Early regression index (ERI) on MR images as response predictor in esophageal cancer treated with neoadjuvant chemo-radiotherapy: Interim analysis of the prospective ESCAPE trial.

PURPOSE: The early regression index (ERI) predicts treatment response in rectal cancer patients. Aim of current study was to prospectively assess tumor response to neoadjuvant chemo-radiotherapy (nCRT) of locally advanced esophageal cancer using ERI, based on MRI. MATERIAL AND METHODS: From January 2020 to May 2023, 30 patients with esophageal cancer were enrolled in a prospective study (ESCAPE). PET-MRI was performed: i) before nCRT (tpre); ii) at mid-radiotherapy, tmid; iii) after nCRT, 2-6 weeks before surgery (tpost); nCRT delivered 41.4 Gy/23fr with concurrent carboplatin and paclitaxel. For patients that skipped surgery, complete clinical response (cCR) was assessed if patients showed no local relapse after 18 months; patients with pathological complete response (pCR) or with cCR were considered as complete responders (pCR + cCR). GTV volumes were delineated by two observers (Vpre, Vmid, Vpost) on T2w MRI: ERI and other volume regression parameters at tmid and tpost were tested as predictors of pCR + cCR. RESULTS: Complete data of 25 patients were available at the time of the analysis: 3/25 with complete response at imaging refused surgery and 2/3 were cCR; in total, 10/25 patients showed pCR + cCR (pCR = 8/22). Both ERImid and ERIpost classified pCR + cCR patients, with ERImid showing better performance (AUC:0.78, p = 0.014): A two-variable logistic model combining ERImid and Vpre improved performances (AUC:0.93, p < 0.0001). Inter-observer variability in contouring GTV did not affect the results. CONCLUSIONS: Despite the limited numbers, interim analysis of ESCAPE study suggests ERI as a potential predictor of complete response after nCRT for esophageal cancer. Further validation on larger populations is warranted.

Clinical characteristics of 80 subjects with KCNQ2-related encephalopathy: Results from a family-driven survey.

Variants of KCNQ2 are associated with a wide spectrum of disorders, ranging from Self-limiting Neonatal Epilepsy (SelNE) to Early Onset Developmental and Epileptic Encephalopathy (KCNQ2-DEE). Comorbidities associated with this end of the spectrum have been seldomly described and their impact on the life of patients and their families is yet to be investigated. Collaborating with caregivers from different European family associations, we have developed a questionnaire aimed at investigating the onset and frequency of epileptic seizures, anti-seizure medications (ASM), hospitalizations, stages of development, and comorbidities. Responses from 80 patients, 40 males, from 14 countries have been collected. Median age 7.6 years (4 months - 43.6 years). Of 76 epileptic patients (93.6%), 55.3% were seizure-free with a mean age at last seizure of 26.7 months. Among patients with active epilepsy, those older have a lower frequency of seizures (p > 0.05). We were able to identify three different clusters of varying severity (Mild, Severe, Profound), based on neurodevelopmental features and symptoms, excluding epilepsy. Patients in a higher severity cluster had a higher mean number of comorbidities, which had a higher impact on families. Notably, patients in different clusters presented different epilepsy onset and courses. This study constitutes the most extensive data collection of patients with KCNQ2-DEE, with a focus on comorbidities in a wide age group. The participation of caregivers helps to define the impact of the disease on the lives of patients and families and can help identify new primary and secondary outcomes beyond seizures in future studies.

Impact of imaging magnification on colorectal surgery: a matched analysis of a single tertiary center.

BACKGROUND: Laparoscopy has been increasingly applied in colorectal surgery, and imaging systems have been improving concurrently. The present study aims to compare outcomes following colorectal surgery with the 4K and traditional high-definition (HD) video systems. METHODS: All consecutive patients undergoing laparoscopic colorectal surgery between April 2016 and June 2020 were retrospectively retrieved from a prospective institutional database. The study population was matched according to the imaging system (4K versus HD groups) through a propensity score matching (PSM) based on perioperative characteristics of 15 patients. A stratified analysis according to surgical procedures (right, left colectomy, and low anterior resection) was also performed. Primary endpoints were intraoperative blood loss and perioperative transfusions. Also, intra- and postoperative morbidity, operative time, lymph node harvest, and length of hospital stay (LOS) were investigated as secondary outcomes. RESULTS: After PSM, 225 patients were included in both 4K and HD groups. The intraoperative blood loss was significantly lower in the 4K group (p = 0.008), although no different volumes of blood transfusion were required. Postoperative complications presented in similar proportions, while significantly higher rates of abdominal collection (p = 0.045), reoperation (p = 0.005), and postoperative urinary disorders occurred in the HD group. After stratification, the right colectomy subgroup shared similar associations with the study population. LOS did not change between groups, although readmissions were significantly lower in the 4K group (p < 0.001). CONCLUSIONS: The 4K imaging system represents a technological advance providing better surgical outcomes, such as the minimization of intraoperative blood loss and postoperative morbidity.

