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Abstract Background Barrett's mucosa is the precursor of esophageal adenocarcinoma. The molecular mechanisms behind Barrett's carcinogenesis are largely unknown. Experimental models of longstanding esophageal reflux of duodenal-gastric contents may provide important information on the biological sequence of the Barrett's oncogenesis. Methods The expression of CDX2 hox-gene product was assessed in a rat model of Barrett's carcinogenesis. Seventy-four rats underwent esophago-jejunostomy with gastric preservation. Excluding perisurgical deaths, the animals were sacrificed at various times after the surgical treatment (Group A: 30 weeks). Results No Cdx2 expression was detected in either squamous epithelia of the proximal esophagus or squamous cell carcinomas. De novo Cdx2 expression was consistently documented in the proliferative zone of the squamous epithelium close to reflux ulcers (Group A: 68%; Group B: 64%; Group C: 80%), multilayered epithelium and intestinal metaplasia (Group A: 9%; Group B: 41%; Group C: 60%), and esophageal adenocarcinomas (Group B: 36%; Group C: 35%). A trend for increasing overall Cdx2 expression was documented during the course of the experiment (p = 0.001). Conclusion De novo expression of Cdx2 is an early event in the spectrum of the lesions induced by experimental gastro-esophageal reflux and should be considered as a key step in the morphogenesis of esophageal adenocarcinoma.

Introduction: Handwriting deteriorates proportionally to the writer's cognitive state. Such knowledge is of special importance in the case of a contested will, where dementia of the testator is claimed, but medical records are often insufficient to decide what the testator's cognitive state really was. By contrast, if the will is handwritten, handwriting analysis allows us to gauge the testator's cognitive state at the precise moment when he/she was writing the will. However, quantitative methods are needed to precisely evaluate whether the writer's cognitive state was normal or not. We aim to provide a test that quantifies handwriting deterioration to gauge a writer's cognitive state., Methods: We consecutively enrolled patients who came for the evaluation of cognitive impairment at the Outpatient Clinic for Cognitive Impairment of the Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics and Maternal and Child Sciences (DINOGMI) of the University of Genoa, Italy. Additionally, we enrolled their caregivers. We asked them to write a short text by hand, and we administered the Mini Mental State Examination (MMSE). Then, we investigated which handwriting parameters correlated with cognitive state as gauged by the MMSE., Results: Our study found that a single score, which we called the COG nitive I mpairment T hrough h A ndwri T ing ( COGITAT ) score, reliably allows us to predict the writer's cognitive state., Conclusion: The COGITAT score may be a valuable tool to gage the cognitive state of the author of a manuscript. This score may be especially useful in contested handwritten wills, where clinical examination of the writer is precluded., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Balestrino, Brugnolo, Girtler, Pardini, Rizzetto, Alì, Cocito and Schiavetti.)

Implant-based breast reconstruction is part of breast cancer treatment, and increasingly optimized reconstructive procedures exploit highly biocompatible materials to ensure enhanced aesthetic-functional results. Acellular dermal matrices (ADMs) are collagen-based materials that made prepectoral implant placement possible, thanks to their bioactive antifibrosis action. Recently, the first three-dimensional ADM, BRAXON ® Fast , has been produced. Its 3D design represents the technological evolution of BRAXON ® ADM, a flat collagen matrix, and allows for a time-saving complete wrapping of the synthetic prosthesis, thus creating a total biological interface on the implant with patient's tissues. Here, we report our experience on the first 23 eligible patients who received BRAXON ® Fast -assisted prepectoral reconstruction. On a total of 27 breasts, the overall complication rate was 11.1%, including one minor seroma (3.7%), one case of necrosis (3.7%), and one implant removal due to infection. As new-generation devices, 3D ADMs showed an effective performance, allowing to reduce the overall exposure time for implant preparation and providing an optimal safety profile ., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2022 Berna, De Grazia, Antoniazzi, Romeo, Dell'Antonia, Lovero, Marchica, Rizzetto and Burelli.)

Background: Neuropsychological testing plays a cardinal role in the diagnosis and monitoring of Alzheimer's disease. A major concern is represented by the heterogeneity of the neuropsychological batteries currently adopted in memory clinics and healthcare centers. The current study aimed to solve this issue., Methods: Following the initiative of the University of Washington's National Alzheimer's Coordinating Center (NACC), we presented the Italian adaptation of the Neuropsychological Test Battery of the Uniform Data Set (I-UDSNB). We collected data from 433 healthy Italian individuals and employed regression models to evaluate the impact of demographic variables on the performance, deriving the reference norms., Results: Higher education and lower age were associated with a better performance in the majority of tests, while sex affected only fluency tests and Digit Span Forward., Conclusions: The I-UDSNB offers a valuable and harmonized tool for neuropsychological testing in Italy, to be used in clinical and research settings., (© 2022. The Author(s).)

