Parathyroid Retrospective Analysis of Neoplasms Incidence (pTRANI Study): An Italian Multicenter Study on Parathyroid Carcinoma and Atypical Parathyroid Tumour.

BACKGROUND: Parathyroid cancer (PC) is a rare sporadic or hereditary malignancy whose histologic features were redefined with the 2022 WHO classification. A total of 24 Italian institutions designed this multicenter study to specify PC incidence, describe its clinical, functional, and imaging characteristics and improve its differentiation from the atypical parathyroid tumour (APT). METHODS: All relevant information was collected about PC and APT patients treated between 2009 and 2021. RESULTS: Among 8361 parathyroidectomies, 351 patients (mean age 59.0 ± 14.5; F = 210, 59.8%) were divided into the APT (n = 226, 2.8%) and PC group (n = 125, 1.5%). PC showed significantly higher rates (p < 0.05) of bone involvement, abdominal, and neurological symptoms than APT (48.8% vs. 35.0%, 17.6% vs. 7.1%, 13.6% vs. 5.3%, respectively). Ultrasound (US) diameter >3 cm (30.9% vs. 19.3%, p = 0.049) was significantly more common in the PC. A significantly higher frequency of local recurrences was observed in the PC (8.0% vs. 2.7%, p = 0.022). Mortality due to consequences of cancer or uncontrolled hyperparathyroidism was 3.3%. CONCLUSIONS: Symptomatic hyperparathyroidism, high PTH and albumin-corrected serum calcium values, and a US diameter >3 cm may be considered features differentiating PC from APT. 2022 WHO criteria did not impact the diagnosis.

Robot-assisted minimally invasive esophagectomy (RAMIE) with side-to-side semi-mechanical anastomosis: analysis of a learning curve.

Minimally invasive esophagectomy (MIE) reduces mortality and morbidity related to esophageal surgery, but a long learning curve is necessary due to the technical difficulties of thoracoscopy (35 to 119 patients required as reported in literature). Robot-assisted minimally invasive esophagectomy (RAMIE) with side-to-side semi-mechanical (SM) anastomosis may shorten completion of the learning curve. We present the results of the first 40 RAMIEs performed by a single surgeon with experience in esophageal and minimally invasive surgery. Patients included in this study underwent RAMIE between April 1, 2018 and April 30, 2021. According to the risk-adjusted cumulative sum analysis for postoperative complications, the first 19 patients were compared to the last 21. Pulmonary complications and atrial fibrillation occurred in 2.5% and 5% of cases, respectively. A single case of anastomotic leak in the early group was registered. Thirty-day mortality was 2.5%. R0 resection was obtained in all cases. No anastomotic strictures occurred during the follow-up (median of 20 months). A significant difference between the early group and the late one was observed for median operative time (425 vs 393 min, p = 0.001), estimated intraoperative blood loss (100 vs 50 ml, p = 0.003), Intensive Care Unit stay (days 2 vs 1, p = 0.004), hospital stay (days 13 vs 10, p = 0.007) and number of lymph nodes harvested (17 vs 21, p = 0.020). In conclusion, this study showed RAMIE to be safe and effective even in the early phase of its application. The learning curve resulted shorter than in MIE, with 19 patients needed to gain proficiency in our series.

Impact of Tissue Enolase 1 Protein Overexpression in Esophageal Cancer Progression.

Enolase (ENO) 1 is a key glycolytic enzyme and important player in tumorigenesis. ENO1 overexpression has been correlated with tumor progression and/or worse prognosis in several solid malignancies. However, data concerning the impact of ENO1 in cancer conflict. The study correlated local and circulating ENO1 protein levels in esophageal cancer (EC) with clinicopathological data, to assess its potential clinical value. ENO1 expression was analyzed by immunohistochemistry in paired tumor and non-tumor tissue samples from 40 EC cases and mucosal biopsies from 45 Barrett's esophagus (BE) cases, plus in plasma from these patients and 25 matched healthy controls. ENO1 was abnormally elevated in cancer-cell cytoplasm in both EC types, in esophageal squamous cell carcinoma and in adenocarcinoma (EAC), increasing significantly with tumor stage progression and the transition from BE to EAC. EAC patients exhibited significantly lower ENO1 plasma concentrations than normal subjects. Neither local nor systemic ENO1 expression levels were significantly associated with overall survival. These results indicate ENO1 as potential biomarker, delineating a population of patients with Barrett's esophagus at high risk of cancer, and as new therapeutic opportunity in EC patient management. However, further confirmation might be necessary.

