In Silico Modeling of the Antiplatelet Pharmacodynamics of Low-dose Aspirin in Health and Disease.

The influence of platelet turnover on cyclooxygenase (COX-1) inhibition by low-dose aspirin remains largely uncharacterized due to limited feasibility of studying aspirin pharmacodynamics in bone marrow precursors. We developed an in silico compartmental model describing the aspirin effects on COX-1 activity in a population of megakaryocytes (MK) and in peripheral platelets. Model parameters were inferred from the literature and calibrated using measurements of serum thromboxane B2 (sTXB2 ), as proxy of COX-1 activity in peripheral platelets, in 17 healthy subjects and 24 patients with essential thrombocythemia (ET). The model reproduced well the average time-course of sTXB2 inhibition in healthy (accuracy = 10.4%), the reduced inhibition of sTXB2 observed in ET, and the effect of different dosing regimens. In conclusion, the in silico model accurately describes COX-1 inactivation by low-dose aspirin in MK and platelets in different clinical settings, and might help personalize aspirin regimens in conditions of altered megakaryopoiesis.

On-pump Cardiac Surgery Enhances Platelet Renewal and Impairs Aspirin Pharmacodynamics: Effects of Improved Dosing Regimens.

On-pump cardiac surgery may trigger inflammation and accelerate platelet cyclooxygenase-1 renewal, thereby modifying low-dose aspirin pharmacodynamics. Thirty-seven patients on standard aspirin 100 mg once-daily were studied before surgery and randomized within 36 hours postsurgery to 100 mg once-daily, 100 mg twice-daily, or 200 mg once-daily for 90 days. On day 7 postsurgery, immature and mature platelets, platelet mass, thrombopoietin, glycocalicin, leukocytes, C-reactive protein, and interleukin-6 significantly increased. Interleukin-6 significantly correlated with immature platelets. At day 7, patients randomized to 100 mg once-daily showed a significant increase in serum thromboxane (TX)B2 within the 24-hour dosing interval and urinary TXA2 metabolite (TXM) excretion. Aspirin 100 mg twice-daily lowered serum TXB2 and prevented postsurgery TXM increase (P < 0.01), without affecting prostacyclin metabolite excretion. After cardiac surgery, shortening the dosing interval, but not doubling the once-daily dose, rescues the impaired antiplatelet effect of low-dose aspirin and prevents platelet activation associated with acute inflammation and enhanced platelet turnover.

Parotid metastasis of renal cell carcinoma, mimicking primary clear cell oncocytoma: report of a case and brief review of the literature.

Malignancies of the parotid gland are relatively uncommon, accounting for only 3-6% of all head and neck cancers. Most of them are primary neoplasms, metastases are uncommon. Renal cell carcinoma (RCC) represents 3% of adult malignancies, the clear cell type comprises up to 70% of all RCC. RCC has an unpredictable behavior and the unique potential to metastasize to nearly every organ in the body. Though not as frequent, metastatic RCC to the head and neck has been identified in the thyroid, salivary glands, skull base, sinuses, pharynx, tonsils, tongue, lip and skin. Metastasis to the parotid gland is very rare. Here, we report the case of a clear cell type RCC metastatic to the parotid gland and mimicking a primary clear cell oncocytoma. Differential diagnoses and a brief review of the literature are added.

Qualitative and quantitative modifications of von Willebrand factor in patients with essential thrombocythemia and controlled platelet count.

