Evaluation of the Therapeutic Effects of Harmine on Anaplastic Thyroid Cancer Cells.

Anaplastic thyroid carcinoma (ATC) is an extremely difficult disease to tackle, with an overall patient survival of only a few months. The currently used therapeutic drugs, such as kinase inhibitors or immune checkpoint inhibitors, can prolong patient survival but fail to eradicate the tumor. In addition, the onset of drug resistance and adverse side-effects over time drastically reduce the chances of treatment. We recently showed that Twist1, a transcription factor involved in the epithelial mesenchymal transition (EMT), was strongly upregulated in ATC, and we wondered whether it might represent a therapeutic target in ATC patients. To investigate this hypothesis, the effects of harmine, a ß-carboline alkaloid shown to induce degradation of the Twist1 protein and to possess antitumoral activity in different cancer types, were evaluated on two ATC-derived cell lines, BHT-101 and CAL-62. The results obtained demonstrated that, in both cell lines, harmine reduced the level of Twist1 protein and reverted the EMT, as suggested by the augmentation of E-cadherin and decrease in fibronectin expression. The drug also inhibited cell proliferation and migration in a dose-dependent manner and significantly reduced the anchorage-independent growth of both ATC cell lines. Harmine was also capable of inducing apoptosis in BHT-101 cells, but not in CAL-62 ones. Finally, the activation of PI3K/Akt signaling, but not that of the MAPK, was drastically reduced in treated cells. Overall, these in vitro data suggest that harmine could represent a new therapeutic option for ATC treatment.

Mesenteric Cyst with GI Symptoms: A Fluid Approach to Treatment-Case Report and Literature Review.

Mesenteric cysts are defined as a heterogeneous group of intra-abdominal cystic lesions of the mesentery or omentum that may be found in any portion of the gastrointestinal tract from the duodenum to the rectum. The clinical condition is entirely asymptomatic in many patients, particularly with small cysts. The diagnosis is typically incidental and secondary to imaging performed for other purposes. In symptomatic patients, the clinical picture is characterized by nonspecific gastrointestinal signs and symptoms. Treatment may be surgical or via interventional radiology. We report the case of a 55-year-old female patient complaining of left-sided abdominal discomfort and constipation lasting three months. An abdominal ultrasound showed the presence of a 10 × 14 × 16 cm anechoic cystic mass filling the whole anterior and left abdominal cavity, confirmed by CT and MRI. The cyst, removed laparoscopically, was histologically a simple mesothelial cyst. We reviewed the international literature over the last 10 years of all cases with mesenteric cysts > 10 cm in evaluating gastrointestinal symptoms at diagnosis, histology, performed treatment, and outcome.

Papillary Thyroid Cancer Prognosis: An Evolving Field.

Over the last few years, a great advance has been made in the comprehension of the molecular pathogenesis underlying thyroid cancer progression, particularly for the papillary thyroid cancer (PTC), which represents the most common thyroid malignancy. Putative cancer driver mutations have been identified in more than 98% of PTC, and a new PTC classification into molecular subtypes has been proposed in order to resolve clinical uncertainties still present in the clinical management of patients. Additionally, the prognostic stratification systems have been profoundly modified over the last decade, with a view to refine patients' staging and being able to choose a clinical approach tailored on single patient's needs. Here, we will briefly discuss the recent changes in the clinical management of thyroid nodules, and review the current staging systems of thyroid cancer patients by analyzing promising clinicopathological features (i.e., gender, thyroid auto-immunity, multifocality, PTC histological variants, and vascular invasion) as well as new molecular markers (i.e., BRAF/TERT promoter mutations, miRNAs, and components of the plasminogen activating system) potentially capable of ameliorating the prognosis of PTC patients.

Expression and Clinical Utility of Transcription Factors Involved in Epithelial-Mesenchymal Transition during Thyroid Cancer Progression.