Transhiatal distal esophagectomy for Siewert type II cardia cancer can be a treatment option in selected patients.

BACKGROUND: While surgical treatment of Siewert I and III (S1,S3) Esophagogastric Junction (EGJ) cancer is codified, the efficay of transhiatal procedure with anastomosis in the lower mediastinum for Siewert II (S2) still remains a dibated topic. METHODS: This is a large multicenter retrospective study. The results of 598 consecutive patients submitted to resection with curative intent from January 2000 to January 2017 were reported. Clinical and oncological outcomes of different procedures performed in S2 tumor were analyzed to investigate the efficacy of transhiatal approach. RESULTS: The 5-year overall survival rate (OS) was poor (32%) for all Siewert types. The most performed operations in S2 cancer were proximal gastrectomy + transthoracic esophagectomy (TTE or Ivor-Lewis procedure, 60%), total gastrectomy + transhiatal distal esophagectomy with anastomosis in the chest (THE, 24%) and total gastrectomy + transthoracic esophagectomy (TGTTE, 15%). Cardiovascular and pulmonary complications were higher after TTE. On the contrary, surgical complications were significantly higher after THE. Postoperative mortality was similar. The distribution of TNM stages was different in the 3 types of procedures: patients submitted to THE had an earlier stage disease. With this bias, OS after THE was higher than after TTE but the difference was not significant (49.85% vs 28.42%, p = 0.0587). CONCLUSIONS: Despite a higher rate of postoperative surgical complications, OS after total gastrectomy and transhiatal distal esophagectomy was at least comparable to that of transthoracic approach in less advanced S2 tumors. Therefore, THE with anastomosis in the chest could be a treatmen option in earlier S2 tumors.

Volumetric modulated arc therapy (VMAT) in the treatment of esophageal cancer patients.

The aim of the study is to evaluate feasibility, safety, toxicity profile, and dosimetric results of volumetric modulated arc therapy (VMAT) to deliver definitive or pre-operative radiation in locally advanced esophageal cancer patients. A total of 68 patients were treated with VMAT between March 2014 and March 2018 (44% vs 56% for definitive and neoadjuvant settings, respectively). Dose prescription differed depending on the clinical scenario (54-60 Gy in 30 fractions for definitive treatments; 41.4/45 Gy in 23-25 fractions in the pre-operative setting). Most of the patients were given concurrent chemotherapy. Two coplanar and one non-coplanar arcs were employed for VMAT delivery. Treatment was generally well tolerated. Acute toxicity was generally mild. In patients treated with definitive intent, ≥ G3 toxicities were observed for esophagitis (30%), anorexia (26.7%), fatigue (26.7%), nausea (6.7%), and vomiting (3.3%). In patients treated within a neoadjuvant approach, ≥ G3 anorexia (21%), esophagitis (15.8%), fatigue (13.3%), nausea (5.3%), and vomiting (2.6%) were observed. Dosimetric results were consistent in term of both target coverage and normal tissue sparing. In conclusion, VMAT proved to be a feasible, safe, and effective strategy to deliver definitive or pre-operative radiation in locally advanced esophageal cancer patients.

Pre-operative treatments for adenocarcinoma of the lower oesophagus and gastro-oesophageal junction: a review of the current evidence from randomized trials.

Adenocarcinomas of the lower oesophagus and gastro-oesophageal junction are a complex clinico-pathological setting. Multimodality therapy is considered mandatory in most disease presentations. Nevertheless, the most appropriate treatment package has yet to be established. We herein summarize the evidence derived from randomized phase III trials on pre-operative treatments in this oncological scenario.

