Concomitant Vascular Reconstruction During Pancreatectomy for Malignant Disease: A Propensity Score-Adjusted, Population-Based Trend Analysis Involving 10 206 Patients

OBJECTIVE To assess trends in the frequency of concomitant vascular reconstructions (VRs) from 2000 through 2009 among patients who underwent pancreatectomy, as well as to compare the short-term outcomes between patients who underwent pancreatic resection with and without VR. DESIGN Single-center series have been conducted to evaluate the short-term and long-term outcomes of VR during pancreatic resection. However, its effectiveness from a population-based perspective is still unknown. Unadjusted, multivariable, and propensity score-adjusted generalized linear models were performed. SETTING Nationwide Inpatient Sample from 2000 through 2009. PATIENTS A total of 10 206 patients were involved. MAIN OUTCOME MEASURES Incidence of VR during pancreatic resection, perioperative in-hospital complications, and length of hospital stay. RESULTS Overall, 10 206 patients were included in this analysis. Of these, 412 patients (4.0%) underwent VR, with the rate increasing from 0.7% in 2000 to 6.0% in 2009 (P < .001). Patients who underwent pancreatic resection with VR were at a higher risk for intraoperative (propensity score-adjusted odds ratio, 1.94; P = .001) and postoperative (propensity score-adjusted odds ratio, 1.36; P = .008) complications, while the mortality and median length of hospital stay were similar to those of patients without VR. Among the 25% of hospitals with the highest surgical volume, patients who underwent pancreatic surgery with VR had significantly higher rates of postoperative complications and mortality than patients without VR. CONCLUSIONS The frequency of VR during pancreatic surgery is increasing in the United States. In contrast with most single-center analyses, this population-based study demonstrated that patients who underwent VR during pancreatic surgery had higher rates of adverse postoperative outcomes than their counterparts who underwent pancreatic resection only. Prospective studies incorporating long-term outcomes are warranted to further define which patients benefit from VR.

Fertility preservation in women with malignant tumors and gonadotoxic treatments

Because of improved survival rates and recent advances in reproductive medicine, fertility preservation methods in women of reproductive age with malignant or autoimmune diseases have risen in importance.

Molecular characterization of the porcine deleted in malignant brain tumors 1 gene (DMBT1)

The human gene deleted in malignant brain tumors 1 (DMBT1) is considered to play a role in tumorigenesis and pathogen defense. It encodes a protein with multiple scavenger receptor cysteine-rich (SRCR) domains, which are involved in recognition and binding of a broad spectrum of bacterial pathogens. The SRCR domains are encoded by highly homologous repetitive exons, whose number in humans may vary from 8 to 13 due to genetic polymorphism. Here, we characterized the porcine DMBT1 gene on the mRNA and genomic level. We assembled a 4.5 kb porcine DMBT1 cDNA sequence from RT-PCR amplified seminal vesicle RNA. The porcine DMBT1 cDNA contains an open reading frame of 4050 nt. The transcript gives rise to a putative polypeptide of 1349 amino acids with a calculated mass of 147.9 kDa. Compared to human DMBT1, it contains only four N-terminal SRCR domains. Northern blotting revealed transcripts of approximately 4.7 kb in size in the tissues analyzed. Analysis of ESTs suggested the existence of secreted and transmembrane variants. The porcine DMBT1 gene spans about 54 kb on chromosome 14q28-q29. In contrast to the characterized cDNA, the genomic BAC clone only contained 3 exons coding for N-terminal SRCR domains. In different mammalian DMBT1 orthologs large interspecific differences in the number of SRCR exons and utilization of the transmembrane exon exist. Our data suggest that the porcine DMBT1 gene may share with the human DMBT1 gene additional intraspecific variations in the number of SRCR-coding exons.

