The Hellenic Emergency Laparotomy Study (HELAS): A Prospective Multicentre Study on the Outcomes of Emergency Laparotomy in Greece.

BACKGROUND: Emergency laparotomy (EL) is accompanied by high post-operative morbidity and mortality which varies significantly between countries and populations. The aim of this study is to report outcomes of emergency laparotomy in Greece and to compare them with the results of the National Emergency Laparotomy Audit (NELA). METHODS: This is a multicentre prospective cohort study undertaken between 01.2019 and 05.2020 including consecutive patients subjected to EL in 11 Greek hospitals. EL was defined according to NELA criteria. Demographics, clinical variables, and post-operative outcomes were prospectively registered in an online database. Multivariable logistic regression analysis was used to identify independent predictors of post-operative mortality. RESULTS: There were 633 patients, 53.9% males, ASA class III/IV 43.6%, older than 65 years 58.6%. The most common operations were small bowel resection (20.5%), peptic ulcer repair (12.0%), adhesiolysis (11.8%) and Hartmann's procedure (11.5%). 30-day post-operative mortality reached 16.3% and serious complications occurred in 10.9%. Factors associated with post-operative mortality were increasing age and ASA class, dependent functional status, ascites, severe sepsis, septic shock, and diabetes. HELAS cohort showed similarities with NELA patients in terms of demographics and preoperative risk. Post-operative utilisation of ICU was significantly lower in the Greek cohort (25.8% vs 56.8%) whereas 30-day post-operative mortality was significantly higher (16.3% vs 8.7%). CONCLUSION: In this study, Greek patients experienced markedly worse mortality after emergency laparotomy compared with their British counterparts. This can be at least partly explained by underutilisation of critical care by surgical patients who are at high risk for death.

A Prospective Study of Intraarterial Infusion Chemotherapy in Advanced Wild-Type BRAF Melanoma Patients.

BACKGROUND: Treatment strategies for advanced cutaneous melanoma (CM) patients, resistant or not treatable with novel target and immunotherapeutic drugs, remain a significant challenge, particularly for patients with unresectable stage IIIC/D disease localized to inferior limbs and pelvis, for whom specific outcomes are rarely considered. MATERIALS AND METHODS: This is a prospective study of multidisciplinary treatments, including locoregional melphalan chemotherapy, in 62 BRAF wild-type CM patients with locoregional metastases in the inferior limbs and pelvis, including inguinal regions. Patients were either in progression following or ineligible for, or not treatable with novel immunotherapy. For exclusively inferior limb-localised disease, patients received locoregional melphalan chemotherapy performed by hyperthermic isolated limb perfusion (n = 19) or isolated limb infusion (n = 19), and for synchronous lesions localised to inferior limbs and pelvis, received hypoxic pelvic and limb perfusion (n = 24). Additional multidisciplinary therapy included local, locoregional and systemic treatments and the primary endpoint was tumour response. RESULTS: The objective response rate following first cycle of locoregional chemotherapy was 37.1% at 3 mo and median progression-free survival was 4-mo, with 12.9% procedure-related complications, 30.6% low-grade haematological toxicity and 11.3% severe limb toxic tissue reactions. Multivariate logistic regression showed that the odds of response were significantly higher for patients ≤ 75 y of age and for patients with locoregional metastases exclusively located in the inferior limbs. CONCLUSION: In this subgroup of CM patients with BRAF wild-type status, locoregional metastases localized to inferior limbs and pelvis, in progression following or ineligible for immunotherapy, melphalan locoregional chemotherapy demonstrated a safe and effective profile. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT01920516; date of trial registration: August 6, 2013.

A feasibility study of circulating melanoma cells in the perioperative context of hyperthermic isolated limb perfusion (HILP) in 20 patients.