The transcription factors involved in epithelial-mesenchymal transition (EMT-TFs) silence the genes expressed in epithelial cells (e.g., E-cadherin) while inducing those typical of mesenchymal cells (e.g., vimentin). The core set of EMT-TFs comprises Zeb1, Zeb2, Snail1, Snail2, and Twist1. To date, information concerning their expression profile and clinical utility during thyroid cancer (TC) progression is still incomplete. We evaluated the EMT-TF, E-cadherin, and vimentin mRNA levels in 95 papillary TC (PTC) and 12 anaplastic TC (ATC) tissues and correlated them with patients' clinicopathological parameters. Afterwards, we corroborated our findings by analyzing the data provided by a case study of the TGCA network. Compared with normal tissues, the expression of E-cadherin was found reduced in PTC and more strongly in ATC, while the vimentin expression did not vary. Among the EMT-TFs analyzed, Twist1 seems to exert a prominent role in EMT, being significantly associated with a number of PTC high-risk clinicopathological features and upregulated in ATC. Nonetheless, in the multivariate analysis, none of the EMT-TFs displayed a prognostic value. These data suggest that TC progression is characterized by an incomplete EMT and that Twist1 may represent a valuable therapeutic target warranting further investigation for the treatment of more aggressive thyroid cancers.

Evaluation of Clinicopathological and Molecular Parameters on Disease Recurrence of Papillary Thyroid Cancer Patient: A Retrospective Observational Study.

The American Joint Committee on Cancer has revised the Tumor-Node-Metastasis (TNM) staging system for papillary thyroid cancer (PTC) patients. We examined the impact of this new classification (TNM-8) on patient stratification and estimated the prognostic value of clinicopathological features for the disease-free interval (DFI) in a cohort of 1148 PTC patients. Kaplan-Meier analyses showed that all clinicopathological parameters analyzed, except age and multifocality, were associated significantly with DFI. Cox regression identified tall cell PTC variant and stage as independent risk factors for DFI. When the stage was replaced with age, tumor size, and lymph node (LN) metastases in the set of covariates, the lateral LN metastases stood out as the strongest independent predictor of DFI, followed by tall cell variant and age. A noteworthy result emerging from these analyzes is that regression models had lower Akaike and Bayesian information criterions if variables were categorized based on the TNM-7. In addition, we examined data from a different PTC patient cohort, acquired from The Cancer Genome Atlas database, to verify whether the DFI prediction could be enhanced by further clinicopathological and molecular parameters. However, none of these was found to be a significant predictor of DFI in the Cox model.

Perivascular epithelioid cell neoplasm (PEComa) of the uterus: A systematic review.

BACKGROUND: Perivascular epithelioid cell neoplasm (PEComa) is a rare mesenchymal tumor. Gynecological PEComas account for just over one-fourth of the overall PEComa cases reported in the literature. Surgery is the most recommended primary treatment while adjuvant therapy is generally reserved for high-risk cases. However, the best management of this neoplasia has not been well established, primarily because of the paucity of cases described to date. OBJECTIVES: The aim of this systematic review is to summarize what is known thus far regarding the etiopathogenesis, clinical and pathologic features of PEComas, focusing also on the most valid treatment options for uterine cases. DATA SOURCES: Pubmed articles on PEComas published in various journals over the past 70 years were analyzed. CONCLUSIONS AND KEY FINDINGS: Although the optimal treatment of gynecological PEComas is controversial, surgical resection remains the cornerstone. The use of adjuvant treatment is warranted in high risk patients to increase disease control. A multidisciplinary approach should be key in treatment decision-making regarding gynecological PEComas.

Chievitz' juxtaparotid organ, free from cancer.

INTRODUCTION: Up to the half of twentieth century, Chievitz organ was considered an embryonal organ, disappearing with growth. But Zenker, in 1953, demonstrated the existence of this organ in adult life, too4. REVIEW: In this article we review the embryology, the macroscopic and microscopic anatomy, the ultrastructure, the functional significance and the pathology of the Chievitz'Juxtaparotid Organ (CJO). The CJO is not a macroscopic apparent organ, but it looks like a nerve. The CJO takes connections with buccinator muscle, at the level of the parotid duct, and the medial pterygoid muscle. The cell parenchyma is enveloped by the connective tissue, that is divided into three layers15, 16: the inner layer -"stratum fibrosum internum"-, composed of collagenous and elastic microfibrils; the middle layer - "stratum nervosum" - containing a lamellar inner core and Ruffini SNF5; the external layer - "stratum fibrosum externum", that is a collagen capsule. The parenchymal cells show a rich enzyme activity. The parenchymal cells may play the same role as glomus cells of the 1st type and Merkel cells20, 21. When a surgical resection is performed for an oral carcinoma, the CJO may be present in the specimen25. The CJO may be wrongly diagnosed as perineural invasion by carcinoma26, 27, 28. CONCLUSION: We report that Chievitz' organ is the only organ in which the cancer does not occur. KEY WORDS: Chievitz' organ, Juxtaoral organ, Parotid gland.