Leiomyomatoid angiomatous neuroendocrine tumor (LANT) of the pituitary: a distinctive biphasic neoplasm with primitive secretory phenotype and smooth muscle-rich stroma

We describe a hitherto undocumented variant of dimorphic pituitary neoplasm composed of an admixture of neurosecretory cells and profuse leiomyomatous stroma around intratumoral vessels. Radiologically perceived as a macroadenoma of 3.8 cm in diameter, this pituitary mass developed in an otherwise healthy 43-year-old female. At the term of a yearlong history of amenorrhea and progressive bitemporal visual loss, subtotal resection was performed via transsphenoidal microsurgery. Discounting mild hyperprolactinemia, there was no evidence of excess hormone production. Histologically, solid sheets, nests and cords of epithelial-looking, yet cytokeratin-negative cells were seen growing in a richly vascularized stroma of spindle cells. While strong immunoreactivity for NCAM, Synaptophysin and Chromogranin-A was detected in the former, the latter showed both morphological and immunophenotypic hallmarks of smooth muscle, being positive for vimentin, muscle actin and smooth muscle actin. Architectural patterns varied from monomorphous stroma-dominant zones through biphasic neuroendocrine-leiomyomatous areas, to pseudopapillary fronds along vascular cores. Only endothelia were labeled with CD34. Staining for S100 protein and GFAP, characteristics of sustentacular cells, as well as bcl-2 and c-kit was absent. Except for alpha-subunit, anterior pituitary hormones tested negative in tumor cells, as did a panel of peripheral endocrine markers, including serotonin, somatostatin, calcitonin, parathormone and vasoactive intestinal polypeptide. Mitotic activity was absent and the MIB-1 labeling index low (1-2%). While assignment of this lesion to any established neoplastic entity is not forthcoming, we propose it is being considered as a low-grade neuroendocrine tumor possibly related to null cell adenoma.

Cyclin D1 in non-small cell lung cancer: a key driver of malignant transformation

PURPOSE: To review the evidence implicating the deregulation of cyclin D1 in the pathogenesis of non-small cell lung cancer (NSCLC), and to discuss the opportunities for targeted clinical intervention. METHODS: Data published until June 2006 are summarized, and previously unpublished results from our own research are included. RESULTS: In normal cells, cyclin D1 complexes with and activates cyclin-dependent kinases (CDK) and acts as a transcriptional regulator. The protein is frequently overexpressed in a wide range of cancers, sometimes coincident with CCND1 (cyclin D1) gene amplification (5-20% of tumours). A low level of somatic mutations have been seen in certain tumours. CCND1 is amplified in NSCLC and cyclin D1 is frequently overexpressed in tumours and pre-invasive bronchial lesions, generally from one parental allele. Mutation analyses revealed a frequent CCND1 gene polymorphism (A870G) that modulates alternative splicing and allows expression of an alternative cyclin D1 transcript (transcript cyclin D1b). The encoded cyclin D1b protein lacks a specific phosphorylation site required for nuclear export. Genotype has been correlated with the risk and/or severity of disease or drug response across a range of malignancies, including lung cancer. Together, these findings suggest a strong pathological role for cyclin D1 deregulation in bronchial neoplasia. CONCLUSION: Current data indicate that cyclin D1 overexpression is not a consequence of, but rather a pivotal element in the process of malignant transformation in the lung and other tissues. This understanding may open new avenues for lung cancer diagnosis, treatment and prevention.

Oral lichen planus and malignant transformation: a retrospective follow-up study of clinical and histopathologic data

OBJECTIVE: Patients in the stomatology service of the Department of Oral Surgery and Stomatology who were clinically and histopathologically diagnosed with oral lichen planus (OLP) in the years 1995 to 2001 were examined for a possible malignant transformation of a previously biopsied OLP site. METHOD AND MATERIALS: For the 145 patients included, the recordings were searched for initial localization and type of OLP lesion, potential noxious agents, distribution between symptomatic and asymptomatic OLP types, and for a malignant transformation of a known OLP site during the follow-up period up to December 2003. RESULTS: The group comprised 47 men and 98 women with a mean age of 56.3 years. Of the 497 lesions, almost half were classified as reticular or papular, predominantly located on the buccal mucosa, gingiva, and borders of the tongue. Four patients did not adhere to their scheduled control visits and were dropped from the study. During the follow-up period 4 patients developed malignant transformation of OLP. In 3 of these cases, dysplasia was present at the initial diagnosis of OLP. This results in a malignant transformation rate of 2.84% among the remaining 141 patients; if the 3 patients with initial dysplasia are excluded, the rate drops to 0.71%. CONCLUSIONS: Until further knowledge is derived from large prospective studies, the data supporting or negating a potential malignant character of OLP lesions remains inconclusive. Special emphasis has to be directed toward unified inclusion and exclusion criteria regarding clinical and histologic findings and identifiable risk factors to allow the comparison of different studies.