INTRODUCTION: Hyperthermic Ιsolated Limb Perfusion using melphalan and TNFα (TM-HILP) is a regional chemotherapy method for advanced melanoma. PURPOSE: To explore the feasibility of the study of Circulating Melanoma Cells (CMCs) in the context of acute physiological changes induced by TM-HILP and their association with oncological outcomes. METHODS: The study included 20 patients undergoing TM-HILP for unresectable in-transit melanoma of the limbs, stage III(B/C/D). CMCs in the peripheral blood were analyzed at 5-time points from the preoperative day until day 7 from surgery using the following biomarkers: MITF, Tyrosinase mRNA, Melan-A and S100b, through quantitative RT-PCR. RESULTS: No CMCs according to Tyrosinase and Melan-A biomarkers were found in any sample. Friedman test showed significant alterations perioperatively for MITF (p < .001) and S100b (p = .001). Pairwise tests showed a significant increase of MITF levels on postoperative day 7 compared with postoperative day 1, intraoperative and preoperative levels (p < .05). Pairwise tests for S100b showed a significant difference between intraoperative sample and postoperative day 7 (p < .0001). Patients who experienced a complete response to TM-HILP (n = 12) had higher mean levels of MITF and the difference was significant at the time point immediately after the operation (0.29 ± 0.27 vs. 0.06 ± 0.06, p = .014) and on postoperative day 1 (1.48 ± 2.24 vs. 0.41 ± 0.65, p = .046). There was no association of MITF or S100b levels with 4-year disease specific survival. CONCLUSION: TM-HILP is associated with increased levels of CMCs, but there was no association of this increase with survival. Patients with complete response to HILP demonstrate higher values of MITF shortly after the operation.

Analysis of Sentinel Node Biopsy and Clinicopathologic Features as Prognostic Factors in Patients With Atypical Melanocytic Tumors.

BACKGROUND: Atypical melanocytic tumors (AMTs) include a wide spectrum of melanocytic neoplasms that represent a challenge for clinicians due to the lack of a definitive diagnosis and the related uncertainty about their management. This study analyzed clinicopathologic features and sentinel node status as potential prognostic factors in patients with AMTs. PATIENTS AND METHODS: Clinicopathologic and follow-up data of 238 children, adolescents, and adults with histologically proved AMTs consecutively treated at 12 European centers from 2000 through 2010 were retrieved from prospectively maintained databases. The binary association between all investigated covariates was studied by evaluating the Spearman correlation coefficients, and the association between progression-free survival and all investigated covariates was evaluated using univariable Cox models. The overall survival and progression-free survival curves were established using the Kaplan-Meier method. RESULTS: Median follow-up was 126 months (interquartile range, 104-157 months). All patients received an initial diagnostic biopsy followed by wide (1 cm) excision. Sentinel node biopsy was performed in 139 patients (58.4%), 37 (26.6%) of whom had sentinel node positivity. There were 4 local recurrences, 43 regional relapses, and 8 distant metastases as first events. Six patients (2.5%) died of disease progression. Five patients who were sentinel node-negative and 3 patients who were sentinel node-positive developed distant metastases. Ten-year overall and progression-free survival rates were 97% (95% CI, 94.9%-99.2%) and 82.2% (95% CI, 77.3%-87.3%), respectively. Age, mitotic rate/mm2, mitoses at the base of the lesion, lymphovascular invasion, and 9p21 loss were factors affecting prognosis in the whole series and the sentinel node biopsy subgroup. CONCLUSIONS: Age >20 years, mitotic rate >4/mm2, mitoses at the base of the lesion, lymphovascular invasion, and 9p21 loss proved to be worse prognostic factors in patients with ATMs. Sentinel node status was not a clear prognostic predictor.

CRHR2/Ucn2 signaling is a novel regulator of miR-7/YY1/Fas circuitry contributing to reversal of colorectal cancer cell resistance to Fas-mediated apoptosis.

