[Peritoneal carcinomatosis secondary to CUP syndrome : Diagnosis and indications for multimodal treatment]. / Peritonealkarzinose beim CUP­Syndrom : Diagnostik und Indikationsstellung für die multimodale Therapie.

CLINICAL PROBLEM: Peritoneal carcinomatosis secondary to cancer of unknown primary (CUP) syndrome is a rare entity for which there are no uniform treatment recommendations or guidelines. The median survival time is 3 months. DIAGNOSIS: Computed tomography (CT), magnetic resonance imaging (MRI), and 18F­FDG positron emission tomography (PET)/CT are valid imaging modalities for the detection of peritoneal carcinomatosis. The sensitivity of all techniques is highest for large, macronodular peritoneal carcinomatosis manifestations. A limitation of all imaging techniques is limited and small-nodular peritoneal carcinomatosis. Also, peritoneal metastasis in the small bowel mesentery or diaphragmatic domes can only be visualized with low sensitivity. Therefore, exploratory laparoscopy should be considered as the next diagnostic step. In half of these cases an unnecessary laparotomy can be avoided, because the laparoscopy revealed diffuse, small-nodule involvement of the small bowel wall and thus an irresectable situation. TREATMENT: In selected patients, performing complete cytoreduction followed by hyperthermic intra-abdominal chemotherapy (HIPEC) is a good therapeutic option. Therefore, the identification of the extent of peritoneal tumor manifestation as accurately as possible is important for the definition of the increasingly complex oncological therapy strategies.

Validation of a Transcriptome-Based Assay for Classifying Cancers of Unknown Primary Origin.

INTRODUCTION: Cancers assume a variety of distinct histologies, and may originate from a myriad of sites including solid organs, hematopoietic cells, and connective tissue. Clinical decision-making based on consensus guidelines such as the National Comprehensive Cancer Network (NCCN) is often predicated on a specific histologic and anatomic diagnosis, supported by clinical features and pathologist interpretation of morphology and immunohistochemical (IHC) staining patterns. However, in patients with nonspecific morphologic and IHC findings-in addition to ambiguous clinical presentations such as recurrence versus new primary-a definitive diagnosis may not be possible, resulting in the patient being categorized as having a cancer of unknown primary (CUP). Therapeutic options and clinical outcomes are poor for patients with CUP, with a median survival of 8-11 months. METHODS: Here, we describe and validate the Tempus Tumor Origin (Tempus TO) assay, an RNA-sequencing-based machine learning classifier capable of discriminating between 68 clinically relevant cancer subtypes. Model accuracy was assessed using primary and/or metastatic samples with known subtype. RESULTS: We show that the Tempus TO model is 91% accurate when assessed on both a retrospectively held out cohort and a set of samples sequenced after model freeze that collectively contained 9210 total samples with known diagnoses. When evaluated on a cohort of CUPs, the model recapitulated established associations between genomic alterations and cancer subtype. DISCUSSION: Combining diagnostic prediction tests (e.g., Tempus TO) with sequencing-based variant reporting (e.g., Tempus xT) may expand therapeutic options for patients with cancers of unknown primary or uncertain histology.

Metástasis cervical con primario desconocido, cambios en los paradigmas: revisión sobre el enfrentamiento clínico, estudio y tratamiento / Cervical metastases from unknown primary tumor, paradigm changes: review on clinical confrontation, study and treatment