p53-induced apoptosis occurs in the absence of p14(ARF) in malignant pleural mesothelioma

Malignant pleural mesotheliomas (MPMs) are usually wild type for the p53 gene but contain homozygous deletions in the INK4A locus that encodes p14(ARF), an inhibitor of p53-MDM2 interaction. Previous findings suggest that lack of p14(ARF) expression and the presence of SV40 large T antigen (L-Tag) result in p53 inactivation in MPM. We did not detect SV40 L-Tag mRNA in either MPM cell lines or primary cultures, and treatment of p14(ARF)-deficient cells with cisplatin (CDDP) increased both total and phosphorylated p53 and enhanced p53 DNA-binding activity. On incubation with CDDP, levels of positively regulated p53 transcriptional targets p21(WAF), PIG3, MDM2, Bax, and PUMA increased in p14(ARF)-deficient cells, whereas negatively regulated survivin decreased. Significantly, p53-induced apoptosis was activated by CDDP in p14(ARF)-deficient cells, and treatment with p53-specific siRNA rendered them more CDDP-resistant. p53 was also activated by: 1) inhibition of MDM2 (using nutlin-3); 2) transient overexpression of p14(ARF); and 3) targeting of survivin using antisense oligonucleotides. However, it is noteworthy that only survivin downregulation sensitized cells to CDDP-induced apoptosis. These results suggest that p53 is functional in the absence of p14(ARF) in MPM and that targeting of the downstream apoptosis inhibitor survivin can sensitize to CDDP-induced apoptosis.

Local targeting of malignant gliomas by the diffusible peptidic vector 1,4,7,10-tetraazacyclododecane-1-glutaric acid-4,7,10-triacetic acid-substance p

PURPOSE: Malignant glial brain tumors consistently overexpress neurokinin type 1 receptors. In classic seed-based brachytherapy, one to several rigid (125)I seeds are inserted, mainly for the treatment of small low-grade gliomas. The complex geometry of rapidly proliferating high-grade gliomas requires a diffusible system targeting tumor-associated surface structures to saturate the tumor, including its margins. EXPERIMENTAL DESIGN: We developed a new targeting vector by conjugating the chelator 1,4,7,10-tetraazacyclododecane-1-glutaric acid-4,7,10-triacetic acid to Arg(1) of substance P, generating a radiopharmaceutical with a molecular weight of 1,806 Da and an IC(50) of 0.88 +/- 0.34 nmol/L. Cell biological studies were done with glioblastoma cell lines. neurokinin type-1 receptor (NK1R) autoradiography was done with 58 tumor biopsies. For labeling, (90)Y was mostly used. To reduce the "cross-fire effect" in critically located tumors, (177)Lut and (213)Bi were used instead. In a pilot study, we assessed feasibility, biodistribution, and early and long-term toxicity following i.t. injection of radiolabeled 1,4,7,10-tetraazacyclododecane-1-glutaric acid-4,7,10-triacetic acid substance P in 14 glioblastoma and six glioma patients of WHO grades 2 to 3. RESULTS: Autoradiography disclosed overexpression of NK1R in 55 of 58 gliomas of WHO grades 2 to 4. Internalization of the peptidic vector was found to be specific. Clinically, the radiopharmeutical was distributed according to tumor geometry. Only transient toxicity was seen as symptomatic radiogenic edema in one patient (observation period, 7-66 months). Disease stabilization and/or improved neurologic status was observed in 13 of 20 patients. Secondary resection disclosed widespread radiation necrosis with improved demarcation. CONCLUSIONS: Targeted radiotherapy using diffusible peptidic vectors represents an innovative strategy for local control of malignant gliomas, which will be further assessed as a neoadjuvant approach.

