Asynchronous Metastases Research Articles

The Impact of Metastasectomy on Survival Outcomes of Renal Cell Carcinoma: A 10-Year Single Center Experience.

The role of surgical metastasectomy (MST) in solitary or oligometastasis from renal cell carcinoma (RCC) and its impact on survival outcomes remains poorly addressed. We evaluated the impact of MST on overall survival (OS) in patients with oligometastatic (m)RCC. The institutional renal cancer prospective database was examined for cases treated with partial or radical nephrectomy who developed metastatic disease during follow-up. Patients with evidence of clinical metastasis at first diagnosis were excluded. Patients considered unfit for MST received systemic treatment (ST); all others received MST. The impact of MST vs. the ST only cohort was assessed with the Kaplan-Meier method. Age, gender, bilaterality, histology, AJCC stage of primary tumor, surgical margins, local vs. distant metastasis and MST were included in univariable and multivariable regression analyses to assess the predictors of OS. Overall, at a median follow-up of 16 months after primary treatment, 168 patients with RCC developed asynchronous metastasis at the adrenal gland, lung, liver, spleen, peritoneal, renal fossa, bone, nodes, brain and thyroid gland. Nine patients unfit for any treatment were excluded. The site of metastasis was treated with surgical MST (77/159, 48.4%), with or without previous or subsequent ST, while 82/159 cases (51.2%) received ST only. The 2-year, 5-year and 10-year OS probabilities were 93.8%, 82.8% and 79.5%, respectively. After multivariable analysis, MST and the primary tumor AJCC stage were independent predictors of OS probabilities (p = 0.019 and p = 0.035, respectively). After Kaplan-Meier analysis, MST significantly improved OS probabilities versus patients receiving ST (p < 0.001). The main drawbacks of our research were the small sample size from a single-tertiary referral institution, as well as the absent or different ST lines in the cohort of patients receiving MST. When an NED status is achievable, surgical MST of mRCC significantly impacts OS, delaying and not precluding further subsequent ST.

MP28-05 THE IMPACT OF METASTASECTOMY ON SURVIVAL OUTCOMES OF RENAL CELL CARCINOMA: A 10-YEAR SINGLE CENTER EXPERIENCE

You have accessJournal of UrologyCME1 Apr 2023MP28-05 THE IMPACT OF METASTASECTOMY ON SURVIVAL OUTCOMES OF RENAL CELL CARCINOMA: A 10-YEAR SINGLE CENTER EXPERIENCE Mariaconsiglia Ferriero, Manuela Costantini, Riccardo Mastroianni, Gabriele Tuderti, Umberto Anceschi, Aldo Brassetti, Alfredo Maria Bove, Leonardo Misuraca, Andrea Iannuzzi, Salvatore Guaglianone, Michele Gallucci, and Giuseppe Simone Mariaconsiglia FerrieroMariaconsiglia Ferriero More articles by this author , Manuela CostantiniManuela Costantini More articles by this author , Riccardo MastroianniRiccardo Mastroianni More articles by this author , Gabriele TudertiGabriele Tuderti More articles by this author , Umberto AnceschiUmberto Anceschi More articles by this author , Aldo BrassettiAldo Brassetti More articles by this author , Alfredo Maria BoveAlfredo Maria Bove More articles by this author , Leonardo MisuracaLeonardo Misuraca More articles by this author , Andrea IannuzziAndrea Iannuzzi More articles by this author , Salvatore GuaglianoneSalvatore Guaglianone More articles by this author , Michele GallucciMichele Gallucci More articles by this author , and Giuseppe SimoneGiuseppe Simone More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003256.05AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Solitary or oligometastasis from renal cell carcinoma (RCC) are considered the ideal candidate for target treatments to delay the time to systemic therapies. The role of surgical metastasectomy and its impact on survival outcomes remains poorly addressed. We evaluated the impact of mestastasectomy on overall survival in patients with oligometastatic (m) RCC. METHODS: Institutional renal cancer prospective database was queried for cases treated with partial or radical nephrectomy who developed metastatic disease during follow up. Patients with evidence of clinical metastasis at first diagnosis were excluded. Patients were unfit for metastasectomy based on surgeon's discretion (not achievable a non evident disease [NED] status after surgery), all other patients received systemic treatment. Survival probabilities were computed at 12, 24, 60 and 120 months after primary treatments. The impact of metastasectomy vs systemic treatment only cohort (reference category) was assessed with the Kaplan Meier method. Age, gender, bilaterality, histology, AJCC stage of primary tumor, surgical margins and metastasectomy were included in univariable and multivariable regression analyses to assess predictors of overall survival (OS). RESULTS: Overall, at a median follow up of 16 months after primary treatment, 168 patients with RCC developed asynchronous metastasis at adrenal gland, lung, liver, spleen, peritoneal, renal fossa, bone, nodes, brain and thyroid gland. Nine patients unfit for any treatment were excluded. The site of metastasis was treated with surgical metastasectomy (77/159, 48.4%), with or without previous or subsequent systemic treatment (Table 1), while 82/159 cases (51.2%) received only systemic treatment. Two-yr, 5-yr and 10-yr overall survival probabilities were 82.9%,72%, 62.7% respectively. At multivariable analysis, primary tumor AJCC stage and metastasectomy were independent predictors of OS probabilities (p=0.009 and <0.001, respectively). At Kaplan Meier analysis, metastasectomy improved significantly OS probabilities versus patients receiving systemic therapy (p<0.001). (Figure 1) CONCLUSIONS: When a NED status is achievable, surgical metastasectomy of mRCC significantly impact on OS delaying and not precluding further subsequent systemic treatments. Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e370 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Mariaconsiglia Ferriero More articles by this author Manuela Costantini More articles by this author Riccardo Mastroianni More articles by this author Gabriele Tuderti More articles by this author Umberto Anceschi More articles by this author Aldo Brassetti More articles by this author Alfredo Maria Bove More articles by this author Leonardo Misuraca More articles by this author Andrea Iannuzzi More articles by this author Salvatore Guaglianone More articles by this author Michele Gallucci More articles by this author Giuseppe Simone More articles by this author Expand All Advertisement PDF downloadLoading ...