Segmental tracheal resection for invasive differentiated thyroid carcinoma. Our experience in eight cases.

PURPOSE: In differentiated thyroid carcinoma (DTC), complete resection of local disease provides the longest survival and the best palliation. In pursuit of this goal, segmental tracheal or laryngotracheal resection can be performed on patients with DTC invading the airway. The study summarizes the technical aspects of the intervention and analyzes its results in eight patients. METHODS: The results of eight tracheal or laryngotracheal resections for DTC invading the airway were analyzed. Three patients presented with local recurrent disease, whereas five underwent airway resection at the time of thyroidectomy or shortly after. All received a circumferential sleeve resection of the trachea (2­4 tracheal rings) that in three cases extended to the cricoid, followed by end-to-end anastomosis. RESULTS: Pathologic evaluation identified seven papillary and one poorly differentiated carcinomas. No postoperative deaths occurred; one patient required surgical reexploration because of postoperative bleeding, and two air leaks resolved with conservative treatment. Functional results were excellent. During follow-up, one patient died of lung and bone metastases, while in two cases locally persistent/recurrent disease has been detected; two patients are currently free of disease, and in the last three cases only persistent thyroglobulin levels are indicative of residual disease. CONCLUSIONS: In our experience, segmental airway resection is safe, provides excellent functional results, and can warrant adequate control of local disease.

Comparative evaluation of cancer stem cell markers in normal pancreas and pancreatic ductal adenocarcinoma.

Chemoresistance and self-renewal of cancer stem cells (CSC), found in many tumors including pancreatic ductal adenocarcinoma (PDAC), are believed to underlie tumor mass regrowth. The distribution of cells carrying the putative stem-cell markers CD133, Nestin, Notch1-4, Jagged1 and 2, ABCG2 and aldehyde dehydrogenase (ALDH1) was assessed immunohistochemically using PDAC and normal pancreas tissue microarrays. The immunoreactivity was semi-quantitatively graded against the normal pancreas and was correlated with the differentiation grade and disease stage. No statistical significant differences were found between normal pancreas and PDAC in the expression of Nestin, Notch1, 3 and 4, ABCG2 or ALDH1. Notch2 and Jagged1 and 2 expression were increased in PDAC. CD133-positive cells were above-normal in PDAC, but the difference was not statistically significant. Nestin, Notch1-4, Jagged1, ABCG2 and ALDH1 immunostaining scores were not correlated with tumor grade or disease stage. CD133 and Notch2 expression was significantly inversely correlated with tumor grade, but not disease stage. Notch3 immunostaining positively correlated with tumor stage, but not with differentiation grade. Jagged2 protein expression correlated inversely with disease stage, but not with tumor grade. From the clinical standpoint, improved delineation of the tumor CSC signature, putatively responsible for tumor initiation and recurrence after initial response to chemotherapy, may offer novel therapeutic targets for this highly lethal cancer.

Hyperparathyroidism, an emerging disease.

A retrospective study based on 35 years of personal experience was done. Up to today 2,175 patients were operated, 1,318 for primary hyperparathyroidism (HPT) and 857 for secondary and tertiary HPT. Considering recent years (1999 to July 2010), 918 patients were operated for primary HPT. Preoperatively all the patients performed a cervical ultrasound and/or a sestamibi scan. Open mininvasive procedure was preferred: it is an easily reproducible and costless technique. Using magnifying glasses up to 2.5, an excellent three-dimensional vision was obtained. The operating time is short and if there are any doubts it is possible to extend the exploration to the other side of the neck. Immediate and long-term results were excellent, with a cure rate greater than 99%. Complications in the treatment of a single adenoma are around 0.3%. Patients can be discharged 24-48 h after the operation. Regarding reoperations, a correct diagnostic and therapeutic approach is essential. CT, MRI and SPECT must correlate with the information given by ultrasound and scintigraphy. The intraoperative PTH assay (io-PTH) is required and the approach should be limited to the area where the missed gland probably is. The functionality of the autotransplantation (AT) performed immediately was good. The functionality of the cryopreserved tissue is better for the HPT I in comparison with HPT II. Considering HPT I or HPT II the use of io-PTH is helpful. MIBI scanning is helpful but not essential, except in reoperations. Surgeon experience is another very important factor for good results.

