Showing papers by "Min-Han Tan published in 2011"

A Clinical Scoring System for Selection of Patients for PTEN Mutation Testing Is Proposed on the Basis of a Prospective Study of 3042 Probands

Abstract: Cowden syndrome (CS) and Bannayan-Riley-Ruvalcaba syndrome are allelic, defined by germline PTEN mutations, and collectively referred to as PTEN hamartoma tumor syndrome. To date, there are no existing criteria based on large prospective patient cohorts to select patients for PTEN mutation testing. To address these issues, we conducted a multicenter prospective study in which 3042 probands satisfying relaxed CS clinical criteria were accrued. PTEN mutation scanning, including promoter and large deletion analysis, was performed for all subjects. Pathogenic mutations were identified in 290 individuals (9.5%). To evaluate clinical phenotype and PTEN genotype against protein expression, we performed immunoblotting (PTEN, P-AKT1, P-MAPK1/2) for a patient subset (n = 423). In order to obtain an individualized estimation of pretest probability of germline PTEN mutation, we developed an optimized clinical practice model to identify adult and pediatric patients. For adults, a semiquantitative score—the Cleveland Clinic (CC) score—resulted in a well-calibrated estimation of pretest probability of PTEN status. Overall, decreased PTEN protein expression correlated with PTEN mutation status; decreasing PTEN protein expression correlated with increasing CC score (p < 0.001), but not with the National Comprehensive Cancer Network (NCCN) criteria (p = 0.11). For pediatric patients, we identified highly sensitive criteria to guide PTEN mutation testing, with phenotypic features distinct from the adult setting. Our model improved sensitivity and positive predictive value for germline PTEN mutation relative to the NCCN 2010 criteria in both cohorts. We present the first evidence-based clinical practice model to select patients for genetics referral and PTEN mutation testing, further supported biologically by protein correlation.

Novel FH mutations in families with hereditary leiomyomatosis and renal cell cancer (HLRCC) and patients with isolated type 2 papillary renal cell carcinoma

Abstract: Background Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an autosomal dominant disorder predisposing humans to cutaneous and uterine leiomyomas; in 20% of affected families, type 2 papillary renal cell cancers (PRCCII) also occur with aggressive course and poor prognosis. HLRCC results from heterozygous germline mutations in the tumour suppressor fumarate hydratase ( FH ) gene. Methods As part of the French National Cancer Institute (INCa) ‘Inherited predispositions to kidney cancer’ network, sequence analysis and a functional study of FH were preformed in 56 families with clinically proven or suspected HLRCC and in 23 patients with isolated PRCCII (5 familial and 18 sporadic). Results The study identified 32 different germline FH mutations (15 missense, 6 frameshifts, 4 nonsense, 1 deletion/insertion, 5 splice site, and 1 complete deletion) in 40/56 (71.4%) families with proven or suspected HLRCC and in 4/23 (17.4%) probands with PRCCII alone, including 2 sporadic cases. 21 of these were novel and all were demonstrated as deleterious by significant reduction of FH enzymatic activity. In addition, 5 asymptomatic parents in 3 families were confirmed as carrying disease-causing mutations. Conclusions This study identified and characterised 21 novel FH mutations and demonstrated that PRCCII can be the only one manifestation of HLRCC. Due to the incomplete penetrance of HLRCC, the authors propose to extend the FH mutation analysis to every patient with PRCCII occurring before 40 years of age or when renal tumour harbours characteristic histologic features, in order to discover previously ignored HLRCC affected families.

Differential regulation of PTEN expression by androgen receptor in prostate and breast cancers

