Advances in the Characterization of Circulating Tumor Cells in Metastatic Breast Cancer: Single Cell Analyses and Interactions, and Patient-Derived Models for Drug Testing.

Metastasis is the major cause of breast cancer death worldwide. In metastatic breast cancer, circulating tumor cells (CTCs) can be captured from patient blood samples sequentially over time and thereby serve as surrogates to assess the biology of surviving cancer cells that may still persist in solitary or multiple metastatic sites following treatment. CTCs may thus function as potential real-time decision-making guides for selecting appropriate therapies during the course of disease or for the development and testing of new treatments. The heterogeneous nature of CTCs warrants the use of single cell platforms to better inform our understanding of these cancer cells. Current techniques for single cell analyses and techniques for investigating interactions between cancer and immune cells are discussed. In addition, methodologies for growing patient-derived CTCs in vitro or propagating them in vivo to facilitate CTC drug testing are reviewed. We advocate the use of CTCs in appropriate microenvironments to appraise the effectiveness of cancer chemotherapies, immunotherapies, and for the development of new cancer treatments, fundamental to personalizing and improving the clinical management of metastatic breast cancer.

Bisphosphonates as a therapeutic choice for multifocal epithelioid hemangioma of bone: A case report.

RATIONALE: Epithelioid hemangioma (EH) of bone is an intermediate vascular tumor that can be locally aggressive. The optimum management of multifocal EH of bone is not well delineated. We described our experience treating one patient with multifocal EH of bone in an effort to document the effect of bisphosphonates in bone EH. PATIENT CONCERNS: In this report, a 53-year old male patient presented with back pain which was initially been diagnosed of multiple bone metastatic carcinoma by 18F-FDG PET/CT scan and bone scintigraphy. DIAGNOSIS: CT-guided bone biopsy of ilium indicated that puncture tissue had irregular hyperplasia of thick and thin-walled blood vessels, immunohistochemistry revealed positive staining for CD31 and CD34, negative for CAMTA-1, PCK and EMA, which confirmed the diagnosis of multiple EH. INTERVENTIONS: The patient was treated with 4 times of intravenous Zometa (zoledronate, 4 mg each time) with average three-month interval. Bone metabolic markers including serum bone specific alkaline phosphatase (BALP) and type I collagen cross-linked C-terminal telopeptide (CTX) levels were closely monitored before and after use of bisphosphonates each time. OUTCOME: BALP and CTX were significantly lowered following intravenous Zometa and the back pain improved with integrated therapy including bone graft fusion internal fixation surgery and vertebroplasty. CONCLUSIONS: EH of multiple bones responded favorably to intravenous Zometa with improvement of bone metabolic markers. After 1 year on follow-up, the patient was doing well with no significant pain. We suggest that bisphosphonates should be considered in the treatment of multifocal osteolytic EH of bone.

The ongoing French metastatic breast cancer (MBC) cohort: the example-based methodology of the Epidemiological Strategy and Medical Economics (ESME).

PURPOSE: The currently ongoing Epidemiological Strategy and Medical Economics (ESME) research programme aims at centralising real-life data on oncology care for epidemiological research purposes. We draw on results from the metastatic breast cancer (MBC) cohort to illustrate the methodology used for data collection in the ESME research programme. PARTICIPANTS: All consecutive ≥18 years patients with MBC treatment initiated between 2008 and 2014 in one of the 18 French Comprehensive Cancer Centres were selected. Diagnostic, therapeutic and follow-up data (demographics, primary tumour, metastatic disease, treatment patterns and vital status) were collected through the course of the disease. Data collection is updated annually. FINDING TO DATE: With a recruitment target of 30 000 patients with MBC by 2019, we currently screened a total of 45 329 patients, and >16 700 patients with a metastatic disease treatment initiated after 2008 have been selected. 20.7% of patients had an hormone receptor (HR)-negative MBC, 73.7% had a HER2-negative MBC and 13.9% were classified as triple-negative BC (ie, HER2 and HR status both negative). Median follow-up duration from MBC diagnosis was 48.55 months for the whole cohort. FUTURE PLANS: These real-world data will help standardise the management of MBC and improve patient care. A dozen of ancillary research projects have been conducted and some of them are already accepted for publication or ready to be issued. The ESME research programme is expanding to ovarian cancer and advanced/metastatic lung cancer. Our ultimate goal is to achieve a continuous link to the data of the cohort to the French national Health Data System for centralising data on healthcare reimbursement (drugs, medical procedures), inpatient/outpatient stays and visits in primary/secondary care settings. TRIAL REGISTRATION NUMBER: NCT03275311; Pre-results.