BACKGROUND: Essential thrombocythemia (ET) is characterized by increased platelets and prevalent thrombosis. An acquired von Willebrand factor (VWF) disease has been hypothesized and inconsistently associated with extreme thrombocytosis or rare bleeding in ET. Whether VWF is modified in ET patients with controlled platelet count remains unclear. OBJECTIVES: We studied different VWF- and platelet-associated parameters in ET patients treated according to current recommendations. PATIENTS/METHODS: Sixty-nine ET patients (M = 29; median age, 62 [48-70] years; platelets, 432 [337-620] × 10(3)  µL(-1) ), 69 matched controls and 10 subjects with reactive thrombocytosis (RT) were studied. VWF:antigen (Ag), activity (act), electrophoretic patterns, VWF:propeptide, plasma glycocalycin (GC), glycoproteinV (GpV), ADAMTS-13, elastase, C-reactive protein and serum thromboxane (TX)B2 were measured. RESULTS: In ET patients, VWF:Ag was increased by 31 ± 13% vs. controls (P < 0.01), without dependence of blood groups, while VWF:act was reduced by 21 ± 12% vs. controls and by 50 ± 24% vs. RT (P < 0.01). The VWF:act/VWF:Ag ratios in ET were reduced by 35 ± 17% vs. controls and RT patients (P < 0.001) and significantly associated with: immature or total platelet counts, GC, GpV and TXB2 . In multivariable analysis, only GC inversely predicted ET patients' VWF:act/VWF:Ag ratios (ß = -0.42, P = 0.01). By electrophoresis analyses, high-molecular-weight VWF multimers were variably reduced with atypical cleavage bands in ET only. VWF:propeptide, ADAMTS-13 and elastase levels were normal in ET patients. Platelet-associated ADAM-10 and ADAM-17 hydrolyzed VWFm in vitro, showing patterns similar to those in ET samples. CONCLUSIONS: In ET patients with controlled platelet counts, the VWF:act/VWF:Ag ratio is decreased and predicted by GC, a product of platelet activation. ADAM-10 and/or ADAM-17 might be involved. In vivo platelet activation, which characterizes ET, might contribute to disease-specific VWF alterations.

Myxoid leiomyosarcoma of the uterus: a case report.

Only 30 cases of myxoid leiomyosarcomas (MLMS) have been reported to date. The authors describe a further case in a 66-year-old woman. The main differential diagnoses include: myxoid inflammatory myofibroblastic tumours, mixoid leiomyoma, and endometrial stromal tumours. Surgery remains the appropriate treatment. However, in spite of an aggressive surgical approach and local and systemic control, recurrences and metastasis are frequent.

Cystic gastrointestinal stromal tumors of the pancreas simulating cystoadenocarcinoma. Report of three cases and short review of the literature.

Gastrointestinal stromal tumors (GISTs) represent a distinct subset of mesenchymal tumours of the gastrointestinal tract. They are more common in the stomach and small intestine, and are characterized by the proliferation of spindle or epithelioid cells and by the expression of CD117. Extra-gastrointestinal stromal tumors are rare and only 13 cases of pancreatic GISTs have been reported in the literature, only 1 of which presented as a cystic lesion. Mutational analysis of KIT and Platelet derived growth factor receptor-α genes was performed only in two out of the 13 cases. We report 3 cases of cystic GISTs of the pancreas, radiologically mimicking a cystoadenocarcinoma. Routine histopathology and molecular characterization of the tumours have been performed. In two of them, molecular analysis showed unusual genetic alterations (the internal repeat of codon 502 and 503 in exon 9 of the KIT gene and the KIT exon 9 single nucleotide substitution c.1427G⟩T). Pancreatic GIST should be included in the differential diagnosis of both cystic and solid masses of the pancreas. The diagnosis should be accomplished by a combination of radiology, histology, immunohistochemistry and molecular biology. The evaluation of CD117 expression and the sequence analysis of KIT and Platelet derived growth factor receptor-α gene is mandatory for therapy.

Leiomyomatosis peritonealis disseminata: an additional case.

Leiomyomatosis peritonealis disseminata (PPD) is a rare smooth muscle tumour of women in the reproductive age. It is characterized by multiple small nodules on the peritoneal surface, mimicking a metastatic process. To date, about 100 cases have been reported in literature. The authors herein present an additional case consisting of multiple nodules located on the surface of the omentum, parietal peritoneum, as well as colon and rectum wall in a patient without signs of excess of estrogen, progesterone, or steroid hormones nor treated with hormones for any reason. The patient has been submitted to laparoscopic myomectomy few years ago. Microscopically, these nodules consisted of bundles of spindle-shaped smooth muscle cells (positive for smooth muscle actin, desmin, estrogen, and progesterone receptor). A brief review of the literature on the pathogenesis of the disease is also added.

In vivo prostacyclin biosynthesis and effects of different aspirin regimens in patients with essential thrombocythaemia.

