Intraperitoneal pharmacokinetics of systemic oxaliplatin, 5-fluorouracil and bevacizumab in patients with colorectal peritoneal metastases.

BACKGROUND: Peritoneal metastases (PM) commonly occur in colorectal cancer patients. Systemic chemotherapy yields poor outcomes for these patients. It is hypothesised that traditional systemic chemotherapy is not very effective for this patient population. This study investigates to what extent systemic anti-cancer therapy crosses the peritoneal barrier. METHODS: In a Phase I study, eighteen patients received systemic oxaliplatin, 5-FU, and bevacizumab. Plasma and peritoneal fluid samples were collected to measure drug concentrations. A non-compartmental analysis determined the Area Under the Curve (AUC) for oxaliplatin and 5-FU in both matrices. Intraperitoneal (IP) and intravenous (IV) exposure ratios were calculated, along with the bevacizumab concentration IP/IV ratio. The relationship between tumour load and IP/IV ratios and the correlation between the IP/IV ratios of different treatments were assessed statistically. RESULTS: A total of 438 5-FU samples and 578 oxaliplatin samples were analysed in plasma and peritoneal fluid. Bevacizumab was quantified with 17 measurements in plasma and 15 measurements IP. Median IP/IV ratios were 0.143, 0.352 and 0.085 for 5-FU, oxaliplatin and bevacizumab, respectively. Oxaliplatin exhibited a longer IP half-life than 5-FU. A correlation was found between oxaliplatin and bevacizumab IP/IV ratios (R=0.69, p=0.01). No statistical correlations were found between the other investigated drugs. CONCLUSIONS: Our findings indicate that only a small percentage of systemically administered anti-cancer treatment reaches the IP cavity, questioning their efficacy against PM. This strengthens the hypothesis for repeated intraperitoneal chemotherapy to reach adequate anti-cancer drug levels.

Population pharmacokinetics of intraperitoneal irinotecan and SN-38 in patients with peritoneal metastases from colorectal origin.

Peritoneal metastases (PM) are common in patients with colorectal cancer. Patients with PM have a poor prognosis, and for those who are not eligible for cytoreductive surgery (CRS) with or without hyperthermic intraperitoneal chemotherapy (HIPEC), palliative chemotherapy is currently the only option. Recently, we conducted a phase I trial (INTERACT) in which irinotecan was administered intraperitoneally (IP) to 18 patients ineligible for CRS-HIPEC. The primary objective was to evaluate covariates influencing the PK profile of irinotecan and SN-38 after IP administration. Secondly, a population PK model was developed to support the further development of IP irinotecan by improving dosing in patients with PM. Patients were treated with IP irinotecan every 2 weeks in combination with systemic FOLFOX-bevacizumab. Irinotecan and SN-38 were measured in plasma (588 samples) and SN-38 was measured in peritoneal fluid (267 samples). Concentration-Time data were log-transformed and analyzed using NONMEM version 7.5 using FOCE+I estimation. An additive error model described the residual error, with inter-individual variability in PK parameters modeled exponentially. The final structural model consisted of five compartments. Weight was identified as a covariate influencing the SN-38 plasma volume of distribution and GGT was found to influence the SN-38 plasma clearance. This population PK model adequately described the irinotecan and SN-38 in plasma after IP administration, with weight and GGT as predictive factors. Irinotecan is converted intraperitoneal to SN-38 by carboxylesterases and the plasma bioavailability of irinotecan is low. This model will be used for the further clinical development of IP irinotecan by providing dosing strategies.

Associations of Menstrual Cycle and Progesterone-to-Estradiol Ratio With Alcohol Consumption in Alcohol Use Disorder: A Sex-Separated Multicenter Longitudinal Study.