Background: Dermopigmentation, also known as medical tattooing, is a complementary technique in the reconstruction of the nipple-areola and an adjuvant procedure to improve colour mismatch. In 2009, tattooing of the nipple-areola complex (NAC) was introduced by Treviso Hospital through a project conducted in cooperation with the local section of the Italian Anti-Cancer League (LILT)., Methods: From 2010 to 2016, 169 patients treated for breast cancer underwent dermopigmentation treatments. Patients were selected by the hospital plastic and breast surgeons. Dermopigmentation was performed at the LILT (Lega Italiana per la Lotta contro i Tumori, Italian Cancer League) facility following a specific procedure to ensure safety. A sterile disposable surgical set was used., Results: Of 169 patients treated in 309 treatment sessions, no serious complications were reported after tattooing, with only three cases seen of minor complications. Patients expressed a high level of satisfaction (90%) with the aesthetic results., Conclusion: The study found that dermopigmentation of the NAC is a safe approach, providing benefits both to the patients and the hospital itself. Medical tattooing of the NAC is a simple and safe nonsurgical technique that reduces missed workdays and increases the time available for other commitments. This ultimately translates into savings for society and the healthcare system.

Background: A new manometric classification of esophageal achalasia has recently been proposed that also suggests a correlation with the final outcome of treatment. The aim of this study was to investigate this hypothesis in a large group of achalasia patients undergoing laparoscopic Heller-Dor myotomy., Methods: We evaluated 246 consecutive achalasia patients who underwent surgery as their first treatment from 2001 to 2009. Patients with sigmoid-shaped esophagus were excluded. Symptoms were scored and barium swallow X-ray, endoscopy, and esophageal manometry were performed before and again at 6 months after surgery. Patients were divided into three groups: (I) no distal esophageal pressurization (contraction wave amplitude <30 mmHg); (II) rapidly propagating compartmentalized pressurization (panesophageal pressurization >30 mmHg); and (III) rapidly propagating pressurization attributable to spastic contractions. Treatment failure was defined as a postoperative symptom score greater than the 10th percentile of the preoperative score (i.e., >7)., Results: Type III achalasia coincided with a longer overall lower esophageal sphincter (LES) length, a lower symptom score, and a smaller esophageal diameter. Treatment failure rates differed significantly in the three groups: I = 14.6% (14/96), II = 4.7% (6/127), and III = 30.4% (7/23; p = 0.0007). At univariate analysis, the manometric pattern, a low LES resting pressure, and a high chest pain score were the only factors predicting treatment failure. At multivariate analysis, the manometric pattern and a LES resting pressure <30 mmHg predicted a negative outcome., Conclusion: This is the first study by a surgical group to assess the outcome of surgery in 3 manometric achalasia subtypes: patients with panesophageal pressurization have the best outcome after laparoscopic Heller-Dor myotomy.

Objective: Aim of this study was to evaluate whether delayed surgery after neoadjuvant chemoradiotherapy (CRT) affects postoperative outcomes in patients with locally advanced squamous cell carcinoma (SCC) of the thoracic esophagus., Background: Esophagectomy is usually recommended within 4 to 6 weeks after completion of neoadjuvant CRT. However, the optimal timing of surgery is not clearly defined., Methods: A total of 129 consecutive patients with locally advanced esophageal cancer, treated between 1998 and 2007, were retrospectively analyzed using prospectively collected data. Patients were divided into 3 groups on the basis of timing to surgery: group 1, ≤30 days (n = 17); group 2, 31 to 60 days (n = 83); and group 3, 61 to 90 days (n = 29). Subsequently, only 2-numerically more consistent-groups were studied, using the median value of timing intervals as a cutoff level: group A, ≤46 days (n = 66); and group B, >46 days (n = 63)., Results: Groups were comparable in terms of patient and tumor characteristics, type of neoadjuvant regimen, toxicity, postoperative morbidity and mortality rates, tumor downstaging, and pathologic complete responses. The overall 5-year actuarial survival rate was 0% in group 1, 43.1% in group 2, and 35.9% in group 3 (P = 0.13). After R0 resection (n = 106), the 5-year actuarial survival rate was 0%, 51%, and 47.3%, respectively (P = 0.18). Tumor recurrence after R0 resection seemed to be inversely related, even if not significantly (P = 0.17), to the time interval between chemoradiation and surgery: 50% in group 1, 40.6% in group 2, and 21.7% in group 3. When considering only 2 groups, the overall 5-year survival was 33.1% in group A and 42.7% in group B (P = 0.64); after R0 resection, the 5-year survival was 37.8% and 56.3%, respectively (P = 0.18). The rate of tumor recurrence was significantly lower in group B (25%) than in group A (48.3%) (P = 0.02)., Conclusion: Delayed surgery after neoadjuvant chemoradiation does not compromise the outcomes of patients with locally advanced SCC of the esophagus. Delaying surgery up to 90 days offers relevant advantages in the clinical management of the patients, can reduce tumor recurrences, and may improve prognosis after complete R0 resection surgery.