A Novel Multimodal NIR-II Nanoprobe for the Detection of Metastatic Lymph Nodes and Targeting Chemo-Photothermal Therapy in Oral Squamous Cell Carcinoma.

Current surgical treatment for oral squamous cell carcinoma (OSCC) must be as precise as possible to fully resect tumors and preserve functional tissues. Thus, it is urgent to develop efficient fluorescent probes to clearly identify tumor delineation, as well as metastatic lymph nodes. Chemo-photothermal therapy combination attracted a growing attention to increase anti-tumor effect in various types of cancer, including OSCC. In the present study, we designed a multimodal NIR-II probe that involves combining photothermal therapy with chemotherapy, imaging OSCC tumors and detecting metastatic lymph nodes. Methods: In this study, we synthesized a novel near infrared (NIR)-II probe named TQTPA [4,4'-((6,7-bis(4-(hexyloxy)phenyl)-[1,2,5]thiadiazolo [3,4-g]quinoxaline-4,9-diyl)bis(thiophene-5,2-diyl))bis(N,N-diphenylaniline)] via the Suzuki reaction and prepared multimodal nanoparticles (NPs) loading TQTPA and cis-dichlorodiammine platinum (CDDP) (HT@CDDP) by hyaluronic acid. The characteristics of the NPs, including their photothermal and imaging capabilities were investigated in vitro and in vivo. Their anti-tumor efficacy was evaluated using orthotopic, tongue tumor-bearing, nude mice. Results: The NPs possessed good stability and water solubility and were pH/hyaluronidase sensitive. The good tissue penetration quality and active targeting ability enabled the NPs to draw the outline of orthotopic tongue tumors and metastatic lymph nodes as small as 1 mm in nude mice by IR-808 under NIR exposure. In vitro and in vivo experiments validated the biocompatibility and low systematic toxicity of the NPs. At the same time, the NPs acted as multimodal therapy agents, combining photothermal therapy with chemotherapy. Conclusion: With a good imaging capability and anti-tumor efficacy, our NPs successfully outlined orthotopic tongue tumors and metastatic lymph nodes as well as enabled chemo-photothermal therapy combination. Our study established a solid foundation for the application of new clinical diagnosis and treatment patterns in the future.

Risk factors for metastatic prostate cancer: A sentinel event case series.

BACKGROUND: Root cause analysis is a technique used to assess systems factors related to "sentinel events"-serious adverse events within healthcare systems. This technique is commonly used to identify factors, which allowed these adverse events to occur, to target areas for improvement and to improve health care delivery systems. We sought to apply this technique to men presenting with metastatic prostate cancer (PCa). METHODS: We performed an in-depth case series analysis of 15 patients, who presented with metastatic disease at Johns Hopkins Sidney Kimmel Comprehensive Cancer Center using root cause analysis to refine a list of health system factors that lead to late stage presentation in the current era. RESULTS: Key factors in late diagnosis of PCa included lack of insurance, lack of routine PSA testing, comorbidities, reticence of patients to follow up actionable PSA, and aggressive disease. Three patients had aggressive disease that would not have been discovered at an early stage in the disease process, despite routine screening. However, analysis of the remaining 12 patients illuminated health system factors led to missing important diagnostic information, which might have led to diagnosis of PCa at a curable stage. CONCLUSIONS: The cases help highlight the need for systems based approaches to early diagnosis of PCa. A heterogeneous group of barriers to early diagnosis were identified in our series of patients including economic, health systems, and cultural factors. These findings underscore the need for individualized approaches to preventing delayed diagnosis of PCa. While limited by our single-institution scope, this approach provides a model for research and quality improvement initiatives to identify modifiable systems factors impeding appropriate diagnoses of PCa.

[Interdisciplinary Recommendations for the Treatment of Metastatic Renal Cell Carcinoma]. / Interdisziplinäre Empfehlungen zur Behandlung des metastasierten Nierenzellkarzinoms .