OBJECTIVE: Alcohol use disorder (AUD) constitutes a critical public health issue and has sex-specific characteristics. Initial evidence suggests that progesterone and estradiol might reduce or increase alcohol intake, respectively. However, there is a need for a better understanding of how the menstrual cycle in females and the ratio of progesterone to estradiol in females and males influence alcohol use patterns in individuals with AUD. METHODS: In this sex-separated multicenter longitudinal study, the authors analyzed 12-month data on real-life alcohol use (from 21,460 smartphone entries), menstrual cycle, and serum progesterone-to-estradiol ratios (from 667 blood samples at four individual study visits) in 74 naturally cycling females and 278 males with AUD between 2020 and 2022, using generalized and general linear mixed modeling. RESULTS: Menstrual cycle phases were significantly associated with binge drinking and progesterone-to-estradiol ratio. During the late luteal phase, females showed a lower predicted binge drinking probability of 13% and a higher predicted marginal mean of progesterone-to-estradiol ratio of 95 compared with during the menstrual, follicular, and ovulatory phases (binge drinking probability and odds ratios vs. late luteal phase, respectively: 17%, odds ratio=1.340, 95% CI=1.031, 1.742; 19%, odds ratio=1.523, 95% CI=1.190, 1.949; and 20%, odds ratio=1.683, 95% CI=1.285, 2.206; difference in progesterone-to-estradiol ratios, respectively: -61, 95% CI=-105.492, -16.095; -78, 95% CI=-119.322, -37.039; and -71, 95% CI=-114.568, -27.534). In males, a higher progesterone-to-estradiol ratio was related to lower probabilities of binge drinking and of any alcohol use, with a 10-unit increase in the hormone ratio resulting in odds ratios of 0.918 (95% CI=0.843, 0.999) and 0.914 (95% CI=0.845, 0.988), respectively. CONCLUSIONS: These ecologically valid findings suggest that high progesterone-to-estradiol ratios can have a protective effect against problematic alcohol use in females and males with AUD, highlighting the progesterone-to-estradiol ratio as a promising treatment target. Moreover, the results indicate that females with AUD may benefit from menstrual cycle phase-tailored treatments.

Three-dimensional anatomy of the transantral intraseptal infraorbital canal with the use of cone-beam computed tomography.

The transantral or ectopic infraorbital canal (IOC) courses diagonally through the maxillary sinus (MS), thereby being exposed to risk during a number of surgical procedures. A few prior reports have presented evidence of a septa-embedded IOC, albeit only on single-plane slices. We identified this extremely rare variation of the IOC during a retrospective study of the cone-beam computed tomography files of 2 patients. In the first case, which involved a 34-year-old female patient, the canals and septa within the MS were bilaterally asymmetrical. On the right side, the sinus roof was attached to a short transverse septum that was traversed by the IOC, while the left sinus featured an oblique large septum that divided it into antero-superior and posterior chambers. The left IOC was embedded within the septum rather than within the orbital floor above the septum. In the second case, which concerned a 36-year-old male patient, the left MS featured an almost completely oblique/vertical septum that divided it into anterior and posterior chambers and also embedded the respective IOC, which was thus absent from the orbital floor. In both cases, infraorbital recesses in the anterior chambers of the MS were found that, if not documented on three-dimensional (3D) renderisations, could have been misidentified as infraorbital (Haller) cells. To the best of our knowledge, this is the first report to document the 3D anatomy of an extremely rare variant, namely a septum-embedded transantral IOC. Such a variant, if not adequately documented preoperatively, could divert the transmaxillary corridors down false paths or else expose the IOC to damage during surgical procedures involving access to tumours.

Quality of transition to end-of-life care for cancer patients in the intensive care unit.

BACKGROUND: There have been few studies that have evaluated the quality of end-of-life care (EOLC) for cancer patients in the ICU. The aim of this study was to explore the quality of transition to EOLC for cancer patients in ICU. METHODS: The study was undertaken on medical patients admitted to a specialist cancer hospital ICU over 6 months. Quantitative and qualitative methods were used to explore quality of transition to EOLC using documentary evidence. Clinical parameters on ICU admission were reviewed to determine if they could be used to identify patients who were likely to transition to EOLC during their ICU stay. RESULTS: Of 85 patients, 44.7% transitioned to EOLC during their ICU stay. Qualitative and quantitative analysis of the patients' records demonstrated that there was collaborative decision-making between teams, patients and families during transition to EOLC. However, 51.4 and 40.5% of patients were too unwell to discuss transition to EOLC and DNACPR respectively. In the EOLC cohort, 76.3% died in ICU, but preferred place of death known in only 10%. Age, APACHE II score, and organ support, but not cancer diagnosis, were identified as associated with transition to EOLC (p = 0.017, p < 0.0001 and p = 0.001). CONCLUSIONS: Advanced EOLC planning in patients with progressive disease prior to acute deterioration is warranted to enable patients' wishes to be fulfilled and ceiling of treatments agreed. Better documentation and development of validated tools to measure the quality EOLC transition on the ICU are needed.