Colorectal cancer (CRC) responds poorly to immuno-mediated cytotoxicity. Underexpression of corticotropin-releasing-hormone-receptor-2 (CRHR2) in CRC, promotes tumor survival, growth and Epithelial to Mesenchymal Transition (EMT), in vitro and in vivo. We explored the role of CRHR2 downregulation in CRC cell resistance to Fas/FasL-mediated apoptosis and the underlying molecular mechanism. CRC cell sensitivity to CH11-induced apoptosis was compared between Urocortin-2 (Ucn2)-stimulated parental and CRHR2-overexpressing CRC cell lines and targets of CRHR2/Ucn2 signaling were identified through in vitro and ex vivo analyses. Induced CRHR2/Ucn2 signaling in SW620 and DLD1 cells increased specifically their sensitivity to CH11-mediated apoptosis, via Fas mRNA and protein upregulation. CRC compared to control tissues had reduced Fas expression that was associated with lost CRHR2 mRNA, poor tumor differentiation and high risk for distant metastasis. YY1 silencing increased Fas promoter activity in SW620 and re-sensitized them to CH11-apoptosis, thus suggesting YY1 as a putative transcriptional repressor of Fas in CRC. An inverse correlation between Fas and YY1 expression was confirmed in CRC tissue arrays, while elevated YY1 mRNA was clinically relevant with advanced CRC grade and higher risk for distant metastasis. CRHR2/Ucn2 signaling downregulated specifically YY1 expression through miR-7 elevation, while miR-7 modulation in miR-7high SW620-CRHR2+ and miR-7low HCT116 cells, had opposite effects on YY1 and Fas expressions and cell sensitivity to CH11-killing. CRHR2/Ucn2 signaling is a negative regulator of CRC cell resistance to Fas/FasL-apoptosis via targeting the miR-7/YY1/Fas circuitry. CRHR2 restoration might prove effective in managing CRC response to immune-mediated apoptotic stimuli.

Inverse correlation between the metastasis suppressor RKIP and the metastasis inducer YY1: Contrasting roles in the regulation of chemo/immuno-resistance in cancer.

Several gene products have been postulated to mediate inherent and/or acquired anticancer drug resistance and tumor metastasis. Among these, the metastasis suppressor and chemo-immuno-sensitizing gene product, Raf Kinase Inhibitor Protein (RKIP), is poorly expressed in many cancers. In contrast, the metastasis inducer and chemo-immuno-resistant factor Yin Yang 1 (YY1) is overexpressed in many cancers. This inverse relationship between RKIP and YY1 expression suggests that these two gene products may be regulated via cross-talks of molecular signaling pathways, culminating in the expression of different phenotypes based on their targets. Analyses of the molecular regulation of the expression patterns of RKIP and YY1 as well as epigenetic, post-transcriptional, and post-translational regulation revealed the existence of several effector mechanisms and crosstalk pathways, of which five pathways of relevance have been identified and analyzed. The five examined cross-talk pathways include the following loops: RKIP/NF-κB/Snail/YY1, p38/MAPK/RKIP/GSK3ß/Snail/YY1, RKIP/Smurf2/YY1/Snail, RKIP/MAPK/Myc/Let-7/HMGA2/Snail/YY1, as well as RKIP/GPCR/STAT3/miR-34/YY1. Each loop is comprised of multiple interactions and cascades that provide evidence for YY1's negative regulation of RKIP expression and vice versa. These loops elucidate potential prognostic motifs and targets for therapeutic intervention. Chiefly, these findings suggest that targeted inhibition of YY1 by specific small molecule inhibitors and/or the specific induction of RKIP expression and activity are potential therapeutic strategies to block tumor growth and metastasis in many cancers, as well as to overcome anticancer drug resistance. These strategies present potential alternatives for their synergistic uses in combination with low doses of conventional chemo-immunotherapeutics and hence, increasing survival, reducing toxicity, and improving quality of life.

Hyperthermic isolated limb perfusion. The switch from Steinmann pins to Omni-tract assisted isolation.

BACKGROUND: Hyperthermic isolated limb perfusion (HILP) represents an alternative to amputation for patients with either in-transit melanoma or unresectable soft tissue sarcoma, entailing delivery of high-dose chemotherapy after isolation of the extremity, under hyperthermic conditions. Stabilization of the Esmarch elastic bandage is so far performed with the use of Steinmann pins. In this study, we presented our experience with HILP and demonstrated an alternative technique for limb isolation using an Omni-tract retractor instead of the traditional Steinmann pin, while comparing the two methods. METHODS: Forty patients, 28 with recurrent in-transit melanoma and 12 with locally advanced/recurrent sarcoma of the limbs, underwent HILP in a single institution and were included in the study. The Steinmann pin was applied in the first 23 cases, whereas the Omni-tract retractor was applied in the latter 17 patients. RESULTS: The median follow-up for the whole study group was 17.5 mo, whereas the overall response rate was 92.9% for melanoma and 75% for sarcoma patients. Both overall survival and local progression-free survival differed significantly between patients with complete response and those with partial response, stable disease or progressive disease. The use of the Omni-tract retractor was advantageous in every examined field, with the overall complication rate, duration of analgesic administration, and total opioid and paracetamol dose, being significantly less in the Omni-tract patient group. CONCLUSIONS: Although this study was not a randomized trial, we consider that the noninvasive application of the Omni-tract retractor will gain significant acceptance, by contributing to the reduction of HILP complications.