In Barrett's mucosa, both aneuploidy and TP53 mutations are consistently recognized as markers of an increased risk of Barrett's adenocarcinoma. Overexpression of the mitotic kinase encoding gene (AURKA) results in chromosome instability (assessed from the micronuclei count) and ultimately in aneuploidy. Eighty-seven esophageal biopsy samples representative of all the phenotypic lesions occurring in the multistep process of Barrett's carcinogenesis (gastric metaplasia in 25, intestinal metaplasia in 25, low-grade intraepithelial neoplasia in 16, high-grade intraepithelial neoplasia in 11, and Barrett's adenocarcinoma in 10) were obtained from long segments of Barrett's mucosa. Twenty-five additional biopsy samples of native esophageal mucosa were used for control purposes. In all tissue samples, the immunohistochemical expression of both AURKA and TP53 gene products was scored; and the micronuclei index was calculated. AURKA immunostaining increased progressively and significantly along with dedifferentiation of the histologic phenotype (P < .001). Nine of 10 Barrett's adenocarcinomas showed AURKA immunostaining. AURKA expression correlated significantly with p53 expression and the micronuclei index (both Ps < .001). AURKA overexpression is significantly associated with Barrett's mucosa progressing to Barrett's adenocarcinoma and contributes to esophageal carcinogenesis via chromosome instability. The identification of AURKA as a novel molecular target of cancer progression in Barrett's mucosa provides a lead for the development of new therapeutic approaches in Barrett's mucosa patients., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Screening for genes down-regulated in esophageal cancers (Oncomine database) pinpointed programmed cell death 4 (PDCD4) as one of the most consistently involved. PDCD4 is a new putative tumor suppressor gene implicated in cell transformation, tumorigenesis, and invasiveness. Based on such a biological rationale, the aim of the present study was to evaluate the prognostic value of PDCD4 in esophageal cancers. The immunohistochemical expression of PDCD4 protein was assessed in 111 consecutive esophageal cancers (63 adenocarcinomas and 48 squamous cell carcinomas) and paired non-cancerous samples. PDCD4 immunostaining was significantly lower in cancer samples than in non-cancerous mucosa (p<0.001). In all cases, the native esophageal epithelium consistently expressed nuclear PDCD4, which was significantly less expressed (37/111 cases) or completely lacking (31/111 cases) in the cancer samples. A significant inverse correlation emerged between nuclear PDCD4 expression and tumor stage (p=0.002), pT (p<0.001), nodal metastasis (p=0.038), and with both vascular (p=0.005) and perineural invasion (p=0.004). Nuclear PDCD4 expression was associated with a longer disease-free (p=0.011) and overall (p=0.021) survival. PDCD4 expression predicts the patient outcome in esophageal cancers. Additional functional studies should look into the role of PDCD4 in the multistep process of esophageal oncogenesis also inquiring on the clinical usefulness of the protein expression as prognostic marker in esophageal precancerous lesions.

Background: Barrett's mucosa is the precursor of esophageal adenocarcinoma. The molecular mechanisms behind Barrett's carcinogenesis are largely unknown. Experimental models of longstanding esophageal reflux of duodenal-gastric contents may provide important information on the biological sequence of the Barrett's oncogenesis., Methods: The expression of CDX2 hox-gene product was assessed in a rat model of Barrett's carcinogenesis. Seventy-four rats underwent esophago-jejunostomy with gastric preservation. Excluding perisurgical deaths, the animals were sacrificed at various times after the surgical treatment (Group A: <10 weeks; Group B: 10-30 weeks; Group C: >30 weeks)., Results: No Cdx2 expression was detected in either squamous epithelia of the proximal esophagus or squamous cell carcinomas. De novo Cdx2 expression was consistently documented in the proliferative zone of the squamous epithelium close to reflux ulcers (Group A: 68%; Group B: 64%; Group C: 80%), multilayered epithelium and intestinal metaplasia (Group A: 9%; Group B: 41%; Group C: 60%), and esophageal adenocarcinomas (Group B: 36%; Group C: 35%). A trend for increasing overall Cdx2 expression was documented during the course of the experiment (p = 0.001)., Conclusion: De novo expression of Cdx2 is an early event in the spectrum of the lesions induced by experimental gastro-esophageal reflux and should be considered as a key step in the morphogenesis of esophageal adenocarcinoma.