Resumen En adultos, una masa cervical detectada mediante examen físico o un estudio de imagen puede ser la única manifestación de un cáncer proveniente de cabeza y cuello. Un retraso en el diagnóstico repercute en el pronóstico de la enfermedad, por lo que debe haber un alto índice de sospecha. Las metástasis cervicales con primario desconocido (MCCPD) son tumores metastásicos en los que el estudio diagnóstico no logró identificar el sitio primario del cáncer, con una histología predominantemente de tipo escamosa. Según algunos estudios, el origen más frecuente resultó ser la orofaringe, incluyendo amígdala palatina y base de lengua. Factores de riesgo conocidos son edades avanzadas, consumo de tabaco y de alcohol. Actualmente, la infección por el virus del papiloma humano (VPH) está teniendo un rol cada vez más importante como factor de riesgo, formando parte de entre 20%-25% de los cánceres de cabeza y cuello. Al enfrentarse a un paciente con masa cervical es importante realizar una completa anamnesis y examen físico acucioso para detectar cualquier elemento sugerente de malignidad. Se debe complementar con nasofibroscopía para visualizar estructuras que no alcanzan a evaluarse en el examen habitual. También se puede orientar la búsqueda del primario desconocido en base a los patrones de drenaje linfático. Dentro del estudio complementario se puede comenzar con una tomografía computada (TC) y se puede considerar también el ultrasonido o un PET/TC. Si con esto aún no se logra definir el primario, continuar con una punción aspirativa con aguja fina (PAAF), luego biopsia core que consiste en tomar una muestra del centro de la lesión guiada por ecografía, si fuese necesario, incluyendo inmunohistoquímica para VPH; ambos estudios histológicos son preferibles en vez de una biopsia abierta debido al menor riesgo de diseminación y complicaciones. El siguiente paso incluye estudio endoscópico y biopsias bajo anestesia. El tratamiento de los pacientes con MCCPD, va a depender de factores relacionados con el estadio de la enfermedad: desde cirugía o radioterapia (RT) únicas, cirugía más RT, y en algunos casos quimioterapia. Se recomienda seguimiento clínico frecuente durante los primeros años y con imágenes dentro de los 6 primeros meses postratamiento.

Abstract In adults, a cervical mass detected by physical examination or an imaging study may be the only manifestation of cancer from the head and neck. A delay in the diagnosis affects the prognosis of the disease, so there must be a high index of suspicion. Cervical metastases from unknown primary tumor (CUP) are metastatic tumors in which the diagnostic study failed to identify the primary site of cancer, with predominantly squamous histology. According to some studies, the most frequent origin was the oropharynx, including palatine tonsil and tongue base. Known risk factors are advanced ages, tobacco and alcohol consumption. Currently, human papilloma virus (HPV) infection is playing an increasingly important role as a risk factor, being the cause of between 20-25% of cancers of the head and neck. When confronting a patient with cervical mass it is important to carry out a complete anamnesis and a thorough physical examination to detect any element suggestive of malignancy. Physical examination could be complemented with a flexible nasal endoscopic to evaluate structures that can not be evaluated in the habitual examination. The search for the unknown primary can also be oriented based on lymphatic drainage patterns. Within the complementary evaluations, one can start with a study of images such as computed tomography (CT) or magnetic resonance imaging (MRI) with contrast, and also could consider ultrasound or PET/CT. If the primary can not be defined yet, fine needle aspiration (FNAP) can be the next choice and then a core biopsy that consisting of taking a sample from the center of the ultrasound-guided lesion, if necessary, including immunohistochemistry for HPV; both histological studies are preferable to an open biopsy because of the lower risk of complications. The next step searching for the primary includes endoscopic study and biopsies under anesthesia. Regarding to the management of patients with CUP, it will depend on factors related to the stage of the disease: from surgery or radiotherapy (RT) only, surgery and RT, and in some cases chemotherapy. Frequent clinical follow-up is recommended during the first years and images within the first 6 months after treatment.

Population-based study of survival for women with serous cancer of the ovary, fallopian tube, peritoneum or undesignated origin - on behalf of the Swedish gynecological cancer group (SweGCG).