Survival outcomes of metastasis-directed therapy for solitary sites of metastatic clear cell renal cell carcinoma.

674 Background: Metastasis directed therapy (MDT) is associated with improved cancer-specific survival and delay in use of systemic therapy for metastatic clear cell RCC (mccRCC). Although the benefits of MDT may differ based on organ site of metastasis due to differences in disease biology, survival based on site of metastasis remain underexplored. We aim to evaluate survival outcomes of patients who underwent MDT for solitary sites of mccRCC. Methods: The Mayo Clinic Nephrectomy Registry was queried to identify adults undergoing radical or partial nephrectomy for unilateral, sporadic ccRCC from 2000 to 2019 with a single site of metastasis treated with MDT including complete metastasectomy or radiation, in lieu of systemic therapy. Overall and cancer-specific survival were estimated using the Kaplan-Meier method, with the duration of follow-up calculated from the date of metastasis to the date of death or last follow-up. Associations with time to death from RCC were evaluated using Cox proportional hazards regression models and summarized with hazard ratios and 95% confidence intervals (CIs). Results: In this cohort of 207 mccRCC patients, 152 underwent complete metastasectomy and 55 underwent radiation. 133 died at a median of 2.7 years (IQR 1.2-4.7) following metastasis, including 105 who died from RCC at a median of 2.2 years (IQR 1.0-3.9). The median duration of follow-up for the 74 patients who were still alive at last follow-up was 8.1 years (IQR 3.7-12.1). Overall survival rates (95% CI) at 2, 4, 6, 8, and 10 years following metastasis were 73% (69-79), 54% (48-62), 45% (38-52), 37% (30-44), and 32% (26-40), respectively; cancer-specific survival rates were 75% (69-81), 56% (50-64), 47% (41-55), 44% (37-52), and 42% (35-50), respectively. Age, poor performance status, presence of synchronous metastasis and asynchronous metastasis &lt;1 year from nephrectomy, tumor size, and bone metastasis were associated with death from RCC (table). Conclusions: These findings provide useful survival benchmarks to patients who are considering MDT as a therapeutic option. In addition, synchronous and asynchronous metastasis &lt;1 year from nephrectomy, poor performance status, and bone metastasis are significantly associated with worse survival from mccRCC. [Table: see text]