Objective: Laparoscopic myotomy is the currently preferred treatment for achalasia. Our objectives were to assess the long-term outcome of this operation and preoperative factors influencing said outcome., Methods: Demographic and clinical characteristics and data on long-term outcome were prospectively collected on patients undergoing laparoscopic myotomy for achalasia at our institution from 1992 to 2007. Treatment failure was defined as a postoperative symptom score higher than the 10th percentile of the preoperative score (>9). Logistic regression analysis was used to identify independent preoperative factors associated with successful myotomy., Results: Four hundred seven consecutive patients (220 men, 187 women) underwent the laparoscopic Heller-Dor procedure during the study period; 89 (22%) of them had previously had endoscopic treatment(s). The mortality rate was 0; the conversion and morbidity rates were 1.5% and 1.9%, respectively. The operation failed in 10% of patients (39/407) and the 5-year actuarial probability of being asymptomatic was 87%. Most failures (25/39, 64%) occurred within 12 months of the operation and can be considered as technical failures (incomplete myotomy). Pneumatic dilation overcome the dysphagia in 75% of patients whose surgery was unsuccessful. Considering both the primary surgery and this ancillary treatment, the operation was effective in 97% of achalasia patients. The frequency of sigmoid esophagus, lower esophageal sphincter (LES) resting pressures, and chest pain scores differed statistically between patients with and without recurrences. At multivariate analysis, high preoperative LES pressures (>30 mm Hg) was an independent predictor of a good response. The presence of chest pain and of sigmoid esophagus independently predicted the failure of the procedure., Conclusion: Laparoscopic myotomy can durably relieve dysphagia symptoms. High preoperative LES pressures represent the strongest predictor of a positive outcome, probably reflecting a less severely damaged esophageal muscle.

Background: Zenker's diverticula (ZD) can be treated by transoral diverticulostomy or open surgery (upper esophageal sphincter myotomy and diverticulectomy or diverticulopexy). The aim of this study was to compare the effectiveness of a minimally invasive (group A) versus a traditional open surgical approach (group B) in the treatment of ZD., Material and Methods: Between 1993 and September 2007, 128 ZD patients underwent transoral diverticulostomy (n = 51) or cricopharyngeal myotomy and diverticulectomy or diverticulopexy (n = 77). All patients were evaluated for symptoms using a detailed questionnaire. Manometry recorded upper esophageal sphincter (UES) pressure, relaxations, and intrabolus pharyngeal pressure. The size of the pouch was measured on the barium swallow. The choice of treatment was based on the size of the diverticulum and the patients' preference. Long-term follow-up data were available for 121/128 (94.5%) patients with a median follow-up of 40 months (interquartile range, 17-83)., Results: Mortality was nil. Three patients in group A (5.8%) and ten in group B (13%) had postoperative complications (p = n.s.). Hospital stays were markedly shorter for patients after diverticulostomy (p < 0.01). Postoperative manometry showed a reduction in UES pressure, improved UES relaxation, and lower intrabolus pressure in both groups (p < 0.05). Four patients in the open surgery group (5.2%) complained of severe dysphagia after surgery (three of them required endoscopic dilations). In the transoral diverticulostomy group, 11 patients (21.5%) required additional septal reduction (n = 8) or a surgical myotomy (n = 3) for persistent symptoms (p < 0.01); nine of these 11 patients had a ZD < or = 3 cm in size. After primary and complementary treatments, symptoms disappeared or improved significantly at long-term follow-up in 93.5% of patients in group A and 96% of those in group B., Conclusion: Diverticulostomy is safe, quick, and effective for most patients with medium-sized ZD, but open surgery offers better long-term results as a primary treatment and should be recommended for younger, healthy patients, especially those with small diverticula. Small ZD may represent a formal contraindication to the transoral approach because an excessively short septum prevents a complete division of the sphincter fibers.