Thanks to the use of targeted therapies, the prognosis of patients with metastatic renal cell carcinoma (mRCC) has improved significantly. A median overall survival of more than 2 years is a realistic claim. These improvements are also reflected in recent discussions about 3 and more lines of therapy.Sunitinib, pazopanib, the combination of bevacizumab and interferon alpha, and temsirolimus are approved for first-line therapy of mRCC. Sunitinib and pazopanib are also approved for second-line therapy, which, for pazopanib, is confined to the use after cytokine failure. Everolimus (after tyrosine kinase inhibitor (TKI) treatment), sorafenib (after cytokines) and axitinib (after treatment with sunitinib or cytokines) are other compounds available for second-line therapy.3 new substances have recently been approved for second-line therapy: Nivolumab, cabozantinib, and lenvatinib combined with everolimus can be used after VEGF-targeted treatment has failed. It is for the first time that targeted immunotherapy and a combination of targeted substances are available for the treatment of mRCC.There is no new insight as to an optimal sequence therapy. Study results from a phase III trial suggest that the sequences sorafenib-sunitinib and sunitinib-sorafenib are equally effective.The purpose of an interdisciplinary expert meeting on RCC was to work out joint treatment recommendations based on current data and clinical experience and to integrate them into clinical routine practice. The results are presented in this publication.

Estudio descriptivo de costes en melanoma cutáneo de diferentes estadios / Cost of cutaneous melanoma by tumor stage: a descriptive analysis

INTRODUCCIÓN Y OBJETIVO: El conocimiento de los recursos utilizados en cada uno de los pasos del diagnóstico y tratamiento de las enfermedades es la base para poder optimizarlos. El melanoma cutáneo es un tipo tumoral en constante incremento, y con un importante coste asociado, por lo que se ha realizado un análisis actualizado de los costes de los procesos de su diagnóstico, terapia y seguimiento en función del estadio de la enfermedad. MÉTODOS: Se han elaborado tablas descriptivas de costes directos a partir de un modelo teórico basado en directrices nacionales e internacionales de manejo de pacientes con melanoma cutáneo dependiendo del momento de diagnóstico y evolución. Estas tablas permiten saber el coste de cada paciente individual y de todos aquellos en un mismo estadio. RESULTADOS: Los costes para un paciente en el primer ańo oscilan entre los 1.689 Euros del estadio I y los 88.268 Euros del estadio IV, las mayores diferencias se encuentran entre el estadio IA y el IB-IIA y entre el III y IV. Si comparamos los costes de los pacientes en estadio precoz con buena evolución con los de aquellos que recidivaron, las diferencias son considerables: llegan a ser de hasta 50 veces mayores en el primer ańo y 20 veces mayores en el seguimiento a 10 ańos. CONCLUSIONES: Los elevados costes del diagnóstico del melanoma cutáneo en estadio avanzado evidencian la necesidad de promocionar la prevención primaria y los programas de detección precoz. Nuestros resultados servirán como base para posteriores estudios de coste-efectividad

BACKGROUND AND OBJECTIVE: The basis for optimal resource allocation is an understanding of requirements during the diagnostic and treatment phases. Costs associated with the rising incidence of cutaneous melanoma are considerable. We undertook an up-to-date analysis of the cost of diagnosis, treatment, and follow-up according to tumor stage. METHODS: We constructed descriptive tables following a theoretical model of direct costs based on amounts published in directives for the Spanish national health system and in international guidelines for managing cutaneous melanoma according to stage at diagnosis and clinical course. The tables allowed us to calculate the cost of treating individual patients as well as the expected cost for all patients with tumors in the same stage. RESULTS: Individual patients would generate costs ranging from Euros 1689 (for a stage I tumor) to Euros 88, 268 (stage IV). The largest differences were between stages IA and IB-IIA and between stages III and IV. Costs differed greatly between patients with early-stage tumors and favorable outcomes and those with recurring tumors, which cost 50-fold more in the first year and 20-fold more after 10 years of follow-up. CONCLUSIONS: The high cost of diagnosing advanced-stage cutaneous melanoma calls attention to the need to promote primary prevention and early detection. Our findings provide the knowledge base for cost-effectiveness studies in this disease

Novel biomarkers in primary breast core biopsies to predict poor response to neoadjuvant chemotherapy and appearance of metastases.