EANM practice guidelines for lymphoscintigraphy and sentinel lymph node biopsy in melanoma.

PURPOSE: Sentinel lymph node biopsy is an essential staging tool in patients with clinically localized melanoma. The harvesting of a sentinel lymph node entails a sequence of procedures with participation of specialists in nuclear medicine, radiology, surgery and pathology. The aim of this document is to provide guidelines for nuclear medicine physicians performing lymphoscintigraphy for sentinel lymph node detection in patients with melanoma. METHODS: These practice guidelines were written and have been approved by the European Association of Nuclear Medicine (EANM) to promote high-quality lymphoscintigraphy. The final result has been discussed by distinguished experts from the EANM Oncology Committee, national nuclear medicine societies, the European Society of Surgical Oncology (ESSO) and the European Association for Research and Treatment of Cancer (EORTC) melanoma group. The document has been endorsed by the Society of Nuclear Medicine and Molecular Imaging (SNMMI). CONCLUSION: The present practice guidelines will help nuclear medicine practitioners play their essential role in providing high-quality lymphatic mapping for the care of melanoma patients.

Development and internal validation of a clinical prediction model for serious complications after emergency laparotomy.

PURPOSE: Emergency laparotomy (EL) is a common operation with high risk for postoperative complications, thereby requiring accurate risk stratification to manage vulnerable patients optimally. We developed and internally validated a predictive model of serious complications after EL. METHODS: Data for eleven carefully selected candidate predictors of 30-day postoperative complications (Clavien-Dindo grade > = 3) were extracted from the HELAS cohort of EL patients in 11 centres in Greece and Cyprus. Logistic regression with Least Absolute Shrinkage and Selection Operator (LASSO) was applied for model development. Discrimination and calibration measures were estimated and clinical utility was explored with decision curve analysis (DCA). Reproducibility and heterogeneity were examined with Bootstrap-based internal validation and Internal-External Cross-Validation. The American College of Surgeons National Surgical Quality Improvement Program's (ACS-NSQIP) model was applied to the same cohort to establish a benchmark for the new model. RESULTS: From data on 633 eligible patients (175 complication events), the SErious complications After Laparotomy (SEAL) model was developed with 6 predictors (preoperative albumin, blood urea nitrogen, American Society of Anaesthesiology score, sepsis or septic shock, dependent functional status, and ascites). SEAL had good discriminative ability (optimism-corrected c-statistic: 0.80, 95% confidence interval [CI] 0.79-0.81), calibration (optimism-corrected calibration slope: 1.01, 95% CI 0.99-1.03) and overall fit (scaled Brier score: 25.1%, 95% CI 24.1-26.1%). SEAL compared favourably with ACS-NSQIP in all metrics, including DCA across multiple risk thresholds. CONCLUSION: SEAL is a simple and promising model for individualized risk predictions of serious complications after EL. Future external validations should appraise SEAL's transportability across diverse settings.

Technical considerations for isolated limb perfusion: A consensus paper.

BACKGROUND: Isolated limb perfusion (ILP) is a well-established surgical procedure for the administration of high dose chemotherapy to a limb for the treatment of advanced extremity malignancy. Although the technique of ILP was first described over 60 years ago, ILP is utilised in relatively few specialist centres, co-located with tertiary or quaternary cancer centres. The combination of high dose cytotoxic chemotherapy and the cytokine tumour necrosis factor alpha (TNFα), mandates leakage monitoring to prevent potentially serious systemic toxicity. Since the procedure is performed at relatively few specialist centres, an ILP working group was formed with the aim of producing technical consensus guidelines for the procedure to streamline practice and to provide guidance for new centres commencing the technique. METHODS: Between October 2021 and October 2023 a series of face to face online and hybrid meetings were held in which a modified Delphi process was used to develop a unified consensus document. After each meeting the document was modified and recirculated and then rediscussed at subsequent meeting until a greater than 90% consensus was achieved in all recommendations. RESULTS: The completed consensus document comprised 23 topics in which greater than 90% consensus was achieved, with 83% of recommendations having 100% consensus across all members of the working group. The consensus recommendations covered all areas of the surgical procedure including pre-operative assessment, drug dosing and administration, perfusion parameters, hyperthermia, leakage monitoring and theatre logistics, practical surgical strategies and also post-operative care, response evaluation and staff training. CONCLUSION: We present the first joint expert-based consensus statement with respect to the technical aspects of ILP that can serve as a reference point for both existing and new centres in providing ILP.

