carcinoma and bladder urothelial carcinoma both belong to urothelial carcinoma,which is a malignant tumor occurring in the renal pelvis and ureteral urothelium.The incidence rate of UTUC is higher among Asians and it shows various pathogenic factors.Patients of UTUC have a short lifespan,and most of them have shown invasive malignant tumors at the time of initial diagnosis.The treatment of most UTUC patients is limited to surgical resection,radiotherapy and chemotherapy in clinical.Due to its rarity,the studies on targeted therapy are rare.With the development of the targeted therapy and immunotherapy,genomics exploration that affects the prognosis of UTUC becomes particularly important.In this paper,we intend to review the differential expression,clinical significance and some special types of UTUC genomes through the UTUC genome.

A Case Report: High-Grade Urothelial Carcinoma in the Renal Pelvis with Complete Kidney and Ureter Duplication Featuring Heterologous Differentiation

This report describes a considerably rare case of high-grade urothelial carcinoma of the renal pelvis and ureter,presenting with heterologous differentiation,in a patient with bilateral duplicated kidneys.A 73-year-old male experienced intermittent gross hematuria for 5 months,accompanied by lower back and abdominal pain.Ultrasound and computed tomography scans revealed bilateral renal and ureteral duplication with multiple tumors in the left renal pelvis.A total nephroterectomy and bladder cuff resection were performed on the left two nephrons.Multiple space-occupying lesions were identified in the left renal pelvis and ureter.Histopathological examination showed poorly differentiated and diverse tumor cells,manifesting as sarcomatoid carcinoma,papillary adenocarcinoma,and infiltrating high-grade urothelial carcinoma.The tumor infiltrated the subcutaneous fibrous connective tissue of the renal pelvis and the full thickness of the ureter.Given the rarity of recurrent renal urothelial carcinoma with heterogeneous differentiation,comprehensive imaging and pathological assessments are vital to delineate the nature of the lesion and the direction of tissue pathological heterologous differentiation.These evaluations guide early radical surgical interventions,improving survival rates.

Inhibitory Effects of MicroRNA-34a on Cell Migration and Invasion of Invasive Urothelial Bladder Carcinoma by Targeting Notch1

MicroRNAs （miRNAs or miRs） are a class of short, non-coding RNAs that participate in various oncological processes. This study aims to explore the roles of microRNA-34a （miR-34a） in invasive urothelial bladder carcinoma. miR-34a was transfected into bladder cancer cell lines 253J and J82. The miR-34a expression levels in tissues and cells were detected by using qRT-PCR. The Notch1 expression was detected by qRT-PCR and Western blotting. Cell migratory and invasive abilities were measured by Transwell chamber assay. Bioinformatics and luciferase assay were performed to predict and analyze the binding sites between miRNA-34a and Notch1. It was found that there was aberrant expression of miR-34a in bladder cancer tissues. Moreover, we revealed that ectopic expression of miR-34a suppressed cell migration and invasion, while forced expression of Notch1 increased cell migratory and invasive abilities. Finally, we observed that miR-34a transfection significantly down-regulated luciferase activity and reduced the mRNA and protein levels of Notch1. Our study concluded that microRNA-34a antagonizes Notch1 and inhibits cell migration and invasion of bladder cancer cells, which indicates the tumor-suppressive function of microRNA-34a in bladder cancer.

Therapeutic role of template-based lymphadenectomy in urothelial carcinoma of the upper urinary tract

Lymphadenectomy for urothelial carcinoma of the upper urinary tract has attracted the attention of physicians. The mapping study of lymphatic spread has shown that a relatively wide area should comprise the regional nodes for tumors of the right renal pelvis or the right upper two-thirds of the ureter. A prospective study showed that an anatomical templatebased lymphadenectomy significantly improved patient survival in tumors of the renal pelvis. This benefit was more evident for patients with p T2 stage tumors or higher. The risk of regional node recurrence is significant reduced by template-based lymphadenectomy,which is likely to be associated with improved patient survival. The removal of lymph node micrometastases is assumed to be the reason for therapeutic benefit following lymphadenectomy. The number of resected lymph nodes can be used to assess the quality of lymphadenectomy,but not to determine the extent of lymphadenectomy. The guidelines currently recommend lymphadenectomy for patients with muscle-invasive disease,even though the current recommendation grades are still low. The present limitation of lymphadenectomy is the lack of standardization of the extent of lymphadenectomy and the randomized trials. Further studies are warranted to collect the evidence to support lymphadenectomy.