Drug resistance has been one of the major obstacles limiting the success of cancer chemotherapy. In two thirds of breast cancer patients, large (>1cm) residual tumors are present after neoadjuvant chemotherapy (NCT). The residual tumor and involved nodes have been indicators of relapse and survival very important in breast cancer. The goal of this preliminary study was to assess the predictive significance of a panel of molecular biomarkers, related with the response to treatment or drug resistance to NCT, as determined on the diagnostic tumor. The expression of 22 proteins was examined using immunohistochemistry in tissue microarrays (TMA) from 115 patients of stage II-III breast cancer, treated with NCT. Among studied proteins, there are some that are anti-apoptotic, pro-proliferative, cancer stem cell markers and the Vitamin D Receptor. Other proteins are involved in the identification of molecular subtype, cell cycle regulation or DNA repair. Next, a predictive signature of poor response was generated from independent markers of predictive value. Tumors that expressed four or five conditions (biomarkers of chemoresistance with a determinated cutoff) were associated with a 9-fold increase in the chances of these patients of having a poor response to NCT. Additionally, we also found a worse prognostic signature, generated from independent markers of prognostic value. Tumors which expressed two or three conditions of worst prognostic, were associated with a 6-fold reduction in Distant Disease Free Survival. In conclusion, finding biomarkers of chemoresitance (ypTNM II-III) and metastases can become a stepping stone for future studies that will need to be assessed in a bigger scale.

Biopsy Procedures and Molecular Testing Utilization and Related Costs in Patients with Metastatic Lung Cancer.

BACKGROUND: Epidermal growth factor receptor (EGFR) gene mutations and anaplastic lymphoma kinase (ALK) gene rearrangements are key therapeutic targets for biomarker-driven treatment with an EGFR or ALK tyrosine kinase inhibitor (TKI) in patients with metastatic non-small cell lung cancer (NSCLC). To appropriately guide treatment decisions, since 2011, the National Comprehensive Cancer Network and the American Society of Clinical Oncology therefore recommend EGFR and ALK analysis in tumor samples obtained at the time of diagnosis in patients with non-squamous NSCLC. Currently, there are limited data on utilization patterns and cost of biopsy procedures and biomarker tests in patients with metastatic NSCLC who receive an EGFR or ALK TKI. OBJECTIVES: To (a) describe utilization patterns and costs associated with biopsy procedures and biomarker testing in patients with NSCLC who received erlotinib or crizotinib between 2009 and 2012 and (b) investigate the timing of these procedures relative to the erlotinib or crizotinib index date. METHODS: Adult patients with metastatic lung cancer were identified by ICD-9-CM diagnostic codes within the Truven Health Analytic MarketScan database. Patients were included in the analysis if they had an index erlotinib or crizotinib claim between January 1, 2009, and September 30, 2012 (index period) and were continuously enrolled for ≥ 12 months before the index claim. Because there is no specific ICD-9-CM diagnostic code for NSCLC, patients with metastatic lung cancer who received erlotinib or crizotinib were considered to have metastatic NSCLC. Using CPT and ICD-9-CM codes, lung biopsy procedures performed during the 24 months before or 12 months after the index claim date were identified. For every patient, biomarker testing claims for EGFR and ALK were identified using the molecular pathology stacked CPT code during the 2 months before or 1 month after the index date. The frequency of claims for biopsy procedures and biomarker testing was analyzed descriptively. The overall summary measures for biomarker testing, especially frequency of EGFR testing in patients receiving erlotinib, was also described as before and after 2011, the year when biomarker testing became part of the guidelines. Per patient and overall costs for biopsy procedures and biomarker testing were calculated from payer and patient perspectives. RESULTS: Of the 4,926 identified patients, 4,801 (97.5%) received erlotinib, and 125 (2.5%) received crizotinib. Biopsy procedure claims were identified for 3,579 (72.7%) patients, including 3,503 (73.0%) erlotinib recipients and 76 (60.8%) crizotinib recipients. Biomarker testing claims were identified for 675 (13.7%) patients, including 634 (13.2%) erlotinib recipients and 41 (32.8%) crizotinib recipients. Overall, most biomarker testing procedures (476 of 741) were identified in 435 (of 675) patients after year 2011. Also, among erlotinib recipients, percentage of patients receiving EGFR testing was increased over the index period. Per patient mean (SD) numbers of biopsy procedures and biomarker tests were 1.2 (1.1) and 0.2 (0.4), respectively. In the outpatient setting, per patient mean (SD) cost per biopsy procedure was $1,223 ($1,899) from the payer perspective and $60 ($147) from the patient perspective, whereas in the inpatient setting, it was $8,163 ($18,712) and $180 ($691), respectively. Among patients receiving at least 1 biomarker test, the per patient mean (SD) cost for the overall population was $891 ($1,062) and $43 ($229); for erlotinib recipients, it was $906 ($1,084) and $42 ($228); and for crizotinib recipients, it was $664 ($576) and $55 ($243) in payer and patient perspectives, respectively. CONCLUSIONS: This study provides insight into the use and cost of biopsy and biomarker testing procedures in patients with metastatic NSCLC. The low frequency of biomarker testing highlights the need for more awareness of testing to guide treatment decisions in these patients. Costs associated with biopsy procedures and biomarker testing provide insight into the economic impact on metastatic NSCLC patients treated with targeted therapy. DISCLOSURES: This study was sponsored by Merck & Co. Shinde is a study manager working for Merck under contract with AllSourcePPS, an Agile 1 company in Huntington Beach, California. Cao and Kothari are employees of Merck & Co., Kenilworth, New Jersey. Study concept and design were contributed primarily by Shinde and Kothari. Data analysis was performed by Cao. Data interpretation was performed by Shinde, Cao, and Kothari. Shinde wrote the manuscript with assistance from Cao and Kothari. The revision was completed primarily by Shinde and Kothari.