Abstract: Prostate cancer and breast cancer are the most common malignancies in the western world. Androgen receptor (AR) and PTEN both have been well documented to have important roles in prostate carcinogenesis. In contrast, AR and PTEN in breast carcinogenesis have not been well studied. Furthermore, the crosstalk and connection between those two pathways remain unclear. Increased AR expression in prostate cancers, combined with decreased PTEN expression, portends a poor clinical outcome. Paradoxically, both high AR and high PTEN levels, detected by immunohistochemistry, in primary breast carcinomas have been associated with better disease-free survival. Here, we performed in silico analysis of publicly available microarray data sets from prostate or breast carcinomas. We found an inverse correlation between AR and PTEN transcript expression in prostate cancer tissues in contrast to the positive correlation in breast cancer. These data led us to hypothesize that AR may directly affect PTEN transcriptional regulation in prostate and breast cancer cells. Here, we show for the first time that AR inhibits PTEN transcription in prostate cancer cells, whereas AR upregulates PTEN transcription in breast cancer cells, which mechanistically explains both the immunohistochemical PTEN–AR expressional data noted in clinical trials and in our in silico analysis of the transcriptomes of breast and prostate cancers. In addition, we have fine-mapped the AR-binding motif within the PTEN promoter. Here we show that, in patients with Cowden syndrome, an inherited cancer syndrome caused by germline mutations scattered throughout PTEN, point variants affecting the 3′ end of the AR-binding motif result in abrogation of androgen-mediated transcriptional regulation of PTEN expression. We may speculate that the differential AR effect on PTEN may begin to explain organ-specific and perhaps sex-specific neoplasia predisposition in Cowden syndrome, as well as why only a fraction of women with germline PTEN mutations develop breast cancer, depending on the androgen steroid milieu and levels.

Progression‐free survival as a predictor of overall survival in metastatic renal cell carcinoma treated with contemporary targeted therapy

Abstract: BACKGROUND. The majority of metastatic renal cell carcinoma (mRCC) clinical trials that examined targeted agents used progression-free survival (PFS) as the primary endpoint. Whether PFS can be used as a predictor of overall survival (OS) is unknown. METHODS. Patients from 12 cancer centers who received targeted therapy for mRCC were identified. Landmark analyses for progression at 3 months and 6 months after drug initiation were performed to minimize lead-time bias. A proportional hazards model was used to assess the utility of PFS for predicting OS. RESULTS. In total, 1158 patients were included. The median follow-up was 30.6 months, the median age was 60 years, and the median Karnofsky performance status was 80%. For the entire cohort, the median PFS was 7.6 months, and the median OS was 19.7 months. In the landmark analysis, the median OS for patients who progressed at 3 months was 7.8 months compared with 23.6 months for patients who did not progress (log-rank test; P < .0001). Similarly, for patients who progressed at 6 months, the median OS was 8.6 months compared with 26 months for patients who did not progress (P < .0001). Compared with those who did not progress, for the patients who progressed at 3 months and at 6 months, the hazard ratios for death adjusted for adverse prognostic factors were 3.05 (95% confidence interval, 2.42-3.84) and 2.96 (95% confidence interval, 2.39-3.67), respectively. Similar results were demonstrated with landmark analyses at 9 months and at 12 months and in the bootstrap validation. Kendall tau rank correlation and a Fleischer model demonstrated a statistically significant dependent correlation. CONCLUSIONS. PFS at 3 months and at 6 months predicted OS, and the current results indicated that PFS may be a meaningful intermediate endpoint for OS in patients with mRCC who receive treatment with novel agents. Cancer 2011;. © 2010 American Cancer Society.

The Karakiewicz nomogram is the most useful clinical predictor for survival outcomes in patients with localized renal cell carcinoma.

Abstract: BACKGROUND: Outcomes after surgical removal of localized renal cell carcinoma (RCC) are variable. There have been multiple prognostic nomograms and risk groups developed for estimation of survival outcomes, with different models in use for evaluating patient eligibility in ongoing trials of adjuvant therapy. The authors aimed to establish the most useful prognostic model for patients with localized RCC to guide trial design, biomarker research, and clinical counseling. METHODS: A total of 390 consecutive patients who underwent nephrectomy for sporadic localized RCC in a tertiary institution (1990-2006) with 65 months median follow-up were retrospectively evaluated. The Karakiewicz nomogram, the Kattan nomogram, the Sorbellini nomogram, and the Leibovich model were compared in predicting survival outcomes (overall survival, cancer-specific survival, and freedom from recurrence) using likelihood analysis, adequacy indices, decision curve analysis, calibration, and concordance indices. RESULTS: Overall, the Karakiewicz nomogram outperformed the Kattan nomogram, the Sorbellini nomogram, and the Leibovich model. Highly improved accuracy was seen using the Karakiewicz nomogram in survival prediction, using likelihood ratio analysis in bivariate models including the competing prognostic models. The Karakiewicz nomogram showed higher adequacy and concordance indices and improved clinical benefit relative to all other nomograms. All 4 models were reasonably calibrated. Exploratory comparisons of prespecified discretized Karakiewicz nomograms and the SORCE trial recruitment criteria (a discretized Leibovich model) of high-risk patients favored the discretized Karakiewicz nomograms. CONCLUSIONS: The Karakiewicz nomogram was shown to be superior to the other tested nomograms and risk groups in predicting survival outcomes in localized RCC. Routine integration of this model into trial design and biomarker research should be considered. Cancer 2011;. © 2011 American Cancer Society.