OBJECTIVE: The aim of the study was to determine survival outcome in patients with serous cancer in the ovary, fallopian tube, peritoneum and of undesignated origin. METHODS: Nation-wide population-based study of women≥18years with histologically verified non-uterine serous cancer, included in the Swedish Quality Registry for primary cancer of the ovary, fallopian tube and peritoneum diagnosed 2009-2013. Relative survival (RS) was estimated using the Ederer II method. Simple and multivariable analyses were estimated by Poisson regression models. RESULTS: Of 5627 women identified, 1246 (22%) had borderline tumors and 4381 had malignant tumors. In total, 2359 women had serous cancer; 71% originated in the ovary (OC), 9% in the fallopian tube (FTC), 9% in the peritoneum (PPC) and 11% at an undesignated primary site (UPS). Estimated RS at 5-years was 37%; for FTC 54%, 40% for OC, 34% for PPC and 13% for UPS. In multivariable regression analyses restricted to women who had undergone primary or interval debulking surgery for OC, FTC and PPC, site of origin was not independently associated with survival. Significant associations with worse survival were found for advanced stages (RR 2.63, P<0.001), moderate (RR 1.90, P<0.047) and poor differentiation (RR 2.20, P<0.009), neoadjuvant chemotherapy (RR1.33, P<0.022), residual tumor (RR 2.65, P<0.001) and platinum single (2.34, P<0.001) compared to platinum combination chemotherapy. CONCLUSION: Survival was poorer for serous cancer at UPS than for ovarian, fallopian tube and peritoneal cancer. Serous cancer at UPS needs to be addressed when reporting and comparing survival rates of ovarian cancer.

Pseudomyxoma Peritonei of Extra-Appendiceal Origin: A Comparative Study.

BACKGROUND: Pseudomyxoma peritonei (PMP) usually originates from appendiceal neoplasms and, less commonly, from extra-appendiceal lesions. To date, the clinical and therapeutic implications of extra-appendiceal origin are largely unknown. METHODS: A prospective database of 225 PMP patients uniformly treated by cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) was reviewed to identify cases with extra-appendiceal primaries. Histologically, negative appendix defined extra-appendiceal origin. Clinical, pathological, and immunohistochemical features (cytokeratin [CK]-20, CK-7, CDX-2, MUC-2, MUC-5A) were correlated with the site of origin. PMP was categorized into low or high grade, according to the 2010 World Health Organization (WHO) classification. The main independent variable for survival analysis was appendiceal versus extra-appendiceal primary. RESULTS: In 19 patients (8.4 %), PMP origin was the ovary (n = 9), uterine cervix (n = 1), mature cystic teratomas (n = 4), and unknown (n = 5). Appendiceal and extra-appendiceal PMP groups were comparable for all characteristics, except for a prevalence of females in the latter. Median follow-up was 64.1 months (95 % confidence interval [CI] 53.9-80.1), and 10-year overall survival was 63.4 % (median 148.2 months; 95 % CI 131.2-165.2) for appendiceal PMP, and 62.0 % (median not reached) for extra-appendiceal PMP. The difference was not significant at univariate ( p = 0.297) and multivariate analysis (hazard ratio 1.51, 95 % CI 0.78-3.14; p = 0.278). High-grade peritoneal histology (p = 0.007), prior systemic chemotherapy (p = 0.003), more than four visceral resections (p = 0.011), and incomplete cytoreduction (p = 0.021) independently correlated with poorer survival. CONCLUSIONS: Clinical-pathological features of PMP, and outcome after CRS/HIPEC, did not differ according to the primary site, thus suggesting that PMP is a relatively homogeneous disease that can be produced by a range of histopathologic entities. Extra-appendiceal origin does not contraindicate CRS/HIPEC.

Occult Uterine Sarcoma and Leiomyosarcoma: Incidence of and Survival Associated With Morcellation.

