BRAF and RAS mutations as prognostic factors in metastatic colorectal cancer patients undergoing liver resection.

BACKGROUND: Despite major advances in the management of metastatic colorectal cancer (mCRC) with liver-only involvement, relapse rates are high and reliable prognostic markers are needed. METHODS: To assess the prognostic impact of BRAF and RAS mutations in a large series of liver-resected patients, medical records of 3024 mCRC patients were reviewed. Eligible cases undergoing potentially curative liver resection were selected. BRAF and RAS mutational status was tested on primary and/or metastases by means of pyrosequencing and mass spectrometry genotyping assay. Primary endpoint was relapse-free survival (RFS). RESULTS: In the final study population (N=309) BRAF mutant, RAS mutant and all wild-type (wt) patients were 12(4%), 160(52%) and 137(44%), respectively. Median RFS was 5.7, 11.0 and 14.4 months respectively and differed significantly (Log-rank, P=0.043). At multivariate analyses, BRAF mutant had a higher risk of relapse in comparison to all wt (multivariate hazard ratio (HR)=2.31; 95% CI, 1.09-4.87; P=0.029) and to RAS mutant (multivariate HR=2.06; 95% CI, 1.02-4.14; P=0.044). Similar results were obtained in terms of overall survival. Compared with all wt patients, RAS mutant showed a higher risk of death (HR=1.47; 95% CI, 1.05-2.07; P=0.025), but such effect was lost at multivariate analyses. CONCLUSIONS: BRAF mutation is associated with an extremely poor median RFS after liver resection and with higher probability of relapse and death. Knowledge of BRAF mutational status may optimise clinical decision making in mCRC patients potentially candidate to hepatic surgery. RAS status as useful marker in this setting might require further studies.

Thymidine phosphorylase expression and benefit from capecitabine in patients with advanced breast cancer.

BACKGROUND AND AIM: Capecitabine is an orally bioavailable prodrug that is converted to 5-fluorouracil through several enzymatic steps, the last of which is mediated by thymidine phosphorylase (TP). TP has been reported to be expressed at higher levels in cancer tissue compared with normal counterpart. The present study aimed at evaluating the potential relationship between TP expression and benefit from capecitabine in patients with metastatic breast cancer (BC). METHODS: Immunohistochemistry for TP and other biological markers was carried out on paraffin-embedded cancer tissues of 61 patients with BC treated with at least three cycles of capecitabine as single agent for metastatic disease. All patients had received capecitabine 1000 mg/m(2) b.i.d. days 1-14 every 21 days. The following variables were analyzed as potential determinants of benefit from capecitabine: TP expression, estrogen receptor (ER) and progesterone receptor status, human epidermal growth factor receptor-2 (HER-2) status, MIB-1 expression, performance status at the beginning of capecitabine treatment, stage at diagnosis, grade, presence of visceral metastases at the beginning of capecitabine treatment, and previous chemotherapy. RESULTS: Overall, median time to progression (TTP) was 6.5 months (range 1.4-33). On multivariate analysis, ER status [hazard ratio (HR) for progression = 0.31; 95% confidence interval (CI) = 0.15-0.64; P = 0.002], presence of visceral metastases at the beginning of capecitabine treatment (HR = 2.30; 95% CI = 1.21-4.39; P = 0.01), and capecitabine as first- or second-line treatment (HR = 2.28; 95% CI = 1.21-4.32; P = 0.01) independently predicted TTP. TP was highly expressed in 34 of 61 cases (55.7%). In the subgroup of patients with TP-expressing tumor, TTP was significantly longer in patients who received anthracyclines and taxanes before capecitabine (median TTP 7.5 versus 3.3 months, P = 0.01, log-rank test). Similarly, patients with a TP-positive tumor showed a longer TTP if they received taxanes before capecitabine than patients with TP-positive tumor who did not receive this treatment (7.3 versus 3.4 months, P = 0.03). CONCLUSIONS: These data provide further evidence that TP expression in BC could represent a biomarker of sensitivity to capecitabine treatment. Prospective studies with translational approach are desirable to confirm the predictive and prognostic role of TP.

[Chronic renal failure after hematopoietic stem cell transplantation]. / La nefropatia cronica post-trapianto di cellule staminali emopoietich.