The expression and function of Frizzled-7 in human renal cell Carcinoma

Purpose: Wnt/b-catenin has emerged as an important signal pathway in renal cell carcinoma (RCC) pathogenesis. Frizzled 7 (Fzd7) is a member of Frizzled (Fzd) receptor family which binds with Wnt ligands and transduces canonical and non-canonical pathways. However, the expression of Fzd7 in human RCC is poorly investigated. Methods: 53 RCC tissues and peri-tumor tissues were collected from the patients treated with radical nephrectomy. The expression of Fzd7 was investigated by immunohistochemical staining. Three RCC cells were transfected with Fzd7shRNA and GFPshRNA to investigate the function of Fzd7 in RCC cells. Results: The immunohistochemical analysis showed that Fzd7 protein expression level was significantly increased in RCC tissues when compared with peri-tumor tissues, which suggested that Fzd7 might be involved in the formation of tumors. However, the Fzd7 expression was not correlated with clinicopathological parameters. Three RCC cell lines: 786-O, Caki-1, and OS-RC-2 also expressed Fzd7. With Fzd7 expression being interfered by shRNA, the RCC cell proliferation was mildly decreased. Wnt3a could stimulate the RCC cells proliferation, but the stimulation was decreased when Fzd7 expression was interfered. Restoring the Fzd7 expression led to the proliferation stimulation effect of Wnt3a being restored. Conclusions: This paper suggests that Fzd7 may act as one of the molecules that take part in the course of RCC formation. Fzd7 can be activated by Wnt3a to stimulate cell proliferation (AU)

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Patterns of First Recurrence in African American Patients with High Grade Epithelial Ovarian Carcinoma.

BACKGROUND/AIMS: The aim of this study is to compare the distribution of anatomic sites of first recurrence in African American (AA) patients with ovarian carcinoma compared to Caucasians. METHODS: Patients diagnosed with high-grade epithelial ovarian, fallopian tube or peritoneal carcinoma from 2007 to 2013 were identified. Patterns of recurrence were compared for AA and Caucasian patients. Progression-free survival (PFS) and overall survival (OS) were compared. RESULTS: A total of 238 patients were included - 210 Caucasians and 28 AAs. At a follow-up time of 28 months, AAs were more likely to have multiple anatomic sites of recurrence rather than a single site when compared to Caucasians (63.6 vs. 35.5%, p = 0.01). Time to first recurrence was shorter for AA patients (12 vs. 18 months, p < 0.01). PFS and OS did not differ. AA patients with multiple sites of first recurrence had a significantly shorter OS than Caucasian patients with multiple sites of first recurrence (24 vs. 30 months, p = 0.022). CONCLUSION: Patterns of first recurrence differ between AAs and Caucasians. AAs have shorter times to first recurrence and are more likely to have multiple anatomic sites involved. AA patients with multiple sites of recurrence have a shorter OS than Caucasian patients with multiple sites.

Variation in metastatic workup for patients with invasive breast cancer.