Testicular microlithiasis: Recent advances in understanding and management

Abstract: Testicular microlithiasis has been linked to the testicular dysgenesis syndrome, and is thought to be a precursor of testicular germ cell tumor. In this Review, the authors discuss the prevalence of testicular microlithiasis, and its pathogenesis, including a putative link with β–estradiol. They also consider the differing management strategies for three main patient groups diagnosed with testicular microlithiasis. Testicular microlithiasis is an infrequent but well recognized condition, which is usually incidentally identified on testicular ultrasound scan. Interest in testicular microlithiasis has increased over the past few years, owing to an observed association with testicular germ cell tumor (TGCT) and intratubular germ cell neoplasia of unclassified type (ITGCNU). This association has added to evidence that testicular microlithiasis is a feature of the testicular dysgenesis syndrome (TDS), which is postulated to underpin disorders of male reproduction such as subfertility, testicular atrophy, cryptorchidism, TGCT and other abnormalities of sexual development. Although the genetic and environmental components of TDS remain unclear, studies of the molecular basis of TGCT support a genetic component for testicular microlithiasis and have identified multiple genes that are associated with TGCT. These advances in the biological understanding of testicular microlithiasis and TGCT have not, however, resolved key clinical dilemmas in the management of patients with these diseases. The role of testicular microlithiasis in the clinical consideration of testicular biopsy is discussed in the context of the apparently healthy individual, the individual with TGCT and the individual with TDS.

Primary anti-VEGF-refractory metastatic renal cell carcinoma (mRCC): Clinical characteristics, risk factors, and subsequent therapy.

Abstract: 305 Background: A proportion of patients treated with anti-VEGF therapy first line exhibit progressive disease (PD) as best response (per RECIST). The characteristics and outcome of this population...

External validation of the International Metastatic Renal Cell Carcinoma (mRCC) Database Consortium prognostic model and comparison to four other models in the era of targeted therapy.

Abstract: 4560 Background: The Heng et al JCO 2009 prognostic model was developed in the age of VEGF-targeted therapy and this study serves as an external validation while comparing its performance to other models. Methods: 1,028 previously unanalyzed patients were used to externally validate the prognostic criteria for overall survival (OS). The model’s discriminatory value was compared to four other prognostic models using C-indices and Net Reclassification Improvement (NRI) (Pencina et al 2008). NRI indicates how the Heng et al model improves upon other models by reclassifying a percentage of patients (pts) into the more correct risk group based on the observed OS at 2 years. Results: The median OS of all pts was 18.8 mons. On multivariable analysis, the pre-identified Heng’s risk factors (anemia, thrombocytosis, neutrophilia, hypercalcemia, Karnofsky performance status <80% and time from diagnosis to treatment < 1 year) continue to be independent predictors of poor OS (p<0.05). When pts were segregated into 3 r...

The association of clinical outcome to front-line VEGF-targeted therapy with clinical outcome to second-line VEGF-targeted therapy in metastatic renal cell carcinoma (mRCC) patients (Pts).

Abstract: 4555 Background: In mRCC pts who fail first-line VEGF-targeted therapy, there are no available randomized data comparing active drugs. Currently, many clinicians choose a second-line VEGF-targeted therapy based on the type of response to first-line VEGF therapy, although no data exists to support this practice. Methods: Pts treated with targeted therapy in the International mRCC Database Consortium were examined to identify pts who received a second-line VEGF-targeted therapy after failure of a different first-line VEGF-targeted therapy. Response rates and progression-free survival (PFS) were compared in the first- and second-line settings. Results: Of 1,602 total database pts, 464 pts received second-line VEGF-targeted therapy (sunitinib 37%, sorafenib 51%, axitinib 2%, bevacizumab 7%, pazopanib 3%) after failure of first-line VEGF-targeted therapy (sunitinib 54%, sorafenib 33%, bevacizumab 13%). The median overall survival from initiation of first-line therapy for pts who received second-line therapy wa...