Frailty predicts outcome of elective laparoscopic cholecystectomy in geriatric patients.

BACKGROUND: Frailty is a phenotype characterized by complex and challenging medical problems and higher susceptibility to adverse health outcomes. It can be derived at by a multidimensional process known as comprehensive geriatric assessment (CGA), which assesses the functional reserves of the elderly. In this study we report for the first time on a prospective evaluation of the association between CGA and postoperative complications after elective laparoscopic cholecystectomy for biliary disease. METHODS: Fifty-seven patients older than 65 years who were to undergo elective laparoscopic cholecystectomy for uncomplicated biliary disease were prospectively examined. Preoperative CGA was performed and the patients were categorized as fit or frail. The main outcome of the study was the rate of any postoperative complication within 30 days of surgery. RESULTS: There were 29 women (50.9 %) and the median (interquartile range) age of the cohort was 73 (8.8) years. Thirty-two patients (56.1 %) were categorized as frail and 25 (43.9 %) as fit. The overall incidence of postoperative complications was 23.7 %, most of which were grade I and II (18.8 %). Frail patients, according to the CGA assessment, experienced a significantly higher incidence of postoperative complications compared to their fit counterparts (84.6 vs. 15.4 %, p = 0.023). Frail patients experienced a significantly higher frequency of prolonged (more than 2 days) postoperative hospital stay compared with their fit counterparts (p = 0.023). CONCLUSIONS: Preoperative CGA may predict postoperative complications and prolonged postoperative hospital stay of elderly patients who undergo elective laparoscopic cholecystectomy. Larger-scale studies independently assessing this association are warranted.

Pilot study of breast sensation after breast reconstruction: evaluating the effects of radiation therapy and perforator flap neurotization on sensory recovery.

BACKGROUND: Some sensation to the breast returns after breast reconstruction, but recovery is variable and unpredictable. We primarily sought to assess the impact of different types of breast reconstruction [deep inferior epigastric artery perforator (DIEP) flaps versus implants] and radiation therapy on the return of sensation. METHODS: Thirty-seven patients who had unilateral or bilateral breast reconstruction via a DIEP flap or implant-based reconstruction, with or without radiation therapy (minimum follow-up, 18 months; range, 18-61 months) were studied. Of the 74 breasts, 27 had DIEP flaps, 29 had implants, and 18 were nonreconstructed. Eleven breasts with implants and 10 with DIEP flaps had had prereconstruction radiation therapy. The primary outcome was mean patient-perceived static and moving cutaneous pressure threshold in nine areas. We used univariate and multivariate analyses to assess what independent factors affected the return of sensation (significance, P < 0.05). RESULTS: Implants provided better static (P = 0.071) and moving sensation (P = 0.041) than did DIEP flaps. However, among irradiated breasts, skin over DIEP flaps had significantly better sensation than did that over implants (static, P = 0.019; moving, P = 0.028). Implant reconstructions with irradiated skin had significantly worse static (P = 0.002) and moving sensation (P = 0.014) than did nonirradiated implant reconstructions. CONCLUSIONS: Without irradiation, skin overlying implants is associated with better sensation recovery than DIEP flap skin. However, with irradiation, DIEP flap skin had better sensation recovery than did skin over implants. Neurotization trended toward improvement in sensation in DIEP flaps.

Prospective multicenter external validation of postoperative mortality prediction tools in patients undergoing emergency laparotomy.