GPBAR1 is associated with asynchronous bone metastasis and poor prognosis of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death in China. Asynchronous metastasis is the main reason for HCC recurrence, but the current assessment of HCC metastasis and prognosis is far from clinically satisfactory. In our study, we investigated the expression of G-protein-coupled bile acid receptor (GPBAR1) in HCC tissues and tumor-adjacent tissues by qRT-PCR and immunohistochemistry. The associations between GPBAR1 expression, clinicopathological factors, and asynchronous metastases were assessed by the Chi-square test. The overall survival curves of different variables were plotted with the Kaplan-Meier method, and the statistical significance between different subgroups was analyzed with the log-rank test. The independent prognostic factors were identified by the Cox regression hazard model. GPBAR1 was more highly expressed in HCC tissues than in tumor-adjacent tissues. GPBAR1 expression in HCC was significantly higher than that in liver cirrhosis, followed by normal liver tissues. GPBAR1 was significantly associated with poor prognosis in HCC and can be regarded as an independent prognostic biomarker. Interestingly, GPBAR1 expression in HCC was significantly correlated with asynchronous metastasis to the bone but not to the liver or lung. GPBAR1 was found to be an independent, unfavorable prognostic factor of HCC, as well as an indicator of asynchronous bone metastasis but not liver or lung metastases. Our results could provide a new aspect for HCC metastasis studies and help identify high-risk HCC patients, which helps ameliorate the prognostic assessment of HCC.

A case of hepatocellular carcinoma followed by asynchronous metastasis to the lung and thoracic spine following radical ablation treatment

A case of hepatocellular carcinoma followed by asynchronous metastasis to the lung and thoracic spine following radical ablation treatment

Rectal Cancer: Asynchronous Metastasis to the Temporal Bone, Temporomandibular Joint and Middle Ear

Rectal cancer has the potential to metastasize to multiple anatomical sites. The hallmark of treatment presides with sound oncologic surgery, adjunct with chemotherapy and radiation therapy when indicated. The initial presentation determines the management regimen, consisting of physical examination and diagnostic imaging. A 54-year-old female presented with locally advanced rectal cancer. Upon conclusion of neoadjuvant chemotherapy and radiation therapy, she underwent a low anterior resection with total mesorectal excision. Her surgical margins were negative; however, of the 21 lymph nodes retrieved, 11 were positive for cancer. The patient underwent further adjuvant chemotherapy. 2 years, 8 months later, the patient presented to the emergency department with worsening swelling of the right side of the face, with increasing pain, hearing, and visual impairments. Diagnostic imaging revealed a large lesion in the cranial anatomy, invading the temporal bone, temporomandibular joint, sphenoid bone and anterior superior epitympanum of the right middle ear. The patient underwent operative intervention followed by radiation and chemotherapy. Asynchronous metastasis of rectal cancer to the cranium is a rare finding and an invasion into the temporal bone even more scarcely reported. The prognosis for distant metastatic disease is poor because it involves metastatic spread via the lymph channels or vascular system. Patients that have undergone treatment for advanced rectal cancer must be approached with a high index of suspicion for distant metastatic disease, even in the advent of routine negative surveillance

1675 A Rare Case of Rectal Adenocarcinoma With Isolated, Asynchronous Metastasis to the Temporal Bone

INTRODUCTION: Metastatic disease only to the bone without other organ involvement in colorectal cancer patients is extremely rare. Isolated, asynchronous metastasis to the temporal bone, without involvement of the liver or lung is an even further deviation from the traditional presentation. We present the case of a 56-year-old lady with a history of rectal cancer in remission presenting with hearing loss, facial swelling, and facial droop. CASE DESCRIPTION/METHODS: The patient presented with a stage 3C rectal cancer pT3N2bM0 and received adjuvant chemotherapy based on her pathology. The disease was in complete remission, without evidence of any CT, PET, or endoscopic findings of disease recurrence. Three years after her initial diagnosis, the patient began to develop swelling, with associated myalgia and hearing loss on the ipsilateral side. CT and MRI imaging revealed a mass in the right temporal bone, eroding into the bony architecture with peri-orbital and temporal swelling, with inflammatory changes of the right mandibular process. A subsequent biopsy of the cranial mass was consistent with metastatic rectal adenocarcinoma. Repeat imaging had not shown any evidence of abdominal or chest disease. DISCUSSION: More than 90% of colorectal carcinomas are adenocarcinomas originating from epithelial cells of the colorectal mucosa. Approximately 10% of all colorectal carcinomas are mucinous carcinomas. The metastatic pattern of colorectal carcinomas is well known. In a study using more than 49,000 patients with colorectal cancer, it was found that the most common sites of metastasis involved the thoracic organs, the liver, the nervous system, and the peritoneum. Literature review reveals an overall incidence of 5–11% of bony metastasis. This figure includes both isolated skeletal metastases and those with coinciding liver and lung spread. Isolated skeletal metastases are even more infrequently seen, occurring at an estimated frequency of 1–2%. Asynchronous and isolated metastasis to the temporal bone is rare. Assi R, Mukherji D, Haydar A, Saroufim M, Temraz S, Shamseddine A. Metastatic colorectal cancer presenting with bone marrow metastasis: a case series and review of literature. J Gastrointest Oncol. 2016;7(2):284–297.