Olfactory epithelium histopathological findings in long-term coronavirus disease 2019 related anosmia.

BACKGROUND: Olfactory dysfunction represents one of the most frequent symptoms of coronavirus disease 2019, affecting about 70 per cent of patients. However, the pathogenesis of the olfactory dysfunction in coronavirus disease 2019 has not yet been elucidated. CASE REPORT: This report presents the radiological and histopathological findings of a patient who presented with anosmia persisting for more than three months after infection with severe acute respiratory syndrome coronavirus-2. CONCLUSION: The biopsy demonstrated significant disruption of the olfactory epithelium. This shifts the focus away from invasion of the olfactory bulb and encourages further studies of treatments targeted at the surface epithelium.

Simultaneous wireless and high-resolution detection of nucleus accumbens shell ethanol concentrations and free motion of rats upon voluntary ethanol intake.

Highly sensitive detection of ethanol concentrations in discrete brain regions of rats voluntarily accessing ethanol, with high temporal resolution, would represent a source of greatly desirable data in studies devoted to understanding the kinetics of the neurobiological basis of ethanol's ability to impact behavior. In the present study, we present a series of experiments aiming to validate and apply an original high-tech implantable device, consisting of the coupling, for the first time, of an amperometric biosensor for brain ethanol detection, with a sensor for detecting the microvibrations of the animal. This device allows the real-time comparison between the ethanol intake, its cerebral concentrations, and their effect on the motion when the animal is in the condition of voluntary drinking. To this end, we assessed in vitro the efficiency of three different biosensor designs loading diverse alcohol oxidase enzymes (AOx) obtained from three different AOx-donor strains: Hansenula polymorpha, Candida boidinii, and Pichia pastoris. In vitro data disclosed that the devices loading H. polymorpha and C. boidinii were similarly efficient (respectively, linear region slope [LRS]: 1.98 ± 0.07 and 1.38 ± 0.04 nA/mM) but significantly less than the P. pastoris-loaded one (LRS: 7.57 ± 0.12 nA/mM). The in vivo results indicate that this last biosensor design detected the rise of ethanol in the nucleus accumbens shell (AcbSh) after 15 minutes of voluntary 10% ethanol solution intake. At the same time, the microvibration sensor detected a significant increase in the rat's motion signal. Notably, both the biosensor and microvibration sensor described similar and parallel time-dependent U-shaped curves, thus providing a highly sensitive and time-locked high-resolution detection of the neurochemical and behavioral kinetics upon voluntary ethanol intake. The results overall indicate that such a dual telemetry unit represents a powerful device which, implanted in different brain areas, may boost further investigations on the neurobiological mechanisms that underlie ethanol-induced motor activity and reward.

Nosocomial transmission of carbapenem-resistant Klebsiella pneumoniae in an Italian university hospital: a molecular epidemiological study.