BACKGROUND: Accurate preoperative risk assessment in emergency laparotomy (EL) is valuable for informed decision making and rational use of resources. Available risk prediction tools have not been validated adequately across diverse health care settings. Herein, we report a comparative external validation of four widely cited prognostic models. METHODS: A multicenter cohort was prospectively composed of consecutive patients undergoing EL in 11 Greek hospitals from January 2020 to May 2021 using the National Emergency Laparotomy Audit (NELA) inclusion criteria. Thirty-day mortality risk predictions were calculated using the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP), NELA, Portsmouth Physiological and Operative Severity Score for the Enumeration of Mortality and Morbidity (P-POSSUM), and Predictive Optimal Trees in Emergency Surgery Risk tools. Surgeons' assessment of postoperative mortality using predefined cutoffs was recorded, and a surgeon-adjusted ACS-NSQIP prediction was calculated when the original model's prediction was relatively low. Predictive performances were compared using scaled Brier scores, discrimination and calibration measures and plots, and decision curve analysis. Heterogeneity across hospitals was assessed by random-effects meta-analysis. RESULTS: A total of 631 patients were included, and 30-day mortality was 16.3%. The ACS-NSQIP and its surgeon-adjusted version had the highest scaled Brier scores. All models presented high discriminative ability, with concordance statistics ranging from 0.79 for P-POSSUM to 0.85 for NELA. However, except the surgeon-adjusted ACS-NSQIP (Hosmer-Lemeshow test, p = 0.742), all other models were poorly calibrated ( p < 0.001). Decision curve analysis revealed superior clinical utility of the ACS-NSQIP. Following recalibrations, predictive accuracy improved for all models, but ACS-NSQIP retained the lead. Between-hospital heterogeneity was minimum for the ACS-NSQIP model and maximum for P-POSSUM. CONCLUSION: The ACS-NSQIP tool was most accurate for mortality predictions after EL in a broad external validation cohort, demonstrating utility for facilitating preoperative risk management in the Greek health care system. Subjective surgeon assessments of patient prognosis may optimize ACS-NSQIP predictions. LEVEL OF EVIDENCE: Diagnostic Test/Criteria; Level II.

Translating cancer genomes sequencing revolution into surgical oncology practice.

BACKGROUND: Ten years after the first complete human genome sequencing, next-generation sequencing (NGS) technology has revolutionized genomics and biomedical research. Here we discuss potential emerging and future applications of NGS platforms and how cancer genome advances may change current surgical oncology practice. MATERIALS AND METHODS: Publications in PubMed with partial or complete human and cancer genome sequencing over the last decade have been retrieved and analyzed. Recently launched international large-scale consortiums for systematic study of causal (driver) mutations underlying common complex diseases such as cancer and more recent opinion articles by leading scientists have been considered to predict the prospects of integration genomics data into surgical oncology. RESULTS: Two dozen complete human genome sequences, and three full-genome sequencing in three cancer patients have recently been published. These studies and other cancer genome systematic studies evaluating genomic rearrangements and copy-number changes consistently reveal that cancer initiation and metastasis are much more complex than we thought. This high complexity and widespread variability of cancer genes, mutations, and deregulated signaling pathways among patients with the same cancer type, tumor stage, and clinicopathologic features explains the limited effectiveness of currently used biologically targeted agents. CONCLUSIONS: Yet the impact of genomics explosion in surgical oncology is little. Nevertheless, "big" biology consortiums such as the International Cancer Genome Project and other systematic studies in the areas of genetics, genomics, and epigenetics are now providing in-depth understanding of cancer, and shape new more rational ways towards novel therapeutics for improving oncologic outcomes of millions of patients worldwide. At the beginning of the second post-genomic decade, an explosion in genomic technology has revolutionized biomedical sciences. The ability of latest DNA sequencing technology to identify, in an unprecedented level, causal mutations driving cancer initiation and metastasis raises significant expectations for improving oncologic outcomes. Which are the challenges and perspectives to translate this genomic revolution into a surgical oncology-changing era?

Indications for surgery and significance of unrecognized cancer in endemic multinodular goiter.