Introduction: The natural history of esophageal epiphrenic diverticula (ED) is not entirely clear; the decision whether to operate or not is often based on the personal preference of the physician and patient. The aim of this study was to evaluate the long-term fate of operated and unoperated patients with ED., Materials and Methods: Clinical, radiological, and motility findings, and operative morbidity and long-term outcome of 41 patients with ED (January 1993 to December 2005) were analyzed. All patients were reviewed at the outpatient clinic or interviewed over the phone. A symptom score was calculated using a standard questionnaire and subjective patient assessment. The radiological maximum diameter of the ED was measured., Results: Twenty-two patients (12M:10F; median age, 60 years) were operated. One underwent surgery for spontaneous rupture of a large diverticulum. Operative mortality was nil; postoperative morbidity was 22.7%, the most severe complication being suture leakage (4 patients, all managed conservatively); median follow-up was 53 months. Nineteen patients (9M, 10F; median age 70 years) were not operated: 3 received pneumatic dilations; median follow-up was 46 months. None of the patients in either group died for reasons related to their ED. Symptoms decreased in all operated patients and, to a lesser extent, also in unoperated patients. ED recurrence was observed in one operated patient. Four patients had GERD symptoms with esophagitis and/or positive pH-metry after surgery and 3 patients had persistent dysphagia/regurgitation and were dissatisfied with the outcome of surgery., Discussion: Surgery is an effective treatment for ED, but carries a significant morbidity related mainly to suture leakage. Even in the long-term, unoperated patients do not die of their ED, though a better subjective symptom outcome is reported by operated patients. A non-interventional policy can safely be adopted in cases of small, mildly symptomatic ED.

Objective: The loss of myenteric neurons in the lower esophageal sphincter (LES) characterizes achalasia, an esophageal motor disorder. Because the presence of lymphocytic infiltrates suggests an immuno-mediated mechanism ongoing at the sites of disease, we investigated the T-cell receptor (TCR) repertoire and the ability to recognize human herpes virus type 1 (HSV-1) antigens of LES-infiltrating T lymphocytes in achalasia patients., Methods: Fifty-nine patients with idiopathic achalasia and 38 heart-beating cadaveric multiorgan donors (controls) were studied. By flow cytometry evaluation and CDR3 length spectratyping analysis, the lymphocytes of 18 patients and 15 controls were analyzed, whereas 41 patients and 23 controls were employed for functional assays., Results: Achalasia patients were characterized by a significantly higher esophagus lymphocytic infiltrate than controls (24.71%+/- 3.11 and 9.54%+/- 1.34, respectively; P < 0.05), mainly represented by CD3+CD8+ T cells. The characterization of TCR beta chain repertoire of CD3+ cells showed the expression of a limited number of TCR beta variable (BV) gene families (from two to five out of 26), with highly restricted spectratypes, suggesting a disease-associated oligoclonal selection of T cells. Furthermore, lymphocytes from achalasia LES specifically responded to exposure to HSV-1 antigens in vitro as showed by increased proliferation and Th-1 type cytokines release., Conclusions: These data suggest that the oligoclonal lymphocytic infiltrate within the LES of achalasia patients may represent the trace of an immune-inflammatory reaction triggered by HSV-1 antigens and that the Th1-type cytokines released by the activated lymphocytes may contribute to establish the neuronal damage accounting for the clinical features of idiopathic achalasia.

Objective: Our aim was to compare outcome of vagal-sparing esophagectomy with transhiatal and en bloc esophagectomy in patients with intramucosal adenocarcinoma or high-grade dysplasia., Summary Background Data: Intramucosal adenocarcinoma and high grade dysplasia have a low likelihood of lymphatic or systemic metastases and esophagectomy is curative in most patients. However, traditional esophagectomy is associated with significant morbidity and altered gastrointestinal function. A vagal-sparing esophagectomy offers the advantages of complete disease removal with the potential for reduced morbidity and a better functional outcome., Method: Retrospective review of outcome in patients with intramucosal adenocarcinoma or high grade dysplasia that had a vagal-sparing (n=49), transhiatal (n=39) or en bloc (n=21) esophagectomy., Results: The length of hospital stay and the incidence of major complications was significantly reduced with a vagal-sparing esophagectomy compared with a transhiatal or en bloc resection. Further, postvagotomy dumping and diarrhea symptoms were significantly less common, and weight was better maintained postoperatively with a vagal-sparing esophagectomy. Recurrent cancer has developed in only 1 patient., Conclusion: Survival with intramucosal adenocarcinoma or Barrett's with high-grade dysplasia is independent of the type of resection. A vagal-sparing esophagectomy is associated with significantly less perioperative morbidity and a shorter hospital stay than a transhiatal or en bloc esophagectomy. Further, late morbidity including weight loss, dumping, and diarrhea are significantly less likely after a vagal-sparing approach. Consequently a vagal-sparing esophagectomy is the preferred procedure for patients with intramucosal adenocarcinoma or high grade dysplasia.