Essential thrombocythaemia (ET) is characterised by enhanced platelet generation and thrombosis. Once daily (od) aspirin incompletely inhibits platelet thromboxane (TX)A2 production in ET. A twice daily (bid) dosing is necessary to fully inhibit TXA2. Whether this dosing regimen affects in vivo prostacyclin (PGI2) biosynthesis is unknown. PGI2 biosynthesis was characterised in 50 ET patients on enteric-coated (EC) aspirin 100 mg od, by measuring its urinary metabolite, 2,3-dinor-6-keto-PGF1α (PGI-M). Moreover, in a crossover study 22 patients poorly responsive to standard aspirin based on serum TXB2 levels (≥4 ng/ml) were randomised to different seven-day aspirin regimens: EC aspirin 100 mg od, 100 mg bid, 200 mg od, or plain aspirin 100 mg od. PGI-M measured 24 hours after the last aspirin intake (EC, 100 mg od) was similar in patients and healthy subjects both on (n=10) and off (n=30) aspirin. PGI-M was unrelated to in vivo TXA2 biosynthesis, and not affected by EC aspirin 100 mg bid or 200 mg od as compared to EC 100 mg od. PGI2 biosynthesis in aspirin-treated ET patients appears unrelated to TXA2 biosynthesis, and not affected by an improved aspirin regimen, demonstrating its vascular safety for future trials.

Unusual presentation of metastatic adenoid cystic carcinoma: a challenge in aspiration cytology of the thyroid.

INTRODUCTION: Adenoid cystic carcinoma is a malignant neoplasm most commonly originating in the salivary glands. Its occurrence elsewhere is rare and its metastasis to the thyroid gland has been described only once. CASE REPORT: We describe the case of a 66-year-old man who presented for a swelling in the midline neck of six months duration. A solitary palpable nodule was identified in the isthmic region of the thyroid. Fine needle aspiration of the nodule revealed high cellularity, a partial microfollicle-like pattern and the presence of small hyaline globules. The neoplastic population was composed of monomorphic cells with basaloid appearance. Thyroid primitivity was excluded on the basis of the negativity for TTF1 and thyroglobulin. As the patient referred an ulcerative lesion of the inferior lip, fine needle aspiration cytology of the lesion was performed, yielding a diagnosis of adenoid cystic carcinoma. CONCLUSION: The present case highlights the need to be aware of possible metastatic thyroid localisation of adenoid cystic carcinoma also originating in minor salivary glands of the oral cavity. This is a very rare event, but it should be taken into consideration and clinical and cytological findings must be carefully examined.

Renal sinus pseudolymphoma in a patient with multiple carcinomas: a case report and a brief review of the literature.

The term pseudolymphoma refers to a heterogeneous group of benign reactive T-cell or B-cell lymphoproliferative processes of diverse causes that simulate lymphoma clinically and histologically but usually undergo spontaneous remission. Its pathogenesis is still unclear. The prognosis is good although some evidence suggests that pseudolymphoma may progress to lymphoma. Pseudolymphoma of the urinary tract is extremely rare. We herein report a case of pseudolymphoma of the renal sinus in a 70-year-old man, associated with a high grade urothelial carcinoma of the bladder and to a prostatic adenocarcinoma (Gleason score 6). A brief review of the literature is included. The kidney showed a well-defined, whitish soft mass which involved the renal sinus. Microscopically, the lesion of the renal sinus consisted of a proliferation of small to medium size lymphocytes (CD20 positive and Bcl-2 negative) sometimes arranged in hyperplastic follicular structures. The diagnosis was confirmed by molecular studies which showed an oligopolyclonal IgH rearrangement. To the best of our knowledge, this is the second case of pseudolymphoma with a complete molecular characterization ever described in the renal sinus and the first one associated with multiple urogenital carcinomas.

Benign ulcer of the right colon clinically misdiagnosed as carcinoma: an additional case.

Benign solitary ulcer of the colon is an uncommon lesion that was originally described by Cruveilhier in 1832. Its aetiology remains unknown, and there are no pathognomonic lesions or symptoms. Diagnosis is made by exclusion; in fact, diseases such as specific infections (cytomegalovirus, campylobacter jejuni, entamoeba histolytica), common clinical conditions (acute appendicitis, diverticulitis, intestinal obstruction, inflammatory bowel disease), pharmacotherapy (non-steroidal anti-inflammatory medications, oral contraceptives, dicumarolic agents) and malignancies should be excluded. We describe the case of a 72-year-old patient admitted for acute bloody diarrhoea, originally misdiagnosed as carcinoma by colonscopy. The histological evaluation demonstrated a benign ulcerative lesion.