Abnormal expression of Endoglin and its receptor complex (TGF-ß1 and TGF-ß receptor II) as early angiogenic switch indicator in premalignant lesions of the colon mucosa.

The precise timing of the angiogenic switch in colorectal cancer development is still unclear. The simultaneous expression of Endoglin (CD105), transforming growth factor (TGF)-ß1 and TGF-ß receptor (R) II were quantified in surgical specimens comprising normal human colon, pre-malignant dysplastic tissue, in situ, and invasive colon cancer specimens, at mRNA and protein levels, respectively by real-time PCR and immunohistochemistry. Serum concentrations of soluble Endoglin and TGF-ß1 were evaluated. mRNA and CD105+-microvessel density (MVD) increased significantly in dysplastic colon and carcinoma versus normal tissues; values correlated respectively with dysplasia degree and Dukes' stages. TGF-ß1 expression was significantly upregulated in most severe dysplastic adenoma specimens, while TGF-ß1 transcript and protein signals were intense in carcinoma, positively-correlated with tumor progression. TGF-ß1 RII was overexpressed in adenoma and carcinoma versus normal samples, but unrelated with dysplasia or Dukes' stage. Soluble Endoglin serum levels were equivalent in adenoma and normal tissues; in carcinoma the highest levels were in invasive tumor. Circulating TGF-ß1 levels were increased in severe dysplasia and progressed with tumor progression. Correlations between adenoma dysplasia degree and TGF-ß RII and CD105+-MVD, and between tumor Dukes' staging and TGF-ß1 and CD105+-MVD, were significant. TGF-ß1 and Endoglin and TGF-ß1 serum levels, TGF-ß1 staining and CD105+-MVD were significantly and inversely associated with disease-free survival. TGF-ß1 levels were an independent and significant prognostic factor of disease-free survival. These findings suggest active angiogenesis occurs in many pre-malignant colon cases and supports more careful evaluation of different chemopreventive agents.

The usefulness of preoperative dual-phase 99mTc MIBI-scintigraphy and IO-PTH assay in the treatment of secondary and tertiary hyperparathyroidism.

BACKGROUND: Persistent secondary or tertiary hyperparathyroidism (HPT) results from failure to remove enough hyperfunctioning parathyroid tissue. Ectopically situated parathyroid glands and supernumerary glands make failure more likely. Recurrent HPT after subtotal Ptx is usually due to regrowth of the remaining parathyroid tissue. Recurrence may also develop from a hyperplastic supernumerary gland or rarely from parathyromatosis. Recurrent HPT after total Ptx with autotransplantation is usually due to overgrowth of the autograft or for the previously mentioned reasons. METHODS: Since 1995, 464 patients with SHPT or THPT were treated surgically; intraoperative parathormone (PTH) was measured in 277 patients. Sixty-eight patients also had a preoperative MIBI scan. We compared the preoperative MIBI scan results with intraoperative findings, parathyroid gland weight and histology. We questioned whether MIBI uptake corresponded to parathyroid gland size and weight. We also correlated the number of Ki67 nuclear positive cells with MIBI uptake. For SHPT in group I with 145 patients, neither intraoperative PTH (IO-PTH) assay nor MIBI scanning was done. In group II with 163 patients IO-PTH was used and in group III with 48 patients both IO-PTH and MIBI scanning was used. For THPT in group I with 42 patients, neither IO-PTH assay nor MIBI scanning was done. In group II with 46 patients IO-PTH was used and in group III with 20 patients both IO-PTH and MIBI scanning was used. RESULTS: Parathyroid weight correlated directly with MIBI uptake. No correlation, however, occurred between MIBI uptake and parathyroid histology or between Ki67 staining and MIBI scanning. For SHPT in group I the persistence rate was 6.2% and recurrence rate 11%; in group II the persistence rate was 4.9% and recurrence rate 4.9%; in group III the persistence rate was 2%, and recurrence 4.2% (P < 0.05 between group I and III for persistence and recurrence). We obtained similar results in THPT, but recurrence was 0 in groups II and III, also when only 3 glands were removed, probably due to asymmetric hyperplasia commonly seen in this particular population (P < 0.05 regarding recurrence between group I and II-III, no difference between group II and III). CONCLUSION: In conclusion our findings support that the surgeon experience is a very important factor for good results in patients with SHPT and THPT. Preoperative MIBI scanning and IO-PTH are helpful but not essential except in reoperations.