WNT/β-catenin signaling in urothelial carcinoma of bladder

Urothelial carcinoma of bladder is the second most prevalent genitourinary disease.It is a highly heterogeneous disease as it represents a spectrum of neoplasms,including non-muscle invasive bladder cancer(NMIBC),muscle invasive bladder cancer(MIBC)and metastatic lesions.Genome-wide approaches and candidate gene analysis suggest that malignant transformation of the bladder is multifactorial and a multitude of genes are involved in the development of MIBC or NMIBC phenotypes.Wnt signaling is being examined to control and maintain balance between stemness and differentiation in adult stem cell niches.Owing to its participation in urothelial development and maintenance of adult urothelial tissue homeostasis,the components of Wnt signaling are reported as an important diagnostic and prognostic markers as well as novel therapeutic targets.Mutations/epigenetic alterations in the key molecules of Wnt/β-catenin canonical pathway have been linked with tumorigenesis,development of drug resistance and enhanced survival.Present review extends our understanding on the functions of key regulatory molecules of canonical Wnt/β-catenin pathway in urothelial tumorigenesis by inducing cancer stem cell phenotype(UCSCs).UCSCs may be responsible for tumor heterogeneity,high recurrence rates and complex biological behavior of bladder cancer.Therefore,understanding the role of UCSCs and the regulatory mechanisms that are responsible for high relapse rates and metastasis could help to develop pathway inhibitors and augment current therapies.Potential implications in the treatment of urothelial carcinoma of bladder by targeting this pathway primarily in UCSCs as well as in bulk tumor population that are responsible for high relapse rates and metastasis may facilitate potential therapeutic avenues and better prognosis.

Laparoscopic nephroureterectomy for upper tract urothelial carcinoma-Update

Upper urinary tract urothelial carcinomas(UTUCs)are uncommon and account for only 5%e10%of urothelial carcinomas.Pyelocaliceal tumors are about twice as common as ureteral tumors.Sixty percent of UTUCs are invasive at diagnosis.Radical nephroureterectomy,including the excision of the distal ureter and bladder cuff is standard of care for treatment of localized UTUCs,because of the high potential for recurrence,multifocality,and progression.Since first laparoscopic nephroureterectomy(LNU)was introduced by Clayman et al.in 1991 and improvement of laparoscopic technique and equipment,LNU has been reported to be equivalent to conventional open method.We reviewed the current literature of patients with UTUCs treated by LNU focusing on technical aspects,peri-operative and oncological outcomes.Laparoscopic radical nephroureterectomy offers the advantages of minimally invasive surgery without deteriorating the oncological outcome for treatment of UTUCs.Indications tend to increase as operator skills increase.Indications for laparoscopic or open nephroureterectomy are in principle the same.The basic requirement for laparoscopic surgery in UTUCs is to achieve benefits of minimal invasive surgery and maintain oncologic principles.