Bloodless surgery in geriatric surgery.

In bloodless surgery a series of measures has to be implemented to reduce the perioperative need for transfusion of whole blood or its components. Jehovah's Witness are the most representative group of patients opting for bloodless surgery as their faith follows strict believes that prohibits receiving blood. Geriatric patients requiring bloodless surgery are even more delicate and represent a challenge for surgeons. The physiological response of the over 65 year population to decreased hemoglobin level is slower and less effective than in young and adult patients. Herby we describe the perioperative protocol implemented in our surgical Department offered to geriatric Jehovah's Witness patients. Preoperative optimization of the patients is the key step in the preparation period. Intraoperative anesthetic and surgical measures are also required along with a strict postoperative follow-up. From our experience, bloodless surgery is feasible in the geriatric population as long as it is performed in specialized centers where a multidisciplinary team is prepared to specifically manage this scenario. Rigorous patients selection and preparation are mandatory.

Association between Pituitary Langerhans Cell Histiocytosis and Papillary Thyroid Carcinoma.

Here we report a case of panhypopituitarism caused by pituitary Langerhans cell hystocitosis (LCH) in a 22-year-old woman affected by papillary thyroid carcinoma (PTC). Although several cases of the coexistence of PTC and LCH within thyroid tissue have been described in relative literature, in this case, the patient presented a unique suprasellar retrochiasmatic histocytosis localization which, to the best of our knowledge, had never been described before in association with PTC. Even if this aspect is not addressed in the present case report, it is worth noting that about 50% of the patients affected either by LCH or PTC are characterized by activating mutations of the proto-oncogene BRAF. This, along with other clinical studies, may warrant further biomolecular large-scale case study investigations in order to evaluate a possible connection between the 2 conditions and shed light on the etiology of these diseases, which are still largely unknown.

Long-term survival and recurrences after total nerve-sparing surgery for rectal cancer.

BACKGROUND/AIMS: In advanced extraperitoneal rectal cancer Japanese surgeons perform the lateral pelvic nodal dissection with only partial pelvic autonomic nerves preservation; instead most Western surgeons prefer the total mesorectal excision (TME) with complete pelvic nerve sparing except for evident neoplastic nervous involvement. Long-term oncological results of the total nerve-sparing TME are reported. METHODOLOGY: From January 1992 to October 1998 71 [corrected] patients with extraperitoneal rectal carcinoma underwent TME with total nerve sparing except in two cases in which only a partial sparing was possible because of macroscopic neoplastic nervous infiltration: 54 anterior resections and 17 abdominoperineal resections were performed. Sixty-one curatively operated patients (9 stage I, 20 stage II, 29 stage III and 3 stage IV) were included. RESULTS: No postoperative death occurred. Postoperative radiochemotherapy was performed in 31 cases, radiotherapy in 9 cases and chemotherapy in 9 cases. The mean follow-up was 98.7 months. The 5-year overall and disease-free survival rates were 88.8% and 77.7%, 90% and 75.1%, 62.3% and 45% for stage I, II and III respectively. The 8-year actuarial overall and disease-free survival rates were 77.7% and 77.7%, 78.3% and 75.1%, 50.4% and 40% for stage I, II and III respectively. Local failures with or without distant metastases were 6 (9.8%). CONCLUSIONS: Total nerve-sparing surgery is not contraindicated unless grossly neoplastic involvement is present.

Laparoscopic retroperitoneal lymphadenectomy for stage I non-seminomatous testicular tumors.

Retroperitoneal lymph node dissection (RPLND) is the most accurate method to evaluate the presence and extent of retroperitoneal nodal metastases in clinical stage I non-seminomatous germ cell testicular carcinoma. In our Department the open "nerve sparing" RPLND is already the standard surgical treatment for these tumors and laparoscopic technique is employed in surgical treatment of digestive diseases as cholelithiasis, hiatal hernias and gastrointestinal tumors; we report our first experience with laparoscopic RPLND in patients with low stage non-seminomatous germ cell testicular tumors (NSGCTT). A laparoscopic modified template RPLND was performed in 5 high-risk patients with non-seminomatous germ cell clinical stage I tumors by a transperitoneal approach. In 4 of the 5 cases a template dissection was performed. In one pathological stage II tumor a limited lymph node dissection was performed and the patient underwent postoperative chemotherapy. Mean operative time was 190 minutes (range 160-210). No retrograde ejaculation occurred. The mean number of dissected nodes was 21 (range 16-25). At mean follow-up of 16.3 months (range 12-21) the 4 operated patients with pathological stage I NSGCTT are disease free without ejaculatory or urinary dysfunction. Our preliminary experience suggests that laparoscopic RPLND for stage I NSGCTT is feasible and safe for surgeons largely trained in either laparoscopic digestive surgery or open RPLND for whom the learning curve of that minimally invasive approach is lower than expected.