BACKGROUND: Despite guidelines, surgeons vary in the metastatic workup they order for their breast cancer patients. METHODS: Surgeons were surveyed as to their practices in ordering staging studies for their breast cancer patients using a Web-based survey. Nonparametric analyses were performed to determine factors associated with guideline adherence. RESULTS: Two hundred fifty-three surgeons responded to the survey; 55.8% had practices with ≥50% breast patients; 7.3% of respondents stated they always did a metastatic workup before surgery, 8.6% never did; only 52.4% ordered a metastatic workup only in patients with clinical stage III disease. Surgeons who had ≥50% breast-related practices were more likely to follow these guidelines (P = .031). Only 17% stated that a computed tomography chest/abdomen and bone scan was their "usual" metastatic workup. CONCLUSIONS: Nearly 40% of surgeons perform metastatic workup when they are not indicated, and few adhere to National Comprehensive Cancer Network guidelines in terms of the tests ordered.

Preclinical imaging and translational animal models of cancer for accelerated clinical implementation of nanotechnologies and macromolecular agents.

The majority of animal models of cancer have performed poorly in terms of predicting clinical performance of new therapeutics, which are most often first evaluated in patients with advanced, metastatic disease. The development and use of metastatic models of cancer may enhance clinical translatability of preclinical studies focused on the development of nanotechnology-based drug delivery systems and macromolecular therapeutics, potentially accelerating their clinical implementation. It is recognized that the development and use of such models are not without challenge. Preclinical imaging tools offer a solution by allowing temporal and spatial characterization of metastatic lesions. This paper provides a review of imaging methods applicable for evaluation of novel therapeutics in clinically relevant models of advanced cancer. An overview of currently utilized models of oncology in small animals is followed by image-based development and characterization of visceral metastatic cancer models. Examples of imaging tools employed for metastatic lesion detection, evaluation of anti-tumor and anti-metastatic potential and biodistribution of novel therapies, as well as the co-development and/or use of imageable surrogates of response, are also discussed. While the focus is on development of macromolecular and nanotechnology-based therapeutics, examples with small molecules are included in some cases to illustrate concepts and approaches that can be applied in the assessment of nanotechnologies or macromolecules.

Nodule and eminence on frenulum labii superioris: diagnostic markers for metastatic colorectal cancer.

OBJECTIVE: To determine whether the nodule and eminence on the frenulum labii superioris, location of Yinjiao (DU28) according to the meridian theory, could be used to prognosticate the recurrence of patients with colorectal cancer. METHODS: The data of 101 patients with colorectal cancer in Tianjin Medical University Cancer Institute and Hospital from May 2011 to November 2011 was analyzed. The photos of all patients' frenulum labii superioris were taken. Nodule and eminence on frenulum labii superioris were the positive standard. Biopsy and pathological testing for the nodule were carried out on one patient with large nodule on frenulum labii superioris. RESULTS: Patients with positive frenulum labii superioris had a higher risk of recurrence and/or metastasis than patients with negative frenulum labii superioris. There were no significant differences in diagnosis of recurrence and/or metastasis between the status of frenulum labii superioris and the traditional diagnostic criteria (P =0.238). The Kappa was 0.606 (P <0.001). The sensitivity was 76.0% and the specificity was 85.4%. The pathological report demonstrated that the nodule on frenulum labii superioris was mucosal excrescence with normal structure. CONCLUSION: Nodule and eminence on frenulum labii superioris are potential diagnostic markers for metastatic colorectal cancer.

Brain metastases.

PURPOSE OF REVIEW: Brain metastases are the most common neurologic complication related to systemic cancer. With continued improvements in systemic treatment, the incidence is expected to increase. This article reviews the clinical presentation, pathophysiology, prognostic factors, and treatment of metastatic brain tumors. RECENT FINDINGS: Brain metastases from systemic cancer are up to 10 times more common than primary malignant brain tumors and are a significant burden in the management of patients with advanced cancer. Common presenting symptoms include headache, focal weakness or numbness, mental status change, and seizure. Management and treatment of metastatic brain tumors is complex and dependent on several factors, including age, performance status, number of metastases at presentation, and status of systemic disease. At the time of diagnosis, most patients have more than one brain metastasis, and treatment has traditionally consisted of whole-brain radiation therapy (WBRT). For those patients with single brain metastases, aggressive local treatment with surgery or stereotactic radiosurgery (SRS) combined with WBRT has been shown to improve survival and neurologic outcomes compared with WBRT alone. In patients with a limited number of brain metastases, SRS alone is being increasingly explored as a treatment option that spares the upfront toxicity of WBRT. Currently, the role of chemotherapy is limited to experimental settings and salvage after radiation therapy. SUMMARY: Patients with brain metastases have complex needs and require a multidisciplinary approach in order to optimize intracranial disease control while maximizing neurologic function and quality of life. Patients with multiple metastases, uncontrolled systemic disease, and poor functional status are typically treated with WBRT alone, whereas surgery and SRS may be used for additional local control in a subset of patients with fewer tumors and good functional status. The incorporation of neuropsychological outcomes, neurologic function, and quality of life as end points in future studies will offer further guidance for providing comprehensive care to patients with metastatic brain tumors.