Carcinosarcoma of the esophagogastric junction.

Carcinosarcoma of the esophagus and the stomach are rare neoplasms characterized by the simultaneous presence of carcinomatous and sarcomatous elements. There is no report in the literature of carcinosarcoma of the esophagogastric junction. We present a case of carcinosarcoma of the esophagogastric junction whose unique clinical presentation, surgical issues, morphological and immunohistochemical features makes it quite distinctive from similar cases observed in the esophagus or in the stomach.

Successful surgical management of a delayed pharyngo-esophageal perforation after anterior cervical spine plating.

A case report of a 41-year-old man who had a delayed pharyngo-esophageal perforation without instrumentation failure 7 years after anterior cervical spine plating is presented and the literature on this issue is reviewed. This injury resulted from repetitive friction/traction between the retropharyngo-esophageal wall and the cervical plate construct leading to a pseudodiverticulum and perforation. Successful treatment of the perforation was obtained after surgical repair using a sternocleidomastoid muscle flap. This case stresses the necessity of careful long-term follow-up in patients with anterior cervical spine plating for early detection of possible perforation and the use of muscle flap as the treatment of choice during surgical repair.

Transforming growth factor-beta binding receptor endoglin (CD105) expression in esophageal cancer and in adjacent nontumorous esophagus as prognostic predictor of recurrence.

BACKGROUND: We hypothesized that the potent neovascularization marker endoglin (CD105), by differentially highlighting a subset of microvessels (MV) in esophageal cancer (EC), could provide better prognostic/therapeutic information than the panendothelial marker CD34, which also highlights MV. METHODS: Endoglin messenger ribonucleic acid (mRNA) expression in normal, malignant, and adjacent nontumorous esophagus tissue was quantified by real-time reverse-transcription polymerase chain reaction (RT-PCR). Sections of formalin-fixed, paraffin-embedded tissues were analyzed immunohistochemically for CD105 and CD34. MV density was counted following a standard protocol. Circulating soluble endoglin levels were determined in patient and control sera, and compared with clinical outcome. RESULTS: CD105 mRNA was upregulated by a median factor of 2.89 in ECs versus controls. In 28% of patients, CD105 mRNA was upregulated by a median factor of 2.65 in adjacent non-tumorous versus normal tissue. In tumor tissues, CD105 was stained negatively or positively only in a subset of MV. CD34 always showed positive extensive MV staining. In adjacent nontumorous esophagus, CD105 rarely showed diffuse MV staining, while CD34 stained blood-vessel endothelial cells in all non-neoplastic tissue. CD105 expression was high in residual highly dysplastic Barrett's-type mucosa associated with some adenocarcinomas. No statistically significant difference in endoglin serum levels appeared between patients and normal subjects. Correlation with clinicopathological data showed higher intra-tumor MV-CD105+ scores at more-advanced clinical stages. High-scoring MV-CD105+ patients had significantly shorter disease-free and overall survival; MV-CD34+ density was not survival related. Diffuse CD105 expression in adjacent nontumorous esophagus predicted poorer disease-free and overall survival. CONCLUSIONS: Our findings could help identify EC patients who may benefit from targeted anti-angiogenic therapies.