Nasal metastases from renal cell carcinoma are associated with Memorial Sloan-Kettering Cancer Center poor-prognosis classification.

Abstract: Unusual sites of metastases are recognized in patients with renal cell carcinoma (RCC). However, the prognostic implications of these sites are not well understood. We used the Memorial Sloan-Kettering Cancer Center (MSKCC) risk classification for metastatic RCC to evaluate 912 consecutive patients with RCC managed at the Singapore General Hospital between 1990 and 2009. Among these patients, 301 had metastases either at diagnosis or during the course of illness. Nasal metastases, all arising from clear cell RCC, were identified histologically in 4 patients (1.3% of those with metastasis). All 4 patients were classified as MSKCC poor prognosis by current risk criteria. Nasal metastases were significantly associated with lung and bone metastases. The frequency of nasal metastases in patients with metastatic RCC is about 1 %, occurring predominantly in patients with clear cell RCC. Nasal metastases are associated with poor prognosis as estimated by the MSKCC risk classification, with attendant implications for selection of targeted therapy, and are usually associated with multi -organ dissemination, including concurrent lung and bone involvement.

Stage T1N0M0 renal cell carcinoma: the prognosis in Asian patients.

Abstract: The prognostic features of T1N0M0 renal cell carcinoma (RCC) in Asian patients have not been well explored in large sample studies. In this study, we retrospectively analyzed the records of 713 patients undergoing nephrectomy for T1N0M0 RCC between 1991 and 2009 in three Asian hospitals. Univariate and multivariate analysis were performed to identify the independent predictive factors for T1N0M0 RCC prognosis among a series of clinicopathological parameters, including age, gender, tumor size, Fuhrman grade, and histological classification. Our results showed that 388 of 713 patients had tumors 4.0 cm or smaller (stage T1a) and 325 of 713 patients had tumors 4.0-7.0 cm in size (stage T1b). Five-year cancer-specific survival (CSS) and recurrence-free survival (RFS) rates for this group of patients were 96.0% and 93.5%, respectively. The patients with T1b RCC had a significantly lower 5-year CSS and RFS rates than did those with T1a RCC (CSS, 93.1% vs. 98.6%, P = 0.026; RFS, 90.0% vs. 96.5%, P < 0.001). Patients with low grade (grades I-II) tumors had a higher 5-year CSS (97.8% vs. 91.2%, P = 0.001) and RFS (95.5% vs. 85.5%, P < 0.001) rate than did those with high grade (grades I-II) tumors. More interestingly, when stratifying patients to T1a and T1b groups, the role of grade in distinguishing prognosis could be only observed in patients with T1b disease. Cox regression showed tumor size and Fuhrman grade were significant in predicting CSS and RFS. Our study suggests that the prognosis of patients with T1N0M0 RCC is excellent, and these results are comparable to previously reported studies in Western patients. Furthermore, our data indicates that patients with T1b disease and high Fuhrman grade have high risk of tumor recurrence and death, thus requiring more frequent follow-up.

The effect of low serum sodium on treatment outcome to vascular endothelial growth factor (VEGF)-targeted therapy in metastatic renal cell carcinoma: Results from a large international collaboration.

Abstract: 322 Background: Hyponatremia has been associated with poor survival in many solid tumors and more recently found to be of prognostic and predictive value in metastatic renal cell cancer (mRCC) patients (pts) treated with immunotherapy (Jeppesen et al, Br J Cancer. 2010). We sought to investigate the influence of baseline hyponatremia in mRCC pts treated with contemporary vascular endothelial growth factor (VEGF)- targeted therapy in a larger international and multi-institutional database. Methods: Baseline characteristics and outcomes on 855 pts treated with first-line anti-VEGF therapy for mRCC were available from 8 Cancer Centers to study the impact of hyponatremia (defined as serum Na<135 mmol/L) on clinical outcome as measured by overall survival (OS), time to treatment failure (TTF), best response (CR, PR, SD and PD). Results: Median OS after treatment initiation was 16.8 months (mos) (95% CI: 14.9, 18.5 mos), with 334 (39%) of patients remaining alive. Median follow-up in pts alive was 18.8 mos. Med...