Expression Patterns of Biomarkers in Primary Tumors and Corresponding Metastases in Breast Cancer.

Tumor heterogeneity has been shown for several cancers including breast cancer (BC). Despite the fact that expression of tumor markers may change throughout the metastatic process, rebiopsies at the time of recurrence are still not performed routinely at all institutions. The aims of the study were to evaluate changes in biomarker profiles during the metastatic process and to investigate whether previous anthracycline or endocrine therapy given in the adjuvant setting could affect the biomarker profile in metastatic lesions. We investigated the expression pattern of ER, HER2, TOP2a, TOP1, p53, Bcl-2, and Ki-67 in 110 paired samples of primary BC and corresponding asynchronous metastases. We found discordant expressions in primary tumor and metastasis for all biomarkers, although only significant for Ki-67. Changes in the expression profile of the metastatic lesions would have altered treatment decisions in 14% of patients. We found no effect of previous anthracycline or endocrine therapy on the expression profiles. Our data confirm that discordant expressions of biomarkers are common in BC and often carry therapeutic consequences. This emphasizes the need for biopsies from metastatic lesions, even in cases where the localization of the metastatic process is not easily accessible.

PD48-06 THE ROLE OF METASTASECTOMY IN PATIENTS WITH RENAL CELL CARCINOMA WITH SARCOMATOID DEDIFFERENTIATION: A MATCHED CONTROLLED ANALYSIS

You have accessJournal of UrologyKidney Cancer: Localized: Surgical Therapy VI1 Apr 2016PD48-06 THE ROLE OF METASTASECTOMY IN PATIENTS WITH RENAL CELL CARCINOMA WITH SARCOMATOID DEDIFFERENTIATION: A MATCHED CONTROLLED ANALYSIS Arun Thomas, Mehrad Adibi, Rebecca Slack, Borregales Leonardo, Megan Merrill, Pheroze Tamboli, Kanishka Sircar, Eric Jonasch, Surena Matin, Christopher Wood, and Jose Karam Arun ThomasArun Thomas More articles by this author , Mehrad AdibiMehrad Adibi More articles by this author , Rebecca SlackRebecca Slack More articles by this author , Borregales LeonardoBorregales Leonardo More articles by this author , Megan MerrillMegan Merrill More articles by this author , Pheroze TamboliPheroze Tamboli More articles by this author , Kanishka SircarKanishka Sircar More articles by this author , Eric JonaschEric Jonasch More articles by this author , Surena MatinSurena Matin More articles by this author , Christopher WoodChristopher Wood More articles by this author , and Jose KaramJose Karam More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2016.02.2728AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Renal cell carcinoma with sarcomatoid dedifferentiation (sRCC) is an aggressive tumor generally associated with a poor clinical course. Management of metastatic sRCC remains a therapeutic challenge with no standard treatment strategies. Our objective was to evaluate whether metastasectomy has any survival benefit in patients with synchronous or asynchronous metastatic sRCC treated with radical nephrectomy (RN) METHODS From an institutional database of 273 patients with sRCC treated with nephrectomy, we matched 80 patients with synchronous and asynchronous metastasis for age, ECOG performance status, histology and nodal status. Matched pairs were then retained only if patients who did not undergo metastasectomy were comparably alive at the time of metastasectomy in matched surgical patients to reduce the bias in survival outcomes. Overall survival (OS) from nephrectomy was studied using univariable and multivariable proportional hazards regression. RESULTS Median OS was 8.3 months (95%CI 6.5-10.5 months) and 18.5 months (95%CI 11.5-42.9 months) for patients with synchronous and asynchronous metastases, respectively. OS for patients undergoing metastasectomy for synchronous metastasis was comparable to non-surgical patients (8.4 and 8.0 months, respectively, p=0.35). Similarly, within the asynchronous cohort, median OS was 36.2 months (95%CI 7.6-Not Reached) in the metastasectomy group and 13.7 months (95%CI 8.8-41.6) in the non-metastasectomy group (p=0.29). On multivariable analysis, positive lymph node (LN) at nephrectomy was associated with increased risk of death in both synchronous and asynchronous patients groups; (HR=2.1 [95%CI 1.1-4.0] p=0.03) and (HR=3.3 [95%CI 1.2-9.2] p=0.02), respectively CONCLUSIONS Metastasectomy in patients with synchronous or asynchronous metastases after nephrectomy does not appear to confer significant survival benefit in patients with sRCC, particularly in patients with pathological LN positive disease at nephrectomy © 2016FiguresReferencesRelatedDetails Volume 195Issue 4SApril 2016Page: e1177 Advertisement Copyright & Permissions© 2016MetricsAuthor Information Arun Thomas More articles by this author Mehrad Adibi More articles by this author Rebecca Slack More articles by this author Borregales Leonardo More articles by this author Megan Merrill More articles by this author Pheroze Tamboli More articles by this author Kanishka Sircar More articles by this author Eric Jonasch More articles by this author Surena Matin More articles by this author Christopher Wood More articles by this author Jose Karam More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