AIM: To describe the phenotypic and genotypic profiles of Klebsiella pneumoniae carbapenemase-producing K. pneumoniae (KPC-Kp) strains isolated from patients with invasive infections at an Italian university hospital in order to assess the epidemiological trend. METHODS: An observational prospective study was undertaken at the University Hospital of Sassari, Italy to detect KPC-Kp strains in patients with invasive bacteraemia. Isolates were identified phenotypically; carbapenemase production was assessed using phenotypic and genotypic methods. Sequencing of blaKPC genes, pulsed-field gel electrophoresis and multi-locus sequence typing were performed. RESULTS: During the period 2015-2017, 46 cases of invasive infection with K. pneumoniae were recorded. Two-thirds (67.4%) of the patients were male, and the mean age was 69.4 years. Most patients had at least one comorbidity (56.5%) and/or had been hospitalized previously (70.5%), 81.8% had current or recent medical device use, and 85.4% had recent antibiotic exposure. The mortality rate was 52.3%. A multi-drug-resistant pattern (including carbapenems, fluoroquinolones, third-/fourth-generation cephalosporins) was shown for all K. pneumoniae isolates. KPC-3 and -2 were produced by all strains. The most common sequence types were 512 (91.3%) and 101 (8.7%), grouped into three clusters (A, A1 and B). CONCLUSIONS: A high incidence of KPC-Kp in patients with invasive infections was recorded at an Italian university hospital compared with the incidence measured before 2015. This study confirmed the importance of the KPC-3 carbapenemase variant, as reported by other Italian studies. High mortality and comorbidity rates appear to be associated with KPC-Kp infection.

Jagged 1 is a major Notch ligand along cholangiocarcinoma development in mice and humans.

Intrahepatic cholangiocarcinoma (ICC) is a rare yet deadly malignancy with limited treatment options. Activation of the Notch signalling cascade has been implicated in cholangiocarcinogenesis. However, while several studies focused on the Notch receptors required for ICC development, little is known about the upstream inducers responsible for their activation. Here, we show that the Jagged 1 (Jag1) ligand is almost ubiquitously upregulated in human ICC samples when compared with corresponding non-tumorous counterparts. Furthermore, we found that while overexpression of Jag1 alone does not lead to liver tumour development, overexpression of Jag1 synergizes with activated AKT signalling to promote liver carcinogenesis in AKT/Jag1 mice. Histologically, tumours consisted exclusively of ICC, with hepatocellular tumours not occurring in AKT/Jag1 mice. Furthermore, tumours from AKT/Jag1 mice exhibited extensive desmoplastic reaction, an important feature of human ICC. At the molecular level, we found that both AKT/mTOR and Notch cascades are activated in AKT/Jag1 ICC tissues, and that the Notch signalling is necessary for ICC development in AKT/Jag1 mice. In human ICC cell lines, silencing of Jag1 via specific small interfering RNA reduces proliferation and increases apoptosis. Finally, combined inhibition of AKT and Notch pathways is highly detrimental for the in vitro growth of ICC cell lines. In summary, our study demonstrates that Jag1 is an important upstream inducer of the Notch signalling in human and mouse ICC. Targeting Jag1 might represent a novel therapeutic strategy for the treatment of this deadly disease.

The 1,4 benzoquinone-featured 5-lipoxygenase inhibitor RF-Id induces apoptotic death through downregulation of IAPs in human glioblastoma cells.

BACKGROUND: Embelin is a potent dual inhibitor of 5-lipoxigenase (5-LOX) and microsomal prostaglandin E2 synthase (mPGES)-1 that suppresses proliferation of human glioma cells and induces apoptosis by inhibiting XIAP and NF-κB signaling pathway. Synthetic structural modification yielded the derivative 3-((decahydronaphthalen-6-yl)methyl)-2,5-dihydroxycyclohexa-2,5-diene-1,4-dione (RF-Id), an embelin constrained analogue, with improved efficiency against 5-LOX in human neutrophils and anti-inflammatory activity in vivo. Taking into account that lipoxygenase (LOX) metabolites, from arachidonic acid and linoleic acid, have been implicated in tumor progression, here, we determined whether RF-Id was able to hinder glioblastoma (GBM) cancer cell growth and the related mechanisms. METHODS: U87MG and LN229 cells were plated in 96-wells and treated with increasing concentrations of RF-Id. Cell viability was evaluated by MTT assay. The effects of the compounds on cell cycle, apoptosis, oxidative stress and autophagy were assessed by flow cytometry (FACS). The mode of action was confirmed by Taqman apoptosis array and evaluating caspase cascade and NFκB pathway by western blotting technique. RESULTS: Here, we found that RF-Id induced a stronger inhibition of GBM cell growth than treatment with embelin. Flow cytometry analysis showed that RF-Id induced about 30 % apoptosis and a slight increase of autophagy after 72 h on U87-MG cells. Moreover, the compound induced an increase in the percentage of cells in G2 and S phase that was paralleled by an increase of p21 and p27 expression but no significant changes of the mitochondrial membrane potential; array analysis showed a significant upregulation of CASP8 and a downregulation of IAP family and NFκB genes in cells treated with RF-Id. RF-Id induced a significant cleavage of caspases 8, 9, 3 and 7, blocked c-IAP2/XIAP interaction by inducing XIAP degradation and inhibited NFκB pathway. CONCLUSIONS: RF-Id induced a caspase-dependent apoptosis in GBM cells by inhibiting IAP family proteins and NFκB pathway and represents a promising lead compound for designing a new class of anti-cancer drugs with multiple targets.