Myeloid sarcoma and adenocarcinoma of the large bowel as collision tumors: a case report.

Myeloid sarcoma is a rare tumor composed of myeloid cells, localized in an extramedullary site, which may be associated with a concurrent myeloid neoplasm involving the bone marrow, although such an association is not required. Most patients present with acute myeloid leukemia and their prognosis is poor. We describe the case of a 76-year old woman with an adenocarcinoma of the right colon infiltrating the subserosa synchronous with a myeloid sarcoma at the same site; one pericolic lymph node was infiltrated by both tumors. The peculiarities of this case are the clinical presentation (as an acute abdomen due to subserosa infiltration by the myeloid sarcoma), the coexistence of a myeloid sarcoma with an adenocarcinoma of the right colon, and the absence of progression to acute leukemia. Coexistence of myeloid sarcoma and adenocarcinoma in the colon is probably incidental, and so it appears likely that the two different tumours arose from different mechanisms. However, a possible common background is conceivable. Some authors have found that p53 has a pivotal role in driving the maturation of myeloid stem cells and p53 is, also, involved in colon carcinogenesis. In our case, it may be hypothesized that synchronous heterogeneous mutations occurred in different types of committed cells or in stem cells secondary to p53 loss. Since only one case report has evaluated the correlation between myeloid sarcoma and adenocarcinoma of the large bowel, further immunohistochemical and molecular studies are needed to clarify the pathogenetic relationship between them.

A case of Stengel-Wolbach sclerosis: a half century after the last report.

Stengel-Wolbach sclerosis is a rare form of granulomatosis of the lymphoid tissue, with largely predominant involvement of the spleen. Firstly described by Wolbach in 1910, it has disappeared from the literature from the beginning of the last century. Herein, we describe the case of a 29-year-old female with splenomegaly due to multiple nodular lesions. On the basis of morphological and molecular biology findings, a diagnosis of Stengel-Wolbach sclerosis of unknown aetiology was made. The presentation of this case may reopen the discussion on this enigmatic entity.

Long pedunculated colonic polyp with diverticulosis: case report and review of the literature.

Colonic muco-submucosal elongated polyp is a rare entity (0.39% in an endoscopic polypectomy series). It is an elongated drumstick-shaped lesion characterized by oedematous, loose connective tissue with a dense submucosal layer showing dilation of blood and lymphatic vessels. First described as a polypoid lesion associated with diverticular disease of the sigmoid colon, it was histologically characterized as a separate entity by Kelly in 1991. In that study, the author reported eight cases in which a red or brown mucosal protrusion or polyp were associated with diverticular disease, and described the syndrome as "polypoid prolapsing mucosal folds in diverticular disease". In 1994, Matake et al. described a new entity defined as colonic muco-submucosal elongated polyp. Herein, we describe another case in a 77-year-old woman with abdominal pain, followed by a review of the literature.

Melanoma of the nipple. An additional case.

The nipple is an unusual site of cutaneous melanoma with only few cases described in literature. We herein report an additional case of malignant melanoma arising on the nipple of a 47-year old woman. The nodular, ulcerated lesion was removed surgically and the diagnosis was that of a vertical growth phase melanoma. The melanocytic origin of the tumour was confirmed by immunohistochemistry. The case pursued a poor clinical outcome with distant metastases and death of the patient.

The interplay between indoleamine 2,3-dioxygenase 1 (IDO1) and cyclooxygenase (COX)-2 in chronic inflammation and cancer.

The enzyme indoleamine 2,3-dioxygenase 1 (IDO1) degrades the essential amino acid tryptophan into kynurenine and other downstream metabolites that suppress effector T-cell function and favor the differentiation of regulatory T cells. IDO1 is traditionally viewed as a general suppressor of T-cell activation and mediator of immune escape in cancer. Recently, evidence has emerged to support a greater functional complexity of IDO1 as modifier of pathogenic inflammation. For instance, IDO1 activity may sustain autoantibody production by B cells, and elicit the development of cancer in the context of chronic inflammation. Cyclooxygenase (COX)-2 metabolizes the first enzymatic step in the conversion of arachidonic acid into prostanoids. In particular, prostaglandin (PG)E2 generated at sites of inflammation and/or immune response is mainly COX-2-derived and has pro-inflammatory and immune regulatory activities. Pharmacological blockade of COX-2 in animal models of cancer translates into down-regulation of IDO1 expression at tumor sites and decreased levels of kynurenine in the circulation, underpinning the view that IDO1 might be downstream of COX-2. This article reviews preclinical studies focusing on IDO1 and COX-2 as inter-related molecular targets for therapeutic intervention in chronic inflammation and cancer. COX-2 inhibition might, in principle, be pursued in cancer-associated inflammation characterized by IDO1 hyper-activity, with the foreseeable aim at altering the immune response within the tumor microenvironment.