The role of metastasectomy in patients with renal cell carcinoma with sarcomatoid dedifferentiation: A matched controlled analysis.

565 Background: Renal cell carcinoma with sarcomatoid dedifferentiation (sRCC) is an aggressive tumor generally associated with a poor clinical course. Management of metastatic sRCC remains a therapeutic challenge with no standard treatment strategies. Our objective was to evaluate whether metastasectomy has any survival benefit in patients with synchronous or asynchronous metastatic sRCC treated with radical nephrectomy (RN). Methods: From an institutional database of 273 patients with sRCC treated with nephrectomy, we matched 80 patients with synchronous and asynchronous metastasis for age, ECOG performance status, histology and nodal status. Matched pairs were then retained only if patients who did not undergo metastasectomy were comparably alive at the time of metastasectomy in matched surgical patients to reduce the bias in survival outcomes. Overall survival (OS) from nephrectomy was studied using univariable and multivariable proportional hazards regression. Results: Median OS was 8.3 months (95%CI 6.5-10.5 months) and 18.5 months (95%CI 11.5-42.9 months) for patients with synchronous and asynchronous metastases, respectively. OS for patients undergoing metastasectomy for synchronous metastasis was comparable to non-surgical patients (8.4 and 8.0 months, respectively, p=0.35). Similarly, within the asynchronous cohort, median OS was 36.2 months (95%CI 7.6-Not Reached) in the metastasectomy group and 13.7 months (95%CI 8.8-41.6) in the non-metastasectomy group (p=0.29). On multivariable analysis, positive lymph node (LN) at nephrectomy was associated with increased risk of death in both synchronous and asynchronous patients groups; (HR=2.1 [95%CI 1.1-4.0] p=0.03) and (HR=3.3 [95%CI 1.2-9.2] p=0.02), respectively. Conclusions: Metastasectomy in patients with synchronous or asynchronous metastases after nephrectomy does not appear to confer significant survival benefit in patients with sRCC, particularly in patients with pathological LN positive disease at nephrectomy.

Clonal expansion and linear genome evolution through breast cancer progression from pre-invasive stages to asynchronous metastasis.

Evolution of the breast cancer genome from pre-invasive stages to asynchronous metastasis is complex and mostly unexplored, but highly demanded as it may provide novel markers for and mechanistic insights in cancer progression. The increasing use of personalized therapy of breast cancer necessitates knowledge of the degree of genomic concordance between different steps of malignant progression as primary tumors often are used as surrogates of systemic disease. Based on exome sequencing we performed copy number profiling and point mutation detection on successive steps of breast cancer progression from one breast cancer patient, including two different regions of Ductal Carcinoma In Situ (DCIS), primary tumor and an asynchronous metastasis. We identify a remarkable landscape of somatic mutations, retained throughout breast cancer progression and with new mutational events emerging at each step. Our data, contrary to the proposed model of early dissemination of metastatic cells and parallel progression of primary tumors and metastases, provide evidence of linear progression of breast cancer with relatively late dissemination from the primary tumor. The genomic discordance between the different stages of tumor evolution in this patient emphasizes the importance of molecular profiling of metastatic tissue directing molecularly targeted therapy at recurrence.

KRAS mutational concordance between primary and metastatic colorectal adenocarcinoma.