Hematopoietic stem cell transplantation, autologous or allogeneic, is a well established hematology procedure. There can be a number of renal complications in this setting, which may occur in every phase but all strongly influence prognosis. Among the late complications, there is the well-known possibility of progressive chronic renal failure, appearing together with hypertension and modest alterations of the urinary sediment, and characterized by pathological findings of thrombotic microangiopathy, often without the corresponding clinical aspects. This clinical picture must be distinguished from other forms of clinically more severe thrombotic microangiopathy, such as those occurring in the early post-transplant period, and from other causes of renal disease in the hematopoietic stem cell transplantation setting. Total body irradiation, chemotherapeutic drugs, calcineurin inhibitors and opportunistic infections have all been considered as causal factors. The nosological classification is still poorly defined, as are the real prognosis and the best treatment. Kidney biopsy is a necessary tool to make a correct diagnosis, assess the frequency of the condition, make a prognostic judgment, and set up rational treatment.

Right ventricular dysplasia: Right and left ventricular involvement morphometrically evaluated.

Right ventricular dysplasia (RVD) is a cardiac anomaly characterized by replacement of variable amounts of right ventricular myocardium by adipose tissue. This condition is believed to be a selective disorder involving extensively the right ventricle, but there are occasional reports of concomitant "minor" abnormalities of the left ventricle. The object of this report concerns a patient who died after heart transplantation because of an unsuspected RVD of the donor heart. We present a morphometric study of the heart in order to evaluate the distribution of the fat on both ventricles and to understand the structural basis of the heart failure. The results show that a large portion of the right ventricle is replaced by fat with a quite homogeneous distribution; the left ventricle is also largely replaced by adipose tissue that is primarily localized at the apex and decreases from the apex to the basis. The remodeling of the heart is attributable to a conspicuous increase in volume of the right ventricle associated with a normal number of myocytes that are longer than normal. For these reasons, according to Starling's law, the heart develops congestive failure.

Remission of nephrotic syndrome after thalidomide therapy in a patient with Castleman's disease.

Castleman's is an uncommon lymphoproliferative disorder secondary to lymphoid follicle hyperplasia and marked capillary proliferation with endothelial hyperplasia. This illness can be associated with glomerulonephritis (GN). Here, we report a case with steroid-dependent nephrotic syndrome secondary to proliferative mesangial glomerulonephritis in a patient with Castleman's disease, that was diagnosed several years before. Considering the involvement of IL-6 in Castleman's disease we treated the patient with thalidomide obtaining the remission of the nephrotic syndrome. Our experience suggests a possible role of thalidomide in the treatment of glomerular pathology when a role of IL-6 is hypothesized.

[Polycystic retroperitoneal leiomyosarcoma. A clinical and anatomo-pathological contribution]. / Leiomiosarcoma retroperitoneale multicistico. Contributo clinico ed anatomo-patologico.

The Authors report an unusual case of retroperitoneal leiomyosarcoma, multicystic, resembling an ovarian cystoma in a patient with simultaneous subclavian-axillary thrombosis. They analyze anatomo-pathological and clinical aspects of this kind of tumor and underline the possible errors they themselves faced. To they come to the conclusion that a careful diagnostic iter of this kind of tumor must be carried out and that the surgical approach must be radical.

[A mucinous cystadenocarcinoma of the pancreas. A clinical and histopathological contribution]. / Cistoadenocarcinoma mucinoso del pancreas. Contributo clinico ed istopatologico.

Two cases of pancreatic cystadenocarcinoma, a very rare pathology, are reported. The authors treat the anatomopathological classification and they underline the diagnosis especially with reference to the new methods of cytologic study. Finally they consider the surgical approach that must be radical because of the potential malignancy of this kind of tumor whose prognosis is quite good with a lasting long-term survival.

[Extraskeletal myxoid chondrosarcoma of the abdominal wall. A clinical, histological, ultrastructural and cytofluorimetric case study]. / Condrosarcoma mixoide extrascheletrico della parete addominale. Contributo clinico, istologico, ultrastrutturale e citofluorimetrico.

The authors present a case of extraskeletal myxoid chondrosarcoma of the abdominal wall, an unusual localization and specific presentation. According to the literature, the clinical characters of this kind of tumor, the diagnostic iter and the therapeutic indications are being examined. The actual anatomopathological patterns used for the diagnosis of this neoplasm are being underlined.

Nesidioblastosis arising from heterotopic pancreas and presenting with hypertension. A clinical, immunohistochemical and ultrastructural study.

A rare case of nesidioblastosis in an adult arising from heterotopic pancreas and presenting with hypertension is reported. To our knowledge it is the first case to be described in literature. The pathogenic mechanisms to explain hypertension are not clear. The stimulating action of glucagon on the adrenal gland or on peripheral beta receptors could be considered as hypothetical factors.