OBJECTIVE: To estimate the incidence of occult uterine sarcoma and leiomyosarcoma in hysterectomies for leiomyomas and the risk associated with their morcellation. METHODS: We conducted a population-based cohort study. All uterine sarcomas from 2006-2013 in an integrated health care system were identified. Age- and race-specific incidences of occult uterine sarcoma were calculated. Kaplan-Meier survival analysis was performed. Crude and adjusted risk ratios of recurrence and death associated with morcellation at 1, 2, and 3 years were estimated using Poisson regression with inverse probability weighting. RESULTS: There were 125 hysterectomies with occult uterine sarcomas identified among 34,728 hysterectomies performed for leiomyomas. The incidence of occult uterine sarcoma and leiomyosarcoma was 1 of 278 or 3.60 (95% confidence interval [CI] 2.97-4.23) and 1 of 429 or 2.33 (95% CI 1.83-2.84) per 1,000 hysterectomies. For stage I leiomyosarcoma (n=111), eight (7.2%) were power and 27 (24.3%) nonpower-morcellated. The unadjusted 3-year probability of disease-free survival for no morcellation, power and nonpower morcellation was 0.54, 0.19, and 0.51, respectively (P=.15); overall survival was 0.64, 0.75, and 0.68, respectively (P=.97). None of the adjusted risk ratios for recurrence or death were significant except for death at 1 year for power and nonpower morcellation groups combined (6/33) compared with no morcellation (4/76) (5.12, 95% CI 1.33-19.76, P=.02). We had inadequate power to infer differences for all other comparisons including 3-year survival and power morcellation. CONCLUSION: Morcellation is associated with decreased early survival of women with occult leiomyosarcomas. We could not accurately assess associations between power morcellation and 3-year survival as a result of small numbers.

Effect of host, tumor, diagnostic, and treatment variables on outcomes in a large cohort with Merkel cell carcinoma.

IMPORTANCE: Merkel cell carcinoma (MCC) is a rare, aggressive, neuroendocrine-derived skin cancer with high rates of recurrence and associated mortality. Few published studies have used comprehensive patient data and long-term follow-up to examine factors that predict MCC outcomes. OBJECTIVE: To characterize MCC in a large defined-population cohort and analyze predictors of disease recurrence and survival. SETTING, DESIGN, AND PARTICIPANTS: Retrospective cohort study of 218 patients with MCC from the cancer registry of Kaiser Permanente Northern California, a large integrated health care delivery system. Patients were diagnosed as having MCC and followed up from January 1, 1995, through December 31, 2009. We examined host (age, sex, race, and immunosuppression), tumor (anatomic site, size, and extent), diagnostic (results of imaging and pathologic nodal evaluation), and treatment (surgery, radiation therapy, and chemotherapy) variables for their association with MCC outcomes. EXPOSURE: Host, tumor, diagnostic, and treatment factors. MAIN OUTCOMES AND MEASURES: Recurrence (locoregional and distant) of MCC and patient survival (overall and MCC specific). RESULTS: We estimated adjusted hazard ratios (AHRs) and 95% CIs for outcomes using Cox proportional hazards regression models. After adjustment for host, tumor, diagnostic, and treatment variables, tumor extent (categorized as local, regional, and distant) remained significantly associated with all outcomes. Immunosuppression was associated with higher MCC-specific mortality (AHR, 4.9 [95% CI, 1.7-14.4]), and an unknown primary site was associated with a lower risk for distant metastasis (0.1 [0.0-0.7]) and improved survival (0.4 [0.2-0.9]). Pathological nodal evaluation was associated with a lower risk for metastasis (AHR, 0.2 [95% CI, 0.0-1.0]) and improved survival. Radiation treatment was associated with a decreased risk for locoregional recurrence (AHR, 0.3 [95% CI, 0.1-0.6]), whereas chemotherapy was not associated with any alteration in outcomes. CONCLUSIONS AND RELEVANCE: Tumor site and extent, results of pathologic nodal evaluation, and the presence of radiation treatment were associated with MCC recurrence. Immunosuppression, tumor extent, and results of pathologic nodal evaluation were associated with MCC-specific survival, whereas chemotherapy was not associated with any outcomes. Our findings may help to inform diagnostic and therapeutic management of MCCs.