KRAS mutation analysis is commonly performed on tissue samples obtained from primary colorectal cancers (CRCs). The metastatic lesions of CRC are usually considered as qualitatively similar or even identical to the primary tumors. The aim of this study was to evaluate the spectrum and distribution of KRAS mutations in a large collection of CRCs, while also evaluating the concordance of primary and metastatic lesions among available paired specimens from the same patients. A total of 729 patients with histologically confirmed advanced CRC at the University Hospital and Local Health Unit (Sassari, Italy) were included. Clinical and pathological features were obtained from medical records and/or pathology reports. Formalin-fixed, paraffin-embedded tissue samples were used for mutation analysis. Genomic DNA was isolated using a standard protocol; the coding sequence and splice junctions of exons 2 and 3 in the KRAS gene were screened by direct automated sequencing. Overall, 219 (30%) KRAS mutations were found; 208 (30.1%) were identified in the 690 primary tumors and 11 (28.2%) in the 39 metastatic tissue samples. Among the 31 (4.3%) patients who had paired samples of primary CRC and synchronous or asynchronous metastases, 28 (90.3%) showed consistent mutation patterns between the primary tumors and metastatic lesions. In one case, an additive mutation (Q61L) was found in the metastatic tissue, while two other discrepant cases exhibited a different mutation distribution; Q61H in the primitive lesion and G13V in the metastatic lesion in one case, and a mutated primary tumor (Q61L) and wild-type metastasis in another case. The results of this study confirm that a high concordance exists between the results of KRAS mutation analysis performed in primitive and metastatic CRCs; independent subclones may be generated in a limited amount of patients.

Heterogeneous distribution of BRAF/NRAS mutations among Italian patients with advanced melanoma.

BackgroundPrevalence and distribution of pathogenetic mutations in BRAF and NRAS genes were evaluated in multiple melanoma lesions from patients with different geographical origin within the same Italian population.MethodsGenomic DNA from a total of 749 tumor samples (451 primary tumors and 298 metastases) in 513 consecutively-collected patients with advanced melanoma (AJCC stages III and IV) was screened for mutations in exon 15 of BRAF gene and, at lower extension (354/513; 69%), in the entire coding DNA of NRAS gene by automated direct sequencing. Among tissues, 236 paired samples of primary melanomas and synchronous or asynchronous metastases were included into the screening.ResultsOverall, mutations were detected in 49% primary melanomas and 51% metastases, for BRAF gene, and 15% primary tumors and 16% secondaries, for NRAS gene. A heterogeneous distribution of mutations in both genes was observed among the 451 primary melanomas according to patients’ geographical origin: 61% vs. 42% (p = 0.0372) BRAF-mutated patients and 2% vs. 21% (p < 0.0001) NRAS-mutated cases were observed in Sardinian and non-Sardinian populations, respectively. Consistency in BRAF/NRAS mutations among paired samples was high for lymph node (91%) and visceral metastases (92.5%), but significantly lower for brain (79%; p = 0.0227) and skin (71%; p = 0.0009) metastases.ConclusionsOur findings about the two main alterations occurring in the different tumor tissues from patients with advanced melanoma may be helpful in improving the management of such a disease.

Different prevalence of BRAF and NRAS somatic mutations in melanomas according to the patients’ origin.

e20013 Background: Genetic factors predisposing to melanoma at germline level have been demonstrated to be geographically heterogeneous. We here evaluated the spectrum of NRAS and BRAF mutations at somatic level, in a large subset of melanoma tissues from patients originating from different Italian geographical areas: Sardinia, whose population is genetically homogeneous, and Middle-South Italy, with a genetically heterogeneous population. Methods: Patients were enrolled consecutively between June 2008 and December 2012. Genomic DNA was isolated from tumor tissues [primary melanomas (N=439) and melanoma metastases (N=269)] or melanoma cell lines (N=32). Paired samples of primary melanomas (n=140) and synchronous or asynchronous metastases from the same patients (n=203) were included. The full coding sequences and splice junctions of NRAS (exons 2-3) and BRAF (exon 15) genes were screened for mutations through automated sequencing. Results: BRAF/NRAS mutations were identified in 63% of primary melanomas (48% BRAF; 15% NRAS), 67% melanoma metastases (51% BRAF; 16% NRAS), and 68% melanoma cell lines (56% BRAF; 12% NRAS). A non-significant increase in mutation frequency after progression from primary melanoma was observed. However, distribution of BRAF/NRAS mutations varied between in vivo tumors and melanoma cell lines, suggesting a preponderant role for BRAF activation in highly proliferating cultured melanoma cells. Among paired samples, consistency of BRAF/NRAS mutation patterns between metastatic and primary melanomas ranged from 71% (skin metastases) to about 90% (lymph node and visceral metastases). A significant inverse distribution of BRAF/NRAS mutation rates was observed in our series on the basis of the geographical origin of patients: for BRAF, 58% Sardinian vs. 42% non-Sardinian cases (p=0.045); for NRAS, 2% Sardinian vs. 21% non-Sardinian cases (p&lt;0.001). Conclusions: Our findings provide additional insights into the spectrum and distribution of BRAF/NRAS mutations in melanoma; moreover, they support the hypothesis that differences in patients’ origins and related genetic backgrounds may contribute to even determine the incidence rate of somatic mutations in such cancer genes.