Extended lymphadenectomy in elderly and/or highly co-morbid gastric cancer patients: A retrospective multicenter study.

BACKGROUND: Gastrectomy with extended lymphadenectomy is considered the gold standard treatment for advanced gastric cancer, with no age- or comorbidity-related limitations. We evaluated the safety and efficacy of curative gastrectomy with extended nodal dissection, verifying survival in elderly and highly co-morbid patients. METHODS: In a retrospective multicenter study, we examined 1322 non-metastatic gastric-cancer patients that underwent curative gastrectomy with D2 versus D1 lymphadenectomy from January 2000 to December 2009. Postoperative complications, overall survival (OS), and disease-specific survival (DSS) according to age and the Charlson Comorbidity Score were analyzed in relation to the extent of lymphadenectomy. RESULTS: Postoperative morbidity was 30.4%. Complications were more frequent in highly co-morbid elderly patients, and, although general morbidity rates after D2 and D1 lymphadenectomy were similar (29.9% and 33.2%, respectively), they increased following D2 in highly co-morbid elderly patients (39.6%). D2-lymphadenectomy significantly improved 5-year OS and DSS (48.0% vs. 37.6% in D1, p < 0.001 and 72.6% vs. 58.1% in D1, p < 0.001, respectively) in all patients. In elderly patients, this benefit was present only in 5-year DSS. D2 nodal dissection induced better 5-year OS and DSS rates in elderly patients with positive nodes (29.7% vs. 21.2% in D1, p = 0.008 and 47.5% vs. 30.6% in D1, p = 0.001, respectively), although it was present only in DSS when highly co-morbid elderly patients were considered. CONCLUSION: Extended lymphadenectomy confirmed better survival rates in gastric cancer patients. Due to high postoperative complication rate and no significant improvement of the OS, D1 lymphadenectomy should be considered in elderly and/or highly co-morbid gastric cancer patients.

Enhanced recovery after surgery (ERAS) pathway vs traditional care in laparoscopic rectal resection: a single-center experience.

BACKGROUND: The aim of this study was to compare the outcome of an enhanced recovery after surgery (ERAS) pathway with traditional perioperative care in laparoscopic rectal resection. METHODS: A retrospective analysis of prospectively collected data was conducted. Single-center consecutive patients who underwent laparoscopic rectal surgery after an ERAS program were compared with patients who received traditional care over an 8-year period. Primary and total length of stay, and readmission, morbidity and mortality rates were analyzed. For ERAS group, the actual adherence to protocol was also evaluated. RESULTS: Two hundred and ninety-seven patients, 162 in the ERAS group and 135 in conventional care, were studied. Median primary and total length of stay were significantly shorter in the ERAS group (9 vs 12 days; p = 0.0001; 10 vs 12 days; p = 0.01; respectively). The ERAS group experienced a faster recovery of bowel function than the traditional care group (p = 0.0001). A similar morbidity rate was observed in the two groups (32.3 % in ERAS vs 36.1 % in traditional care p = 0.41). Readmission rates were 4.9 % in the ERAS versus 1.5 % in the traditional care group (p = 0.19). There was no mortality in either group. Overall mean compliance with the ERAS protocol was 85.7 % (range 54.4-100 %). CONCLUSIONS: The introduction of the ERAS protocol in laparoscopic rectal resection led to a reduction in primary and total length of hospital stay without an increase in morbidity or readmission rates when compared to traditional care.

A systematic review of the effects of adding neostigmine to local anesthetics for neuraxial administration in obstetric anesthesia and analgesia.