Papillary renal cell carcinoma with metastatic laparoscopic port site and vaginal involvement: a case report

Abstract: Laparoscopic port-site metastasis is a rare but well recognized outcome following surgery in urological cancers, with its etiology not clearly understood. Additionally, vaginal metastasis in clear cell renal cell carcinoma is rare, and has not been previously reported in the setting of papillary renal cell carcinoma. We present the case of a 71-year-old Chinese woman with metastatic type II papillary renal cell carcinoma with histologically verified vaginal involvement and a concurrent laparoscopic port-site metastasis. This was also associated with a unique constellation of widely disseminated metastatic sites, which include a local relapse, the peritoneum and the urethra. Laparoscopic port-site metastases are associated with the presence of advanced cancer with multiple sites of metastasis. We hypothesize from the findings of our report and background data that this phenomenon is more likely to be related to tumor factors rather than operative factors. We also present what is, to the best of our knowledge, the first reported case in the literature of vaginal and urethral metastasis and the second reported case of laparoscopic port-site recurrence.

'Prechronous' metastasis in clear cell renal cell carcinoma: a case report

Abstract: Although metastatic carcinoma in the presence of an occult primary tumor is well recognized, underlying reasons for the failure of the primary tumor to manifest are uncertain. Explanations for this phenomenon have ranged from spontaneous regression of the primary tumor to early metastasis of the primary tumor before manifestation of a less aggressive primary tumor. We report a case of 'prechronous' metastasis arising from clear cell renal cell carcinoma, where metastatic disease initially manifested in the absence of a primary renal tumor, followed by aggressive growth of the primary renal lesion. A 43-year-old Malay man initially presented to our facility with fever and cough. He subsequently underwent surgical resection of a 9 cm right-sided lung mass found on radiological examination. Histology showed a high-grade clear cell tumor with sarcomatoid differentiation, suggestive of a metastasis from clear cell renal cell carcinoma. However, no concurrent renal lesions were noted on computed tomographic evaluation at that time. Then, four months after lung resection, he presented with a subcutaneous mass in the left loin, as well as right loin discomfort. Computed tomography scanning revealed a 10 cm right renal mass, with renal vein and inferior vena cava invasion, as well as recurrent disease in the right thorax. Histological examination of the excised subcutaneous mass revealed a high-grade carcinoma consistent with clear cell renal cell carcinoma. This is the first reported case of prechronous metastasis of renal cell carcinoma, with metastatic disease manifesting prior to the development of the primary lesion. The underlying mechanism is uncertain, but our patient's case provides anecdotal support for the early dissemination model of metastasis.

Coexisting metastatic choriocarcinoma and bladder adenocarcinoma of common germ cell origin.

Abstract: Dear Editor, A 51-year-old post-menopausal Chinese woman developed acute retention of urine and was treated with forceps removal of visibly obstructing friable soft tissue. This was not sent for histology. Imaging showed a 10.1 cm by 5.9 cm irregular heterogenous mass involving the bladder and uterus (Fig. 1), right hydronephrosis and hydroureter, and hypodense lesions in the liver and lungs. A pulmonary lesion biopsy yielded choriocarcinoma (Fig. 2). β-HCG levels were 79,091 IU/L (Normal range <1.2 IU/L). She received 8 cycles of etoposide/methotrexate/d-actinomycin alternating with cyclophosphamide/vincristine1 with normalisation of β-HCG levels, radiological reduction in masses, and resolution of the right hydronephrosis and hydroureter (Fig. 3). She then underwent a total hysterectomy and bilateral salpingo-oophorectomy with curative intent. Intraoperatively, a full thickness biopsy for gross thickening of the bladder was performed. Histology showed mucinous adenocarcinoma (Fig. 4) of the bladder wall with extensive peritoneal and regional lymph nodal involvement but no evidence of choriocarcinoma. The patient received palliative radiotherapy to the bladder for haematuria. Meanwhile, her β-HCG level rose from undetectable to >200,000 IU/L with a clinically palpable liver within 3 months.