Identification of DLEC1 D215N Somatic Mutation in Formalin Fixed Paraffin Embedded Melanoma and Melanocytic Nevi Specimens.

DLEC1 has been suggested as a tumor suppressor gene in several cancers. DLEC1 D215N somatic mutation (COSM36702) was identified in a melanoma cell line through whole genome sequencing. However, little is known about the implication and prevalence of this mutation in primary melanomas or in melanocytic nevi. The aim of this study was to genotype DLEC1 D215N mutation in melanoma tissue and melanocytic nevi samples to confirm its occurrence and to estimate its prevalence. Primary melanomas (n = 81) paired with synchronous or asynchronous metastases (n = 21) from 81 melanoma patients and melanocytic nevi (n = 28) were screened for DLEC1 D215N mutation. We found the mutation in 3 primary melanomas and in 2 melanocytic nevi, corresponding to a relatively low prevalence (3.7% and 7.1%, resp.). The pathogenic role of DLEC1 215N mutation is unclear. However, since the mutation has not been previously described in general population, its involvement in nevogenesis and melanoma progression remains a possibility to be clarified in future studies.

BRAF/NRAS Mutation Frequencies Among Primary Tumors and Metastases in Patients With Melanoma

The prevalence of BRAF, NRAS, and p16CDKN2A mutations during melanoma progression remains inconclusive. We investigated the prevalence and distribution of mutations in these genes in different melanoma tissues. In all, 291 tumor tissues from 132 patients with melanoma were screened. Paired samples of primary melanomas (n = 102) and synchronous or asynchronous metastases from the same patients (n = 165) were included. Tissue samples underwent mutation analysis (automated DNA sequencing). Secondary lesions included lymph nodes (n = 84), and skin (n = 36), visceral (n = 25), and brain (n = 44) sites. BRAF/NRAS mutations were identified in 58% of primary melanomas (43% BRAF; 15% NRAS); 62% in lymph nodes, 61% subcutaneous, 56% visceral, and 70% in brain sites. Mutations were observed in 63% of metastases (48% BRAF; 15% NRAS), a nonsignificant increase in mutation frequency after progression from primary melanoma. Of the paired samples, lymph nodes (93% consistency) and visceral metastases (96% consistency) presented a highly similar distribution of BRAF/NRAS mutations versus primary melanomas, with a significantly less consistent pattern in brain (80%) and skin metastases (75%). This suggests that independent subclones are generated in some patients. p16CDKN2A mutations were identified in 7% and 14% of primary melanomas and metastases, with a low consistency (31%) between secondary and primary tumor samples. In the era of targeted therapies, assessment of the spectrum and distribution of alterations in molecular targets among patients with melanoma is needed. Our findings about the prevalence of BRAF/NRAS/p16CDKN2A mutations in paired tumor lesions from patients with melanoma may be useful in the management of this disease.

Abstract 3677: Pattern and distribution of BRAF/NRAS and P16CDKN2A mutations among primary an secondary lesions in melanoma patients