BACKGROUND: The exclusion of cancer in endemic goiter is often difficult mainly because of the high number of nodules and the as-yet unclear natural history of diagnosed cancer in endemic goiter patients. In a large number of consecutive patients who were to undergo total thyroidectomy for endemic multinodular goiter, we assessed indications for surgery and thyroid cancer outcome. METHODS: All patients who were to undergo total thyroidectomy for diffuse multinodular goiter on histological examination between January 1990 and October 2008 were evaluated. RESULTS: Of the 1,161 patients included in the study, 252 were cases of thyroid cancer (21.7%). Sensitivity of thyroid ultrasound (US) and fine-needle aspiration cytology (FNAC) for cancer detection was 30.3 and 64.1%, respectively. Differentiated thyroid carcinoma accounted for most of the tumors (96%), with 54.8% of them being papillary microcarcinomas, while bilateral-multicentric cancer occurred in 20.3%. In multivariate analysis, younger age (p = 0.06), sonographic findings (p = 0.03), and presence of histological thyroiditis (p = 0.09) were independently associated with the occurrence of tumors with diameter greater than 2 cm. The percentage of transient and permanent postoperative complications were approximately 25 and below 2%, respectively. After a median follow-up time of 78.5 months, overall recurrence rate was 6.7% and disease-specific mortality was 1.2%. CONCLUSION: As US and FNAC did not consistently detect cancer in patients with diffuse multinodular goiter in our endemic area, evidence-based indications for surgery in this group of patients is needed, although radical surgery and favorable tumor histology offer favorable outcomes in commonly diagnosed thyroid cancer after total thyroidectomy for endemic multinodular goiter.

Apoptosis and cell proliferation correlated with tumor grade in patients with ampullary carcinoma.

OBJECTIVE: To evaluate apoptosis and cell proliferation on cytologic specimens (smears) from endoscopic retrograde cholangiopancreatography in patients with ampulary carcinoma and to correlate that relationship with the grade of the tumors. STUDY DESIGN: Forty patients (23 males and 17 females) aged 45-81 who underwent endoscopic retrograde cholangiopancreatography were diagnosed by cytology as having ampullary adenocarcinoma and the diagnoses were confirmed histologically after an operation. All smears were stained using Papanicolaou and Giemsa stain. Apoptosis was assessed using terminal digoxigenin-labeled dUTP nick-end labeling (TUNEL assay) and cell proliferation using MIB-1 monoclonal antibody by the alkaline phosphatase method. RESULTS: The TUNEL indices were 0.4 +/- 0.07, 0.91 +/- 0.33 and 3.1 +/- 0.9 in well, moderate and poorly differentiated ampullary carcinoma, respectively. The differences in both TUNEL and MIB-1 labeling indices were statistically significant between well, moderately and poorly differentiated ampullary carcinoma, and a positive correlation was found between TUNEL and the MIB-1 indices. CONCLUSION: Apoptosis (cell death) and cell proliferation increase as the grade of the differentiation decreases in ampullary carcinoma, suggesting a rapid turnover of the tumor cells with lower grates of differentiation, and apoptosis may play an important role in the growth of the tumors in patients with ampullary carcinomas.

Over-the-counter medicines, economic conditions, and citizens most in need in Greece: Is it a challenge for primary care research?

INTRODUCTION: Recent austerity experiences in Greece suggest a plausible link between extensive use of over-the-counter (OTC) medicines and socio-economic peculiarities of life. COMMENTARY: During the economic crisis in Greece, accessibility to healthcare services has been impacted, particularly for people with low income. However, this fact has not been systematically analyzed in conjunction with an observed increase in use of OTC medicines. Gaining a better understanding of the reasons leading to self-care may help to answer additional questions. Further research is needed to assess the gap between self-care and medically assisted care/treatment by designing pilot monitoring actions and focusing on behaviours related to OTC medicine use. Primary care can offer more collaboration between primary care physicians, community pharmacists, patients, and their families. IMPLICATIONS: It is crucial to create a multimodal research plan to gain a better understanding of motivational reasons that eventually lead to increasing use of OTC medicines. Efforts should be made to develop data collection techniques that will elicit information from various social groups that focus on changeable behaviours and perceived needs in relation to medicine consumption.

Hyperthermia During Intraperitoneal Chemotherapy With Paclitaxel or Docetaxel for Ovarian Cancer: Is There Any Benefit?