[Updating case studies of primary tumors of the mesentery: angiofibroma involving the superior mesenteric artery]. / Aggiornamento casistico sui tumori primitivi dei meso: angiofibroma coinvolgente l'arteria mesenterica superiore.

The authors describe a rare case of jejunal mesenteric angiofibroma involving the superior mesenteric artery, referred to them as a clinical finding of an abdominal mass with associated disorders of alimentary transit. A review of the literature reveals the controversies existing to date on the subject of mesenteric neoplasms. In addition to their rare incidence, also confirmed by our personal experience in two surgical centres, intraligamentous abdominal tumours arouse interest owing to the diagnostic difficulties which as a rule hinder a precise pre-operative orientation and to surgical problems of a tactical nature related to the frequent involvement of adjacent anatomical structures.

[Intraoperative extemporaneous examination of the parathyroid gland: what is the role of the pathologist in parathyroid pathology?]. / L'esame estemporaneo intraoperatorio delle paratiroidi: qual'è il ruolo del patologo nella patologia paratiroidea?

Hyperparathyroidism (HPT), once considered a rare disease, is nowadays observed and diagnosed more frequently. Consequently, surgical treatment of HPT is often performed with good therapeutic results. The success of parathyroid surgery depends mainly on the accuracy of histopathologic diagnosis through intraoperative examination of frozen tissue specimens. Yet, parathyroid gland pathology is very complex and some of its topics even controversial. Terminology and clinico-pathological concepts in this field are constantly changing and even basic characteristics such as weight, stromal fat content and "normal " histologic patterns of these glands are still actively discussed. The pathologist must often determine, merely by studying a small bioptic specimen, not only the parathyroidal (or non-parathyroidal) origin of the examined tissue, but also the histological "normal" or "abnormality" of the tissue. In carrying out his work the experienced pathologist takes on an important task and responsibility in distinguishing between normal, early hyperplastic (asymmetric), hyperplastic or adenomatous parathyroid glands. New diagnostic technical approaches (such as Electron Microscopy, intracellular fat morphometric evaluation, parenchymal cell mass study by density gradient, etc.) enhance the possibility of reaching a reliable pathologic diagnosis, but they do not solve all the present problems and sometimes can even lead the pathologist astray. Presently the diagnosis and treatment of primary HPT should be considered an open and current problem inasmuch as definite criteria to be followed in distinguishing between normal or single enlarged glands microscopically are still lacking. Neither the degree of accuracy of intraoperative frozen section examination during parathyroid surgery nor the possibility of misleading observations in such a study has been fully evaluated. A close cooperation between the pathologist and head and neck surgeon is of utmost importance to assure the best therapeutical results obtainable from parathyroid surgery in HPT.

[An anastomotic loop between the recurrent nerves--an anatomical description]. / Ansa anastomotica fra i nervi ricorrenti--descrizione anatomica.

The authors present the results of twelve dissections of the neck carried out during autopsy on non-conserved human corpses. The investigation, centered on the anatomic study of the laryngeal nerve within the framework of the European Research Group on the Larynx (G.R.E.L.), revealed the presence of a connecting nervous anatomic branch between the recurrent laryngeal nerves which was observed in 10 of the 12 corpses examined. Despite a revision of national as well as international literature concerning ramifications and anastomosis of the recurrent laryngeal nerves, the authors were unable to find description of this anastomotic ansa. The anatomic reliefs related to this branch are extremely interesting, although research is still in its initial phase. This ramification is situated between the trachea and the oesophagus and the location of the branching-off point from the recurrent nerves as well as the crossing point of the nervous bundle with the oesophagus-tracheal axis vary greatly. The detachment of the ansa from the recurrent trunk is located at the intrathoracic level, while the crossing with the posterior paries of the trachea is located in proximity of the cervicomediastinal junction. The constant presence of this nervous entity encourages us to continue and extend our research, most of all towards microscopic and ultrastructural anatomy as well as towards histomorphometric studies which can give us precious indications. Moreover, electrophysiological studies are in program so as to enable us to gather the largest amount of useful data regarding any possible use of this anatomic entity.

[Chronic hyperplastic parathyroiditis: the anatomico-clinical and pathogenetic aspects]. / Paratiroidite cronica iperplastica: considerazioni anatomo-cliniche e patogenetiche.