Abstract Background: Mutations of NRAS and BRAF genes have been identified with high frequency in nevi, cutaneous melanomas, and melanoma metastases. Prevalence of such mutations during the disease progression phases and among the different types of metastasis still remains inconclusive. Methods: A total of 275 tumour tissues from 116 melanoma patients were screened for mutations; among them, paired samples of microdissected primary melanomas (N=92) and synchronous or asynchronous metastases (N=156) from same patients were included. Tissue samples underwent mutation analysis by automated DNA sequencing. Secondary lesions were from: lymph nodes (LM; N=77), skin (SM; N=36), visceral (VM; N=23) and brain (BM; N= 44) sites. The full coding sequences and splice junctions of p16CDKN2A (exons 1, 2, and 3) and NRAS (exons 2 and 3) genes as well as the entire sequence at the exon 15 of the BRAF gene were screened for mutations by direct sequencing on automated fluorescence-cycle sequencer (ABIPRISM 3130, Applied Biosystems, Foster City, CA). Results: Overall, mutations were identified in 56/95 (59%) primary melanomas [43% BRAF - 16% NRAS], 49/77 (64%) lymph nodes [48% BRAF - 16% NRAS], 22/36 (61%) subcutaneous metastases [53% BRAF - 8% NRAS], 13/23 (57%) visceral metastases [43% BRAF - 13% NRAS], and 31/44 (70%) brain metastases [48% BRAF - 23% NRAS]. Overall, a slight and not significant increase in mutation frequency after progression from primary melanoma was observed in our series: 115/180 (64%) mutated metastases [48% BRAF - 16% NRAS]. Considering the paired samples from the same patients, LM (92% consistency) and VM (96% consistency) presented a highly similar prevalence and distribution of BRAF/NRAS mutations in comparison with primary melanomas, whereas a discontinuous pattern of mutations was detected in BM (80% consistency) or, mostly, SM (75% consistency). Occurrence of distinct mutation distribution between primary melanomas and correspondent metastases suggests that independent subclones have been generated in a limited fraction of patients. The rate of mutations in p16CDKN2A gene was found to steadily increase moving from primary melanomas (5/69; 7%) to melanoma metastases (21/144; 15%), with the highest prevalence of p16CDKN2A alterations (18/29; 62%) in melanoma cell lines Conclusions: Our results provide further clues about the impact of NRAS and BRAF mutations among the different stages of melanoma progression. Moreover, we confirmed that p16CDKN2A mutation rates are increasing during disease progression. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3677. doi:1538-7445.AM2012-3677

ER, HER2, and TOP2A expression in primary tumor, synchronous axillary nodes, and asynchronous metastases in breast cancer

ER, HER2, and TOP2A expression in primary tumor, synchronous axillary nodes, and asynchronous metastases in breast cancer

Long-Term Survival after Adrenalectomy for Asynchronous Metastasis of Bladder Cancer to the Bilateral Adrenal Glands

Isolated adrenal metastasis of bladder cancer, particularly the bilateral, is quite rare. Systemic chemotherapy is the treatment of choice for metastatic urothelial carcinoma. However, despite initially promising response rates of approximately 45%–71%, most tumors eventually show progression, and the median survival time following chemotherapy regimen is approximately 14-15 months. Recently, favorable results of surgery for metastatic urothelial carcinoma have been reported. Here, we report a rare case of asynchronous metastasis of bladder cancer to the bilateral adrenal glands with long-term survival after bilateral adrenalectomy. A 69-year-old man underwent radical cystoprostatectomy and ileal conduit urinary diversion for invasive bladder cancer. Ten months later, left adrenalectomy was performed for a left adrenal tumor, revealing metastatic urothelial carcinoma. After adjuvant chemotherapy, a tumor in the right adrenal gland was detected. Right adrenalectomy was done, and the tumor was also found to be metastatic urothelial carcinoma. The patient had an uneventful recovery after starting steroid replacement therapy. Three years later, he was doing well and had no evidence of recurrence. Adrenalectomy for isolated adrenal metastasis of urothelial carcinoma may be a reasonable option, even if such metastases are bilateral.

原発巣術後16年目に異時性肝転移を切除した腎カルチノイドの1例

症例は，70歳，女性．平成7年1月に右腎摘出術を施行され，腎細胞癌と診断された．平成22年4月に腹部CT上肝S8に約4cm大の腫瘤を指摘され，当院内科にて肝生検施行された．その結果，肝カルチノイドと診断され，同年7月当科にて肝S8部分切除施行した．摘出腫瘍は，約4×3cmの皮膜を有する境界明瞭な結節性病変で，肝被膜への浸潤もなく，ごく一部でわずかな血管侵襲を認めるのみであった．転移性肝カルチノイドを疑い，原発巣検索のため，平成7年の摘出腎の再検討を行った結果，腎カルチノイドであったことが判明した．腎カルチノイドは非常に稀で1)，その異時性肝転移の切除報告は，われわれの調べ得る限りでは無かった．また，カルチノイド腫瘍は，経過観察期間を過ぎて再発・転移をきたす可能性もあると考えられた．