BACKGROUND/AIM: Intraperitoneal chemotherapy with taxanes provides high locoregional drug concentrations. Regarding their synergy with hyperthermia, results have been inconclusive. In this in vitro study, the thermal enhancement of the effect of paclitaxel and docetaxel on ovarian cancer cells under conditions mimicking those during hyperthermic intraperitoneal chemotherapy (HIPEC) is evaluated. MATERIALS AND METHODS: Cisplatin-resistant SKOV-3 and OVCAR-3 ovarian cancer cells were exposed for 2 h to 0.1, 1 and 3 µΜ of paclitaxel and docetaxel at 37°C (normothermia) and 41.5°C (hyperthermia). Cell proliferation and cell-cycle distribution were evaluated after 24 h, 3 days and 7 days. RESULTS: A concentration-dependent cytotoxic effect on cell proliferation was observed. Concurrent hyperthermia caused an increased arrest of cells in the G2/M phase. At 7 days, thermal enhancement of drug effect was shown only for treatment of OVCAR-3 cells with 1 µM paclitaxel. CONCLUSION: The concentration-dependent cytotoxic effect of paclitaxel and docetaxel supports their intraperitoneal use. Due to the lack of or only minimal thermal enhancement, normothermic may be as effective as hyperthermic intraoperative intraperitoneal chemotherapy with taxanes, avoiding, however, potential oncological and treatment-related adverse effects of concurrent hyperthermia.

PET/CT and PET/MRI in ophthalmic oncology (Review).

Orbital and ocular anatomy is quite complex, consisting of several tissues, which can give rise to both benign and malignant tumors, while several primary neoplasms can metastasize to the orbital and ocular space. Early detection, accurate staging and re­staging, efficient monitoring of treatment response, non­invasive differentiation between benign and malignant lesions, and accurate planning of external radiation treatment, are of utmost importance for the optimal and individualized management of ophthalmic oncology patients. Addressing these challenges requires the employment of several diagnostic imaging techniques, such as high­definition digital fundus photography, ultrasound imaging, optical coherence tomography, optical coherence tomography (OCT)­angiography, computed tomography (CT) and magnetic resonance imaging (MRI). In recent years, technological advances have enabled the development of hybrid positron emission tomography (PET)/CT and PET/MRI systems, setting new standards in cancer diagnosis and treatment. The capability of simultaneously targeting several cancer­related biochemical procedures using positron emitting­radiopharmaceuticals, while morphologically characterizing lesions by CT or MRI, together with the intrinsic quantitative capabilities of PET­imaging, provide incremental diagnostic information, enabling accurate, highly efficient and personalized treatment strategies. Aim of the current review is to discuss the current applications of hybrid PET/CT and PET/MRI imaging in the management of patients presenting with the most commonly encountered orbital and ocular tumors.

Factors Affecting Sentinel Node Metastasis in Thin (T1) Cutaneous Melanomas: Development and External Validation of a Predictive Nomogram.

PURPOSE: Thin melanomas (T1; ≤ 1 mm) constitute 70% of newly diagnosed cutaneous melanomas. Regional node metastasis determined by sentinel node biopsy (SNB) is an important prognostic factor for T1 melanoma. However, current melanoma guidelines do not provide clear indications on when to perform SNB in T1 disease and stress an individualized approach to SNB that considers all clinicopathologic risk factors. We aimed to identify determinants of sentinel node (SN) status for incorporation into an externally validated nomogram to better select patients with T1 disease for SNB. PATIENTS AND METHODS: The development cohort comprised 3,666 patients with T1 disease consecutively treated at the Istituto Nazionale Tumori (Milan, Italy) between 2001 and 2018; 4,227 patients with T1 disease treated at 13 other European centers over the same period formed the validation cohort. A random forest procedure was applied to the development data set to select characteristics associated with SN status for inclusion in a multiple binary logistic model from which a nomogram was elaborated. Decision curve analyses assessed the clinical utility of the nomogram. RESULTS: Of patients in the development cohort, 1,635 underwent SNB; 108 patients (6.6%) were SN positive. By univariable analysis, age, growth phase, Breslow thickness, ulceration, mitotic rate, regression, and lymphovascular invasion were significantly associated with SN status. The random forest procedure selected 6 variables (not growth phase) for inclusion in the logistic model and nomogram. The nomogram proved well calibrated and had good discriminative ability in both cohorts. Decision curve analyses revealed the superior net benefit of the nomogram compared with each individual variable included in it as well as with variables suggested by current guidelines. CONCLUSION: We propose the nomogram as a decision aid in all patients with T1 melanoma being considered for SNB.