Selective neck dissection as a therapeutic option in management of squamous cell carcinoma of unknown primary.

Carcinoma of unknown primary of the neck (CUP) is a metastasis presenting in one or more cervical lymph nodes, with no primary mucosal site identified. Retrospective case notes review of 25 consecutive patients (median age 55, 72% males) diagnosed as CUP who underwent neck dissection in a UK tertiary referral comprehensive cancer centre between 2000 and 2011. Median follow-up was 33 months. Nineteen patients underwent comprehensive neck dissections (six extended), six patients had selective neck dissection. Five year disease specific survival and regional recurrence free survival were 76 and 80% respectively. The overall rate of occult disease (disease not identified on preoperative evaluation, but found on histopathologic examination) was 8%, with rates of 0% in level I and 6% in level V. Our study suggests that in patients without preoperative evidence of disease in levels I or V selective neck dissection might be considered as an option, to facilitate preservation of the submandibular gland and accessory nerve without compromising oncological outcome. Larger studies should be performed before a change in practice can be advised.

Cytoreductive surgery and post-operative heated pleural chemotherapy for the management of pleural surface malignancy.

PURPOSE: We retrospectively analysed the long-term outcomes of cytoreductive surgery and post-operative heated pleural chemotherapy (HPC) for thoracic malignancies with pleural spread. MATERIALS AND METHODS: Between 1987 and 2010, 160 patients were enrolled. There were 101 patients with non-small cell lung cancer (NSCLC), 25 with malignant pleural mesothelioma (MPM), 12 with thymoma, and 22 with tumours metastatic to the lung and pleura. Immediately after intra-thoracic administration of cisplatin or carboplatin, hyperthermia was performed by using an 8.00 MHz radiofrequency capacitive heating device for 1 to 4 courses in each patient. RESULTS: There was no systemic toxicity or treatment-related mortality. Five-year overall survival rates were 37.4% in NSCLC, 15.9% in MPM, 91.7% in thymoma, and 25.8% in metastatic lung tumour. Five-year local relapse-free survival (RFS) rates were 55.2% in NSCLC, 24.4% in MPM, 64.8% in thymoma, and 27.2% in tumours metastatic to the lung and pleura. When 101 NSCLCs were categorised into pleural lavage cytology positive (grade 1: n = 37), limited extent of carcinomatous pleuritis (grade 2: n = 21), and extensive carcinomatous pleuritis (grade 3: n = 43), 5-year overall survival rates were 62.5%, 49.2%, and 13.6%, respectively. The local RFS was significantly better in group 1/2 than in group 3. CONCLUSIONS: Although our study has some of the usual weaknesses of a single institution retrospective study, cytoreductive surgery and HPC are feasible and safe. It is suggested that HPC may have a potential role for local control as adjuvant treatment for cytoreductive surgery in patients with minor pleural spread.

Occult primary breast cancer at a comprehensive cancer center.

BACKGROUND: Management of occult primary breast cancer (OPBC), that is, breast cancer that first presents through regional nodal or distant disease without clinical or mammographic evidence of disease in the breast, has been controversial and inconsistent. Here, we review OPBC patients treated at our institution. METHODS: We conducted a retrospective review of women diagnosed with a first primary breast cancer between March 1999 and September 2010 to identify patients who presented with isolated axillary lymphadenopathy proven to be histologically consistent with primary breast malignancy but had no evidence of a breast mass on physical examination, mammography, or ultrasound. Descriptions of treatments received, recurrence, morbidity, and mortality as of October 2012 are reported. RESULTS: Of 5533 patients reviewed, seven (0.1%) patients were identified. The median age was 65 y old (range, 40-72), and the median length of follow-up was 86 mo (range, 42-124). Four patients underwent modified radical mastectomy, one patient had a lumpectomy and axillary lymph node dissection, and two patients had axillary lymph node dissection without breast surgery. Four patients received adjuvant radiation therapy. All seven patients received chemotherapy. Three patients received endocrine therapy, and two patients received anti-HER2 therapy. At the last follow-up, all seven patients were alive with no evidence of disease. CONCLUSIONS: Although there was some variation in the management of OPBC at our institution, our patients had excellent outcomes after multimodal treatment. Our results support a curative intent approach to the treatment of OPBC and illustrate the need for individualized treatment algorithms based on tumor biology and extent of the disease at diagnosis.