Stapled hemorrhoidectomy: surgical notes and results.

Recently the surgical treatment of hemorrhoids using a circular stapler device has gained increasing approval. The Longo's procedure reduces the rectal mucosal and hemorrhoid prolapse using a circular stapler to resect transversally a mucosal-submucosal rectal ring in order to restore the correct anatomical relationships of the anal canal structures. The recent availability of a dedicated instrument kit (PPH01 Ethicon Endo-Surgery) allowed an easy diffusion of this technique. From March 1999 to September 2001, 198 patients with III-IV degree hemorrhoids were treated by a single expert surgeon using the dedicated kit instrumentation (PPH01) according to the Longo's technique, adopting some variations from the original procedure: 1) The anal dilator is not fixed to the perianal skin with forceps or stitches but is kept by the assistant. 2) In performing the purse-string suture particular care must be given to the apposition of the stitches at the same level also in the posterolateral side where there is a natural trend to apply the stitches at a lower level; furthermore the last stitch of the purse-string suture must be overlapped to the first one in order to allow a better hemostasis when the knot is tightened. 3) After having performed the purse-string and having resected the mucosa and submucosa, an accurate hemostasis with U-shaped 3/0 vicryl stitches firmly reduces the postoperative bleeding. We recorded pain scores, short- and long-term complications (included moderate-severe pain, persistent pain), recurrences and postoperative hospital stay. The data of the last 40 consecutive patients who underwent stapled hemorrhoidectomy were compared with the data obtained by 40 consecutive patients who underwent Milligan-Morgan diathermic hemorrhoidectomy for III-IV degree non-circumferential hemorrhoids by the same surgeon. In the 198 stapled hemorrhoidectomy cases the rate of postoperative moderate-severe pain and persistent pain were 6% and 2.5% respectively, the rate of short-term and long-term bleeding were 4.5% and 3.5%, the recurrence rate was 2.5%. The mean postoperative stay was 1.6 days. The stapled group had significantly lower postoperative moderate-severe pain, bleeding and soiling than the Milligan-Morgan group.

Histopathological features and clinical course of the gastrointestinal stromal tumors.

BACKGROUND/AIMS: C-kit expression is a sensitive marker for a specific group of mesenchymal tumors of the gastrointestinal tract, gastrointestinal stromal tumors, the histogenesis and prognosis of which are uncertain. METHODOLOGY: We have investigated the expression of c-kit by immunohistochemical analysis (APAAP method) in 12 out of 13 cases of mesenchymal gastrointestinal neoplasms operated from January 1991 to December 1998, in which the follow-up data were fully available. Furthermore, the c-kit expression was correlated both with the expression of vimentin, CD34 and the mitotic rate, and with the expression of muscle (muscle-specific actin-HHF35 and desmin) or neural (neuron-specific enolase) differentiation markers. RESULTS: C-kit was expressed in all 12 cases (100%). Two different patterns of expression were observed: cytoplasmic in 7 (58.3%) cases and nuclear in 3 (25%) cases; in 2 (16.7%) cases both cytoplasmic and nuclear immunostaining was detected. Three (60%) out of the five cases showing a nuclear c-kit expression were also neuron-specific enolase positive, whereas none of the cases showing an exclusively cytoplasmic c-kit expression was neuron-specific enolase positive. The correlation between the two patterns of c-kit expression and the follow-up data have shown a trend towards a better prognosis in gastrointestinal stromal tumors with a nuclear c-kit immunostaining and neuron-specific enolase positivity, but the relatively low number of cases does not allow us to draw conclusions. In gastrointestinal stromal tumors the mitotic rate (> 2 x 10 HPF vs. < 2 x 10 HPF) is related with statistically significant differences (P < 0.05) to the 5-year survival (0% vs. 80%, respectively). CONCLUSIONS: These findings, together with the already known c-kit nuclear immunostaining in normal adrenal medullary cells, suggest that a nuclear c-kit expression in gastrointestinal stromal tumors is consistent with a neural differentiation. In this study the mitotic rate has demonstrated a significant influence on the prognosis of gastrointestinal stromal tumors.