The authors described a case of chronic hyperplastic parathyroiditis with hyperparathyroidism occurred in a patient undergone to surgery for laryngeal carcinoma. The morphological picture, the clinical date and the review of the previous studies suggest some hypothesis about the pathogenesis of the chronic hyperplastic parathyroiditis: parainfectious origin, anomalous embryonal development, environmental factors and autoimmune process are considered. The latter pathogenetic mechanism is likely to be involved in most of cases.

[Clinicopathologic correlations in acute renal graft rejection]. / Aspetti clinico-patologici del rigetto acuto nel trapianto renale.

Although the diagnostic and therapeutic outcome of renal transplantation has successfully improved during the last decades, acute graft rejection (AGR) is still an ongoing cause of concern being often associated with irreversible graft dysfunction. Renal biopsy remains a valuable tool in the initial assessment of the potential graft malfunction especially during the early post-transplant period. It is an accurate and sensitive means for detecting prognostically relevant microscopic abnormalities, and assisting in subsequent patient management. For long time, the histopathologic evaluation of AGR has suffered from an irreducible bias with poor interobserver rates. Nowadays, the classification schemes of AGR include the BANFF approach and the National Institute of Heath Collaborative Clinical Trials in Transplantation (NIH-CCTT) system: both have been originally designed in order to improve the diagnostic reproducibility of AGR among pathologists. Arteritis and tubulitis, along to clinical information, constitute the cardinal features of the BANFF classification. Distinguishing features of the traditional NIH-CCTT system includes microscopic criteria such as assessment of interstitial hemorrhage, extent and quality of inflammatory infiltrate, and acute glomerulitis, in addition to tubulitis and arteritis. The BANFF classification has apparently gained more popularity than the time-honored NIH-CCTT system since, if used in the appropriate clinical context, it allows a more accurate assessment of AGR, provides prognostically relevant information, and has a better reproducibility rate among pathologists. Nevertheless, the accuracy trend has not significantly improved during the last few years.

Megaduodenum: an unusual presentation of amyloidosis?

Amyloidosis, a potentially fatal disease, is characterized by an abnormal deposition of autologous proteins. Heart, liver, kidneys, lung, thyroid, skin and the gastrointestinal tract can be involved; in this last case mucosal alterations or disturbances of the motility leading to pseudo-obstruction, bleeding, diarrhea and malabsorption can be present. However, the data concerning the possible gastrointestinal presentations of amyloidosis are scanty and heterogeneous. We report the case of a patient presenting severe gastrointestinal symptoms caused by a megaduodenum. The patient was thoroughly investigated and lesions appeared limited to the upper gastrointestinal tract in the absence of a systemic disorder. However, at follow up the patient developed cardiac dilatation and bioptic samples revealed the presence of amyloidosis.

Dermoscopy of Erythromelanosis Follicularis Faciei et Colli / Dermatoscopia de erythromelanosis folicular faciei et colli

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Embryonal tumor with abundant neuropil and true rosettes. A new entity or only variations of a parent neoplasms (PNETs)? This is the dilemma.

A rare embryonal brain tumor has been diagnosed in a 4-year-old boy. The mass, located at the pons and mesencephalon, has been histologically classified as an embryonal tumor containing abundant neuropil and true rosettes. After surgical complete removal of the neoplasia, the child received intensive combined chemotherapy and radiotherapy. He is alive and free of disease at 34 months from surgery. Difficulties in histological definition, possible suggestions for treatment proposals are discussed.

[Atheroembolism: a form of systemic vascular disease]. / L'ateroembolismo: una forma di vasculopatia sistemica.

Atheroembolism, a systemic vascular disease. Cholesterol crystal embolization (CCE) is an infrequent but serious disorder that is often an unrecognized medical problem. CCE may occur spontaneously from eroded atherosclerotic plaques or most frequently following procedures such as angiography, angioplasty, cardiac catheterization, anticoagulant therapy and aortic surgery. CCE predominantly affects elderly males with a frequent history of hypertension, atherosclerotic vascular diseases and renal insufficiency. CCE may result in protean clinical manifestations and may produce a spectrum of functional impairment. Confusion over the disease's natural history arises because the difficulty of establishing an antemortem diagnosis, and because the laboratory findings are non-diagnostic and non-specific. The mortality was 81% and the causes of death was most often due to multiorgan failure especially renal involvement. The definitive diagnosis depends upon finding the presence of intravascular cholesterol crystal in biopsy or autopsy specimens. The skin, muscle and kidney were the three most common sites for obtaining a premortem diagnostic biopsy.