Should a routine metastatic workup be performed for all patients with pathologic N2/N3 breast cancer?

BACKGROUND: Node-positive breast cancer patients are at risk for metastatic disease. A routine metastatic workup might or might not be necessary for all patients with N2 or N3 diseases. The National Comprehensive Cancer Network guidelines recommend a metastatic workup for patients with T3N1 disease, yet no definitive recommendations are made for N2/N3 diseases. We hypothesized that for patients with operable pathologic N2/N3 diseases, a metastatic workup should only be considered for patients with T3/T4 lesions. STUDY DESIGN: Two hundred and fifty-six patients with pathologic N2/N3 diseases were identified from a prospective breast cancer database of 1,329 patients with stage 0 to III breast cancer. A metastatic workup included chest x-rays, bone scans, CT scans, and PET scans. Primary end point was incidence of stage IV disease at the time of diagnosis or within 1 month of definitive surgery. Statistical analysis included chi-square test, independent t-test, Kaplan-Meier Survival method, log-rank test, and Cox proportional hazard model. A p value ≤ 0.05 was considered statistically significant. RESULTS: There were 158 patients with N2 disease (62%) and 98 with N3 disease (38%). Overall, 16% had stage IV disease (N2 = 15%, N3 = 16%). There was no significant difference in age (p = 0.37), tumor size (p = 0.89), tumor grade (p = 0.09), estrogen-receptor status (p = 0.23), or progesterone-receptor status (p = 0.35) between the N2 and N3 groups. Incidences of stage IV disease were T0/T1, 0%; T2, 6%; T3, 22%; and T4, 36%. Multivariate analysis demonstrated that only T stage (p = 0.0006) and grade (p = 0.026) were independent predictors of overall survival. CONCLUSIONS: A metastatic workup is only indicated for N2/N3 patients with T3 or T4 primary lesions.

Tratamiento del paciente con carcinoma de próstata en progresión bioquímica resistente a castración / Treatment of the patient with castration-resistant biochemical progression of prostate cancer

El carcinoma de próstata resistente a castración (CPRC) se define como la progresión tumoral a pesar de unos niveles eficaces de castración. (testosterona sérica < 50 ng/dL). La progresión bioquímica requiere al menos dos incrementos sucesivos en la cifra de antígeno prostático específico (PSA), separados al menos una semana, y con un valor mínimo de 2 ng/mL. In pacientes con bloqueo androgénico completo, se debe suspender al antiandrógeno antes del diagnóstico de CPRC. El CPRC es una entidad heterogénea. El valor basal de PSA y la velocidad de PSA parecen ser los factores pronósticos más importantes en pacientes con recidiva bioquímica como única manifestación del CPRC. Algunos de estos pacientes pueden ser seguidos sin tratamiento hasta la progresión de la enfermedad. Debido a que un gran porcentaje de tumores que progresan a pesar de la castración siguen siendo hormonodependientes, el empleo de otras terapias hormonales ha sido el tratamiento preferido para la mayoría de estos pacientes. Junto con los inhibidores de la esteroidogénesis suprarrenal, se están investigando actualmente otros enfoques más novedosos para inhibir el efecto del receptor androgénico activado sobre la célula tumoral. Recientemente, ha habido un importante desarrollo de la inmunoterapia, que ha demostrado incrementar la supervivencia en pacientes con CPRC oligosintomáticos. La quimioterapia de primera y segunda línea en CPRC se asocia con incremento de supervivencia, pero generalmente se recomienda para pacientes con metástasis. Hasta que estén disponibles los resultados de ensayos clínicos actualmente en marcha, el tipo y secuencia de tratamientos para los pacientes con CPRC y recaída bioquímica debe realizarse de forma individualizada(AU)