BACKGROUND: Drugs used in obstetric patients must accomplish two goals: efficacy and safety for both mother and fetus. Neostigmine has been co-administered epidurally and intrathecally with local anesthetics and other adjuncts in the obstetric setting. The aim of this meta-analysis was to assess the efficacy and incidence of adverse events related to the use of neostigmine in obstetric anesthesia. METHODS: A meta-analysis of randomized-controlled human trials was conducted using the data sources Google Scholar and PubMed (updated 1 November 2014). Inclusion criteria were: random allocation to treatment; comparison of neostigmine or neostigmine with local anesthetics and/or other adjuvants versus placebo or placebo with local anesthetics and/or other adjuvants; and approval by an ethics committee. RESULTS: The use of neostigmine as an adjuvant in neuraxial anesthesia is associated with a reduction in the dose of local anesthetic during labor analgesia and postoperative analgesia following cesarean section: mean reduction of local anesthetic (ropivacaine or bupivacaine) vs. control -4.08 (95% CI -6.7 to -1.5) mg/h (P=0.002). The risk of nausea was increased vs. control with intrathecal neostigmine (OR 8.99 [95% CI 4.74 to 17.05], P <0.001) but not with epidural neostigmine (OR 0.97 [95% CI 0.46 to 2.05], P=0.94). Use of neuraxial neostigmine was associated with a decrease in the risk of pruritus but there was no increase in the incidence of hypotension, dizziness or sedation and no effect on the incidence of abnormal fetal heart rate patterns or Apgar scores. CONCLUSIONS: Neuraxial administration of neostigmine significantly reduces local anesthetic consumption without serious adverse side effects to the mother or fetus. However, neostigmine is only recommended for epidural administration as intrathecal use significantly increases the incidence of maternal nausea and vomiting.

Epidemiology of ovarian cancer in North Sardinia, Italy, during the period 1992-2010.

INTRODUCTION: The aim of this study was to analyze and describe the incidence and mortality trends of ovarian cancer in North Sardinia, Italy, in the period 1992-2010. MATERIALS AND METHODS: Data were obtained from the tumor registry of Sassari province which makes part of a wider registry web, coordinated today by the Italian Association for Tumor Registries. RESULTS: The overall number of ovarian cancer cases registered in the period under investigation was 600. The mean age of the patients was 62 years. The standardized incidence and mortality rates were 11.2/100,000 and 5.1/100,000 respectively. A substantially stable trend in incidence and mortality of ovarian cancer was evidenced. Relative survival at five years from diagnosis was 44.2%. CONCLUSIONS: The incidence and mortality trends of ovarian cancer in North Sardinia remained relatively stable in the last decades, while prognosis remains relatively poor.

Pituitary apoplexy after laparoscopic surgery: a case report.

The occurrence of unprobable adverse events during laparoscopic surgery has increased over the years. Among them, pituitary apoplexy has been reported only twice. The increase in the abdominal pressure might play a role in the pituitary apoplexy, as well as hemodynamic instability, anticoagulant drugs and air-embolism due to insufflation of CO2 during pneumoperitoneum. We report a case of pituitary apoplexy during laparoscopic resection of sigmoid colon.

Report on incidence and mortality trends of cervical cancer in northern Sardinia, Italy.

INTRODUCTION: The aim of this study was to analyze and describe the incidence and mortality trends of cervical cancer in northern Sardinia, Italy, in the period 1992-2010. MATERIALS AND METHODS: Data were obtained from the tumor registry of Sassari province which is part of a wider registry web, coordinated today by the Italian Association for Tumor Registries. RESULTS: The overall number of cervical cancer cases registered in the period under investigation was 311. The mean age of the patients was 51.8 years. The standardized incidence and mortality rates were 6.6 / 100.000 and 0.7 / 100.000, respectively. A stable trend in incidence and mortality of cervical cancer was evidenced. Relative survival at five years from diagnosis was fairly good (66.3%). CONCLUSIONS: The incidence and mortality trends of cervical cancer in northern Sardinia remained relatively stable in the last decades. Furthermore, survival of patients with cervical cancer is good in the area, sanctioning the adequacy of the preventive and clinical measures in use.

Uterine perivascular epithelioid cell neoplasms (PEComas): report of two cases and literature review.