When to manage level V in head and neck carcinoma?

OBJECTIVES/HYPOTHESIS: As superselective neck dissection strategy is gaining popularity to minimize postoperative morbidity and better life quality, we investigated the metastatic nodal status of level V neck lymph node group for head and neck squamous cell carcinoma in various primary sites. We have also aimed to display the impact of involvement of other nodal groups on level V. STUDY DESIGN: Retrospective review of histopathologic examination of case series at a comprehensive cancer center. METHODS: The study group was composed of 107 patients who underwent a type of neck dissection including level V among 243 patients. The impact of primary site and metastatic nodal status of other levels on metastasis to level V involvement were evaluated. RESULTS: The most common primary tumor site was oropharynx (n = 43), followed by oral cavity (n = 32), larynx (n = 16), carcinoma of unknown primary (n = 10), and hypopharynx (n = 6). General pathologic N positivity for all levels was 78.3% (76 of 97) when 10 carcinoma of unknown primary patients were excluded. Level V was involved in 13 of 107 (12.1%) patients. Level V was not involved in any patient when the other levels were not involved (0 of 21). Even when considering only N+ patients, the ratio of N positivity for level V is still <20% (13 of 86, 15.1%). CONCLUSIONS: Because level V was not involved in any patient when the other levels were not involved, it might be reasonable to preserve level V especially in clinically and intraoperatively N0 patients.

Impact of clinical practice guidelines on the management for carcinomas of unknown primary site: a controlled "before-after" study.

BACKGROUND: In 2002, the French Federation of Comprehensive Cancer Centers published clinical practice guidelines (CPGs) for the management of carcinomas of unknown primary (CUP). METHODS: A controlled "before-after" study at two centers (experimental in Lyon, France and control in Edmonton, Canada) to assess the impact of CPGs on CUP management. Fifty-CUP patients treated in 2000-2001, i.e. before CPG publication, and 50 patients treated in 2003-2004, were analyzed for both centers. RESULTS: In both groups, compliance for diagnostic workup was the same before or after CPGs publication. Non-adenocarcinoma histology and performance status (PS) < 2 were independent factors for CPGs compliance. In the experimental group, 75% of patients underwent inappropriate investigations. The proportion of patients from this group with unfavourable clinicopathologic entity and PS < or = 1, who received cisplatin-based chemotherapy did not significantly change (2000-2001: 27% vs. 2003-2004: 37.5%; P = 0.45). However, most patients treated in the pre period received organ-specific regimens, while most patients treated in the post period received taxane or gemcitabine-based regimens. Patients from the control group generally received taxane/carboplatin. CONCLUSIONS: Our study show that simply distributing CUP CPGs did not change practice and underline the necessity to disseminate and implement CPGs, both to oncologists and organ-specialist physicians.

Indications for breast MRI in the patient with newly diagnosed breast cancer.