The role of aberrant promoter hypermethylation of DACT1 in bladder urothelial carcinoma

The purpose of this study was to determine the relationship between hypermethylation of DACT1 gene pro-moter and lower mRNA expression in bladder urothelial carcinoma tissue.The methylation status of 29 urothelial carcinoma samples and 29 normal tissue samples were examined by methylation-specific polymerase chain reac-tion（MSP）.The DACT1 mRNA transcript levels and DACT1 protein levels in all samples were then evaluated to define the relationship between the methylation status of the DACT1 promoter and its expression at the transcrip-tional and translational levels.Decreased expression of DACT1 was detected in 89.66% of urothelial carcinomas（26/29;P 〈 0.005）.Promoter hypermethylation was found in 58.62%（17/29） urothelial carcinomas and 25%（7/29） normal tissues,respectively（P 〈 0.05）.DACT1 expression was lower in tissues where the DACT1 gene promoter was hypermethylated than in unmethylated tissues（0.25±0.17 vs 0.69±0.30,P 〈 0.05）.DACT1 gene hyper-methylation was closely related to tumor size,grade and stage（P 〈 0.05）.Our results indicate that silencing and downregulation of DACT1 mRNA may be implicated in carcinogenesis and the progression of bladder urothelial carcinoma,and may be a potential prognostic factor.

Percutaneous resection of upper tract urothelial cell carcinoma:When,how,and is it safe?

Introduction:In the management of upper tract urothelial cell carcinoma(UTUC)endoscopic,nephron sparing procedures like ureterorenoscopy(URS)or percutaneous tumour resection(PCTR)still play a very limited role.This could lead to possible unnecessary radical nephroureterectomies(RNU),still being the gold standard treatment.The risk of chronic kidney disease(CKD)later in life is important.In this study we present the results of 24-year experience with PCTR in a single institution.Methods:We identified 44 patients who underwent PCTR between 1992 and 2015.Radical resection was achieved in 40 patients who were included in this study.Demographic and clinical data,including tumour recurrence,progression to RNU,tumour grade and overall survival(OS)were retrospectively acquired.An outcome analysis was conducted.Results:Median age at diagnosis was 68 years(range 42-94 years).Low grade tumours were found in 37 patients(92.5%)and high grade tumours in three patients(7.5%).Median followup was 53 months during which 20 patients developed upper tract recurrences(50.0%).The longest time to recurrence was 97 months.At follow-up 11 patients(27.5%)underwent an RNU and two patients died from UTUC.RNU could be avoided in 29 patients(72.5%).In this study we found that multifocality is a significant risk factor for recurrence,but not for stage progression to RNU.Conclusion:PCTR is a surgically and oncologically safe procedure.Renal preservation in patients with UTUC who are eligible for percutaneous resection can be achieved in the majority of patients.Selection criteria for PCTR should be further refined,leading to a wider application of PCTR in the future.Follow-up needs invasive procedures and should be long term.

Chinese guidelines for diagnosis and treatment of urothelial carcinoma of bladder 2018 (English version)

Contents1. Overview2. Risk factors for urothelial carcinoma of bladder3. Diagnosis of urothelial carcinoma of bladder3.1 Signs and symptoms of urothelial carcinoma of bladder3.1.1 Symptoms3.1.2 Signs3.2 Imaging examination3.2.1 Ultrasonography3.2.2 CT examination3.2.3 MRI examination3.2.4 IVU3.2.5 Chest plain X-ray film/CT plain scan3.2.6 Bone scintigraphy3.2.7 Positron emission tomography-CT (PET-CT).

Prognostic Factors and Oncological Outcomes after Radical Nephroureterctomy for Upper Tract Urothelial Carcinoma: Review of Contemporary Multi-Center Series

Upper tract urothelial cancers (UTUC) are uncommon and the information guiding their management used to be driven from small single center studies. Multi-center international collaborations should provide clinicians with best management practices as well as prognostic factors guiding treatment decisions and outcomes. We reviewed literature from the largest multicenter collaborations for radical nephroureterctomy (RNU) performed for management of UTUC. Our review included over 50 recent manuscripts from 2009-2012 that were published from multi-center UTUC collaboration groups. Our review aims to determine of the prognostic factors predicting oncological outcomes after RNU and to provide insights about possible maximization of cure with utilization of multimodal treatment approaches. Application of approaches comprising RNU including lymphadenectomy and systemic chemotherapy;particularly in neoadjuvant settings;might have implications on improvement of oncological outcomes in high risk patients.