Castration resistant prostatic carcinoma (CRPC) is defined as tumor progression despite an effective castration (serum testosterone levels < 50 ng/dL). Biochemical progression requires at least two successive increases from the previous lowest value of serum prostate-specific antigen (PSA) spaced at least a week, and with a minimum value of 2 ng/mL. In patients receiving complete androgen blockade, antiandrogen should be discontinued prior to diagnosis of CRPC. CPRC is a heterogeneous entity. Baseline PSA and PSA velocity seem to be the most important prognostic factors in patients with biochemical relapse as the only manifestation of CRPC. Some of these patients can be followed without treatment until disease progression. Because of a large proportion of tumors progressing under androgen deprivation therapy remain hormone-dependent, the use of other hormonal therapies has been the preferred treatment for the majority of these patients. Besides inhibitors of adrenal steroidogenesis, other novel hormonal approaches are currently under investigation to avoid the effect of the activated androgenic receptor on the tumor cell. In recent years there has been an important development of immunotherapy, which has demonstrated to increase survival in CRPC oligosymptomatic patients. First and second line chemotherapy in CRPC are associated with an increase in overall survival, but they are usually recommended for patients with metastases. Until the results of ongoing trials are available, the type and timing of the treatment for patients with CRPC and biochemical recurrence should be individualized(AU)

Role of ¹8F 2-fluoro-2-deoxyglucose positron emission tomography in upper gastrointestinal malignancies.

The role of whole-body FDG [((18)F) 2-fluoro-2-deoxyglucose] positron emission tomography (PET) scanning as an imaging modality in the management of patients with malignancy has evolved enormously over the past two decades. FDG-PET has demonstrated significant efficacy in the staging, prognostication and detection of occult metastatic disease in malignancies of the gastrointestinal tract, in addition to assessment of the response to cytotoxic chemotherapy in a more timely manner than has traditionally been possible by more conventional imaging tools. The sensitivity and specificity of FDG-PET for the detection and staging of malignancy depend not only on the site and size of the primary tumor and metastases, but also on histological cell type, reflecting underlying disparities in glucose metabolism. The metabolic response to neo-adjuvant chemotherapy or to chemo-radiotherapy in cancers of the gastro-esophageal junction or stomach has been demonstrated in several prospective studies to correlate significantly with both the histological tumor response to treatment and with consequent improvements in overall survival. This may offer a future paradigm of personalized treatment based on the PET response to chemotherapy. FDG-PET has been less successful in efforts to screen for and detect recurrent upper gastrointestinal malignancies, and in the detection of low volume metastatic peritoneal disease. Efforts to improve the accuracy of PET include the use of novel radiotracers such as ((18)F) FLT (3-deoxy-3-fluorothymidine) or (11)C-choline, or fusion PET-CT with concurrent high-resolution computed tomography. This review focuses on the role of FDG-PET scanning in staging and response assessment in malignancies of the upper gastrointestinal tract, specifically gastric, esophageal and pancreas carcinoma.

Assessing second echelon lymph nodes during sentinel lymph node biopsy: can we have more accurate axillary treatment for breast cancer patients?

Sentinel lymph node biopsy (SLNB) is the standard treatment for breast cancer patients with clinically negative axilla. For patients with positive sentinel lymph nodes, axillary lymph node dissection (ALND) was required. However, approximately a half of the SLNs-positive patients were found to have clear axillary lymph nodes after ALND, indicating that they had received unnecessary ALND without therapeutic benefit. Therefore, we propose a hypothesis for solution of this clinical problem. We defined the second echelon lymph nodes (SELNs) as those nodes receiving lymphatic drainage directly from the SLNs. For patients with positive-SLNs, SELNs can be biopsy and assessed. If SELNs are negative, no more ALND was needed in these patients even if their SLNs are positive. If our hypothesis were confirmed to be true, we can tailored our axillary treatment to more breast cancer patients, avoiding unnecessary ALND and its complications.

Impressive efficacy of sorafenib in a patient with an hepatocellular carcinoma and a portal vein thrombosis associated with a metastatic ENT cancer.

Sorafenib, a new antiangiogenic and antiproliferative agent, is currently used for hepatocellular and renal cell carcinoma. We report here the case of a patient with two cancers, a locally advanced cancer of the piriform sinus and a hepatocellular carcinoma, who was given sorafenib. Tumor response of both cancers might suggest that sorafenib could be effective against head and neck cancer.