Use of breast MRI in the preoperative evaluation of patients recently diagnosed with breast cancer has increased significantly over the past 10 years because of its well-documented high sensitivity for detecting otherwise occult breast cancer in the affected and contralateral breasts. However, published research reports on the impact of this improved cancer detection are limited. Equally important are growing concerns that the quality of breast MRI may vary significantly across practice sites, and therefore the published value of MRI may not be achieved for many patients. This article describes the peer-reviewed, published clinical research trials evaluating breast MRI in patients with newly diagnosed breast cancer on which the National Comprehensive Cancer Network (NCCN) practice guidelines are based. The current NCCN guidelines recommend that breast MRI be considered for patients with a newly diagnosed breast cancer to evaluate the extent of ipsilateral disease and to screen the contralateral breast, particularly for women at increased risk for mammographically occult disease. In addition, the guidelines indicate that breast MRI may be used for patients with axillary nodal adenocarcinoma to identify the primary malignancy. The guidelines stress the importance of having proper equipment, imaging technique, and provider training necessary to achieve high-quality breast MRI, and emphasize that MRI practice sites should have the ability to perform MRI-guided biopsy or needle localization. In addition to describing the data regarding use of breast MRI in women with newly diagnosed cancer, this article provides recommendations for the performance of high-quality breast MRI and suggestions for future research.

The role of radiofrequency ablation in multiple liver metastases to debulk the tumor: a pilot study before alternative therapies.

INTRODUCTION: In this study, our aim was to proceed with the first study of our patients by evaluating different metastatic tumor to the liver to check whether, after debulking the tumor with radiofrequency ablation (RFA), the chemotherapy, could increase the survival in these patients as a pilot study before applying alternative therapies in the future. MATERIALS AND METHODS: We studied 11 patients, 7 male, 4 female; age mean, 68 years (50-84). The tumors considered were carcinoid (3), gastrinoma (3), a new endocrine of unknown origin (2), colorectal (2), and breast (1). RESULTS: All of the patients underwent laparoscopic RFA with a prior confirmatory biopsy and were discharged after 23 hours. No pain, bleeding, or wound infections were reported. One (1) patient with a gastrinoma died 9 months following surgery from a myocardial infarction. All other patients are still alive, although 2 experienced hepatic recurrences. CONCLUSIONS: The 11 patients in this series showed that RFA combined with chemotherapy is a viable therapeutic choice for patients with cancer that has metastasized to the liver. New therapies are still needed.

A phase I and pharmacokinetic study of the selective, non-peptidic inhibitor of matrix metalloproteinase BAY 12-9566 in combination with etoposide and carboplatin.

Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases that degrade the extracellular matrix during the processes of invasion, metastasis and angiogenesis. BAY 12-9566 (BAY) is a selective, non-peptidic biphenyl inhibitor of MMPs, with nanomolar inhibitory activity against MMP-2, -3 and -9, and anti-invasive, anti-metastatic and anti-angiogenic activity in a variety of tumor models. This phase I study of oral BAY was conducted to evaluate the safety and pharmacokinetics of BAY when administered in combination with etoposide (VP-16) or in combination with VP-16 and carboplatin (CBDCA) in subjects with advanced cancer. The first cohort of patients (n=8) received a cycle of VP-16, 60 mg/m, followed 1 week later by a fixed daily oral dose of BAY, 800 mg b.i.d., to which three potential possible doses of VP-16 (low dose: 60 mg/m; mid dose: 90 mg/m; high dose: 120 mg/m) were added every 3 weeks as tolerated. The second cohort (n=5) received VP-16 (120 mg/m) and CBDCA (AUC=5) followed 1 week later by a fixed daily oral dose of BAY (800 mg) b.i.d., to which VP-16 (120 mg/m) and CBDCA (AUC=5) were added. Dose-limiting toxicity (DLT) was defined as toxicity grade 3 or above. Maximum tolerated dose was declared if two or more patients experienced DLT. A performance status of 0-2 and acceptable organ function were required for eligibility. Plasma concentrations of BAY and VP-16 were measured to investigate pharmacokinetic interactions. Eight eligible patients with a variety of tumor types (median age 64 years, range 44-76) were enrolled in the first cohort, six of who whom completed all three levels of VP-16. Progressive disease occurred in five of the eight patients; three patients continued on study with treatment. Drug level and pharmacokinetics analysis of BAY and VP-16 were also determined. The combination of BAY and VP-16 was tolerable in the first cohort, permitting enrollment of the second cohort. In the second cohort (n=5), the combination of BAY, VP-16 and CDBCA was intolerable at the doses used due to excessive hematologic toxicity in the first five patients enrolled. Pharmacokinetics and toxicity analysis was performed for this group of patients. Only Level 1 of treatment was completed for Cohort II. At this point the study was halted due to toxicity and the results of an interim analysis that failed to demonstrate sufficient clinical activity of this compound in other clinical trials. We conclude that the combination of BAY and VP-16 was well tolerated. However, the combination of BAY, VP-16 and CDBCA produces significant hematologic toxicity. Findings from this study may help to direct further studies with other inhibitors of MMPs.