Malignant melanoma and bone resorption

The cellular and humoral mechanisms accounting for osteolysis in skeletal metastases of malignant melanoma are uncertain. Osteoclasts, the specialised multinucleated cells that carry out bone resorption, are derived from monocyte/macrophage precursors. We isolated tumour-associated macrophages (TAMs) from metastatic (lymph node/skin) melanomas and cultured them in the presence and absence of osteoclastogenic cytokines and growth factors. The effect of tumour-derived fibroblasts and melanoma cells on osteoclast formation and resorption was also analysed. Melanoma TAMs (CD14+/CD51-) differentiated into osteoclasts (CD14-/CD51+) in the presence of receptor activator for nuclear factor kappaB ligand (RANKL) and macrophage-colony stimulating factor. Tumour-associated macrophage-osteoclast differentiation also occurred via a RANKL-independent pathway when TAMs were cultured with tumour necrosis factor-alpha and interleukin (IL)-1alpha. RT-PCR showed that fibroblasts isolated from metastatic melanomas expressed RANKL messenger RNA and the conditioned medium of cultured melanoma fibroblasts was found to be capable of inducing osteoclast formation in the absence of RANKL; this effect was inhibited by the addition of osteoprotegerin (OPG). We also found that cultured human SK-Mel-29 melanoma cells produce a soluble factor that induces osteoclast differentiation; this effect was not inhibited by OPG. Our findings indicate that TAMs in metastatic melanomas can differentiate into osteoclasts and that melanoma fibroblasts and melanoma tumour cells can induce osteoclast formation by RANKL-dependent and RANKL-independent mechanisms, respectively.

Multicenter trial of neo-adjuvant chemotherapy followed by extrapleural pneumonectomy in malignant pleural mesothelioma

BACKGROUND: The aim of this multicenter trial was to prospectively evaluate neo-adjuvant chemotherapy followed by extrapleural pneumonectomy (EPP) and radiotherapy, including quality of life as outcome. PATIENTS AND METHODS: Eligible patients had malignant pleural mesothelioma of all histological types, World Health Organization performance status of zero to two and clinical stage T1-T3, N0-2, M0 disease considered completely resectable. Neo-adjuvant chemotherapy consisted of three cycles of cisplatin and gemcitabine followed by EPP. Postoperative radiotherapy was considered for all patients. RESULTS: In all, 58 of 61 patients completed three cycles of neo-adjuvant chemotherapy. Forty-five patients (74%) underwent EPP and in 37 patients (61%) the resection was complete. Postoperative radiotherapy was initiated in 36 patients. The median survival of all patients was 19.8 months [95% confidence interval (CI) 14.6-24.5]. For the 45 patients undergoing EPP, the median survival was 23 months (95% CI 16.6-32.9). Psychological distress showed minor variations over time with distress above the cut-off score indicating no morbidity with 82% (N = 36) at baseline and 76% (N = 26) at 3 months after surgery (P = 0.5). CONCLUSIONS: The observed rate of operability is promising. A median survival of 23 months for patients undergoing EPP compares favourably with the survival reported from single center studies of upfront surgery. This approach was not associated with an increase in psychological distress.

Orthotopic transplantation of v-src-expressing glioma cell lines into immunocompetent mice: establishment of a new transplantable in vivo model for malignant glioma

OBJECT: The aim of this study was to develop and characterize a new orthotopic, syngeneic, transplantable mouse brain tumor model by using the cell lines Tu-9648 and Tu-2449, which were previously isolated from tumors that arose spontaneously in glial fibrillary acidic protein (GFAP)-v-src transgenic mice. METHODS: Striatal implantation of a 1-microl suspension of 5000 to 10,000 cells from either clone into syngeneic B6C3F1 mice resulted in tumors that were histologically identified as malignant gliomas. Prior subcutaneous inoculations with irradiated autologous cells inhibited the otherwise robust development of a microscopically infiltrating malignant glioma. Untreated mice with implanted tumor cells were killed 12 days later, when the resultant gliomas were several millimeters in diameter. Immunohistochemically, the gliomas displayed both the astroglial marker GFAP and the oncogenic form of signal transducer and activator of transcription-3 (Stat3). This form is called tyrosine-705 phosphorylated Stat3, and is found in many malignant entities, including human gliomas. Phosphorylated Stat3 was particularly prominent, not only in the nucleus but also in the plasma membrane of peripherally infiltrating glioma cells, reflecting persistent overactivation of the Janus kinase/Stat3 signal transduction pathway. The Tu-2449 cells exhibited three non-random structural chromosomal aberrations, including a deletion of the long arm of chromosome 2 and an apparently balanced translocation between chromosomes 1 and 3. The GFAP-v-src transgene was mapped to the pericentromeric region of chromosome 18. CONCLUSIONS: The high rate of engraftment, the similarity to the high-grade malignant glioma of origin, and the rapid, locally invasive growth of these tumors should make this murine model useful in testing novel therapies for human malignant gliomas.