Tuberculosis of superficial lymph nodes, a not so rare event to consider in diagnosis. A case in an elderly male.

Tuberculosis (TB) is still one of the most frequent infectious diseases worldwide. Until the 1990s, Western European countries showed a low frequency of TB infection, but the rise of immigration has led to a rapid increase in its occurrence. In the elderly, TB is emerging as a significant health problem (age-related decline of the cell-mediated immunity, associated illnesses, use of immunosuppressive drugs, malnutrition, poor life conditions), although its detection and diagnosis is not easy also considering its subclinical presentation. Almost 70% of all TB infections in Italy are found in the lungs; 50% of the extrapulmonary infections affect lymph nodes. Due to the low incidence of superficial tuberculous lymphadenitis without pulmonary manifestations, the possibility of a TB aetiology is often not taken into consideration in the differential diagnosis of lymphadenopathy, resulting in significant delay of appropriate treatment. Herein, we describe the case of a 78-year-old male with nocturnal fever, weakness, night sweats, loss of weight and decay in general condition. The patient had a past medical history of prostate adenocarcinoma treated with hormone therapy. The past medical history in association with clinical findings and laboratory data (anaemia, high titers of fibrinogen and reactive C-protein) led to the suspect of metastatic adenocarcinoma. Only histological and molecular biology findings allowed us to make a correct diagnosis of TB.

Eosinophilic esophagitis: an Italian experience.

BACKGROUND: Eosinophilic esophagitis is an esophageal disorder characterized by esophageal and/or upper gastrointestinal tract symptoms, and by dense esophageal eosinophilia associated with a normal gastric and duodenal mucosa. Prevalently reported in children, eosinophilic esophagitis has recently been reported with increased frequency also in adults. AIMS: The purpose of this study was to report our experience with eosinophilic esophagitis in Italy, since there are only very few series of such patients in our country. PATIENTS AND METHODS: We retrospectively reviewed the histological data of consecutive patients with a diagnosis of esophagitis or reflux disease in the period September 2004-September 2008. Eosinophils were counted where they appeared most numerous in the biopsy, with a cutoff > 15 eosinophils in more than one high-power field as diagnostic of eosinophilic esophagitis. Patients were excluded if gastric or duodenal biopsies showed a prominent eosinophilic infiltrate. RESULTS: Twenty two patients (14 adults, 8 children, age range 2-59 years) were identified according to the above criteria. The average eosinophil count was 86/ high-power field (range 31-150), associated with other pathologic features (eosinophilic microabscesses eosinophil degranulation, basal zone hyperplasia, papillary elongation). The main clinical complaints were dysphagia, food impaction, and heartburn, and endoscopic findings consisted of mucosal thickening and inelasticity, longitudinal shearing, rings, and white specks, without difference between adults and children for both clinical and endoscopic variables. CONCLUSIONS: Eosinophilic esophagitis is not rare in Italy, and displays clinical, endoscopic, and pathologic features similar to those described in other countries.

Lymphoepithelioma-like carcinoma of the endometrium.

Only three cases of lymphoepithelioma-like carcinoma of the endometrium have been reported to date. We present a new case in a 67-year-old woman involving an exophytic mass that caused postmenopausal bleeding. Histologically, undifferentiated carcinomatous areas were intermingled with abundant lymphoid tissue. Epstein-Barr virus was not detected in either neoplastic or lymphoid cells.

Primary linitis plastica of the right colon.

A case of primary linitis plastica of the colon is presented. This case is of interest for three reasons: the site of origin in the right colon (80% of cases reported develop distally to the splenic flexure), a biopsy previously taken from the mucosa demonstrated the presence of a signet ring cell carcinoma (endoscopic biopsies do not provide a conclusive diagnosis in the majority of cases reported) and hyaline with sparse amyloid nodules were detected in the extensive, dense fibrous tissue intermingled with tumour cells.