Occult breast cancer and axillary mass.

Occult breast cancer presenting with axillary metastases is an unusual presentation and can be a diagnostic and therapeutic challenge. A comprehensive work-up, including mammogram, sonogram, magnetic resonance imaging, and even pathologic examination of the mastectomy specimen may not disclose the primary tumor in up to one third of patients. Traditionally, occult breast cancer is treated with total mastectomy and axillary dissection, but accumulating data suggest that primary breast irradiation following axillary dissection may provide an equivalent survival with the advantage of breast conservation. Occult breast cancer patients are eligible for adjuvant chemotherapy and radiation as stage II/ III node-positive patients would be treated. Overall, the prognosis for occult breast cancer is equivalent to or slightly better than staged counterparts with detectable primary breast tumors.

[Gas gangrene due to Clostridium septicum in a patient with an occult colonic neoplasm. A case report and review of the literature]. / Gangrena gaseosa por Clostridium septicum en un paciente con neoplasia de colon oculta. Presentación de un caso y revisión de la literatura.

A case of gaseous gangrene by Clostridium septicum associated with colorectal cancer is presented. The patient evolved rapidly towards septic shock and death. Autopsy showed occult neoplasm and pelvic and retroperitoneal myonecrosis. An exceptional finding was that of myocarditis in which thick gram-positive bacilli were identified. A review of the literature was carried out regarding the pathogenesis and clinical manifestations of this disease. The association of colonic neoplasm and Clostridium septicum may be related with the sensitivity of the cells of this neoplasm to the toxins of the microorganisms. The usefulness of this cytotoxicity is being tested in the therapeutic reduction of tumoral mass. With respect to clinical attitude, all the authors agree on the need for clinical suspicion as to the possible existence of occult colon neoplasm in individuals with septic shock by gaseous gangrene with no obvious entry site. Diagnosis is performed by imaging techniques with barium enema and if this is normal colonoscopy is carried out. Emergency treatment consists in laparotomy with resection of the neoplasm and debridement of the area accompanied by hyperbaric oxygen and antibiotics.

A radiolabelled iodobenzamide for malignant melanoma staging.

123I-N-(di-ethylamino-2-ethyl) 4 iodobenzamide (I-BZA) has been put forward by the Clermont-Ferrand INSERM U71 group (France) as a tracer for malignant melanoma. We report on the clinical results obtained in 56 studies performed on 48 patients. Whole body scans along with spot views were obtained after injection of 185 MBq of I-BZA. The scans were read by three independent observers and correlated to the clinical findings and the other imaging modalities available, taking into account all lesions larger than 1 cm. Patients were classified into two groups on the basis of a post-treatment survey of patients: group I, in complete remission (24 scans); group II: documented metastases (32 scans). In group 1, 21 studies were truly negative. However, three studies showed positive results. Only one turned out to be a false positive (specificity 95%), the other two revealed unknown lesions and modified the patients' management. In group II, 73% of the known metastases were detected with higher sensitivities (> 80%) for eye and orbit, lung and abdomen. One false positive was reported and four new lesions were detected. I-BZA scintigraphy has the same sensitivity as immunoscintigraphy with higher specificity and without the risk of xenoimmunization. It is a useful tool for staging malignant melanoma which can improve patient management.