Perivascular epithelioid cell tumors (PEComas) are rare tumors characterized by co-expression of melanocytic and smooth muscle markers. PEComas have been reported in a wide variety of anatomic sites. In the female genital tract, PEComas most frequently affect the uterus. PEComas which occur in non-classic anatomic distributions are known as perivascular epithelioid cell tumor-not otherwise specified (PEComa-NOS). PEComas have an unpredictable biologic behavior, with some tumors being unresectable or metastatic at the time of diagnosis. The risk of aggressive behavior of these tumors has been linked to a number of factors evaluable on histopathological review following initial surgical resection. The authors report two cases of PEComa-NOS of the uterus: one with disease confined to uterus and the other case with lung and liver metastasis.

Squamous cell carcinoma arising in mature cystic teratoma of the ovary: report of two cases with molecular analysis.

Mature cystic teratoma (MCT) is the most frequent ovarian tumor and it is generally composed of well-differentiated elements which, nevertheless, have the potential for malignant transformation. The authors report two cases of squamous cell carcinoma (SCC) arising on ovarian MCT. In the present study, no mutation of the CDKN2A gene, whose impairment may deeply affect either the p16(CDKN2A)-CyclinD1-pRb cascade or the p14(CDKN2A)-mdm2-p53 cascade, was observed in tumour tissues from our cases' collection. This suggests that changes in the protein levels for the above-described candidate effectors may be somehow due to epigenetic alterations into the mechanisms controlling their expression. Analogously, no genetic modification among the two main genes (EGFR and KRAS) upstream the MAPK signalling pathway, which has been widely reported to play a major role in both development and progression of vast majority of malignant tumours, was detected in this series. Additional genes and pathways should be therefore investigated in order to identify genomic impairments underlying the MCT malignant transformation.

Linezolid-induced thrombocytopenia in impaired renal function: is it time for a dose adjustment? A case report and review of literature.

PURPOSE: Thrombocytopenia is a common complication in the intensive care unit (ICU), but the incidence of drug-induced thrombocytopenia (DIT) is not well defined. We investigate linezolid-induced thrombocytopenia in patients with impaired renal function. Since recent studies suggest that linezolid clearance is reduced in these patients and there are no precise data confirming that dose-adjustment should be required, we performed a systematic analysis in order to establish whether it is necessary to consider a dose adjustment and promote studies to confirm this concept. METHODS: We report a case of thrombocytopenia (nadir 32 × 10(3)/µl) in a patient with acute kidney injury who was treated with linezolid for a MRSA pulmonary infection. We performed a systematic review of the literature through PubMed with the aim to include every case report, case series, prospective and retrospective clinical study reporting linezolid-induced thrombocytopenia with concomitant impaired renal function. RESULTS: An increasing number of clinical studies suggest a correlation between the onset of linezolid-induced thrombocytopenia and renal dysfunction. Close monitoring of platelet count and hemoglobin is recommended in patients treated with linezolid, especially in those with impaired renal function because the reduction of its clearance causes drug accumulation, as some studies have reported. CONCLUSIONS: Clinicians should consider the potential risk of this complication, especially in elderly patients with end-stage renal disease. Further studies should be encouraged to determine if the incidence of linezolid-related thrombocytopenia could be reduced by a dose adjustment according to renal function, for which currently there is still no specific recommendation.

Immunoreactivity for Ca 125 and INI 1 loss of expression are useful markers in the diagnosis of vulvar proximal-type epithelioid sarcomas: report of two cases.

Epithelioid sarcomas (ES) are rare soft tissue tumours of obscure histogenesis. Diagnosis is often difficult as specific morphological and immunohistochemical patterns do not exist. Two distinct clinico-pathological entities have been identified: the classic or distal type and the proximal type. Recently, immunohistochemical detection of Ca 125 was described in ES, as well as loss of INI 1 expression. The authors describe in this paper the morphological and immunohistochemical features of two cases of proximal ES of the vulva. Immunoreactivity for Ca 125 and loss of INI 1 expression were present in both cases. These results confirm previous observations in Asian reports showing that these markers can be used as immunohistochemical markers for the diagnostic assessment of ES.

Inflammatory bowel disease.

This review focuses on the prominent etiological and pathogenetic aspects of inflammatory bowel disease (IBD), with particular attention being paid to the mucosal immune response to commensal micro-organisms in health and disease. Pathogenetic implications for target therapy will also be discussed. The clinical presentation, diagnostic aspects, and currently recommended therapeutic options for the two main types of IBD are also taken into consideration, including manifestations of these conditions in the oral cavity.