Changes in medical students' attitudes towards end-of-life decisions across different years of medical training.

BACKGROUND: Decisions to forgo life-sustaining medical treatments in terminally ill patients are challenging, but ones that all doctors must face. Few studies have evaluated the impact of medical training on medical students' attitudes towards end-of-life decisions and none have compared them with an age-matched group of non-medical students. OBJECTIVE: To assess the effect of medical education on medical students' attitudes towards end-of-life decisions in acutely ill patients. DESIGN: Cross-sectional study. PARTICIPANTS: Four hundred and two students at The Chinese University of Hong Kong. MEASUREMENTS: Completion of a questionnaire focused on end-of-life decisions. MAIN RESULTS: The number of students who felt that cardiopulmonary resuscitation must always be provided was higher in non-medical students (76/90 (84%)) and medical students with less training (67/84 (80%) in year 1 vs. 18/67 (27%) in year 5) (p < 0.001). Discontinuing life-support therapy was more accepted among senior medical students compared to junior medical and non-medical students (27/66 (41%) in year 5 vs. 18/83 (22%) in year 1 and 20/90 (22%) in non-medical students) (p = 0.003). An unexpectedly large proportion of non-medical students (57/89 (64%)) and year 1 medical students (42/84 (50%)) found it acceptable to administer fatal doses of drugs to patients with limited prognosis. Euthanasia was less accepted with more years of training (p < 0.001). When making decisions regarding limitation of life-support therapy, students chose to involve patients (98%), doctors (92%) and families (73%) but few chose to involve nurses (38%). CONCLUSIONS: Medical students' attitudes towards end-of-life decisions changed during medical training and differed significantly from those of non-medical students.

Randomized controlled trial comparing adaptive-support ventilation with pressure-regulated volume-controlled ventilation with automode in weaning patients after cardiac surgery.

BACKGROUND: Adaptive-support ventilation (ASV) is a minute ventilation-controlled mode governed by a closed-loop algorithm. With ASV, tidal volume and respiratory rate are automatically adjusted to minimize work of breathing. Studies indicate that ventilation in ASV enables more rapid weaning. The authors conducted a randomized controlled trial to determine whether ventilation in ASV results in a shorter time to extubation than pressure-regulated volume-controlled ventilation with automode (PRVCa) after cardiac surgery. METHODS: Fifty patients were randomly assigned to ASV or PRVCa after elective coronary artery bypass grafting. Respiratory weaning progressed through three phases: phase 1 (controlled ventilation), phase 2 (assisted ventilation), and phase 3 (T-piece trial), followed by extubation. The primary outcome was duration of intubation (sum of phases 1-3). Secondary outcomes were duration of mechanical ventilation (sum of phases 1 and 2), number of arterial blood gas samples, and manual ventilator setting changes made before extubation. RESULTS: Forty-eight patients completed the study. The median duration of intubation was significantly shorter in the ASV group than in the PRVCa group (300 [205-365] vs. 540 [462-580] min; P < 0.05). This difference was due to a reduction in the duration of mechanical ventilation (165 [120-195] vs. 480 [360-510] min; P < 0.05). There were no significant differences between the ASV and PRVCa groups in the number of arterial blood gas samples taken or manual ventilator setting changes made. CONCLUSIONS: ASV is associated with earlier extubation, without an increase in clinician intervention, when compared with PRVCa in patients undergoing uncomplicated cardiac surgery.

Involvement of E-cadherin and beta-catenin in germ cell tumours and in normal male fetal germ cell development.

Intercellular contacts, mediated by E-cadherin, are essential for germ cell migration and maturation. Furthermore, it has been suggested that decrease or loss of E-cadherin correlates with tumour progression and invasive behaviour. beta-catenin is involved in a number of different processes, including cell--cell interaction when bound to cadherins, and determination of cell fate in pluripotent cells when activated via the Wnt signal-transduction pathway. To shed more light on the role of these factors in normal fetal germ cell development and the pathogenesis of germ cell tumours (GCTs), the present study investigated the presence and localization of E-cadherin and beta-catenin by immunohistochemistry. E-cadherin was only weakly expressed in or absent from fetal germ cells of the second and third trimesters, and was not expressed in carcinoma in situ/intratubular germ cell neoplasia unclassified (CIS/ITGCNU) and gonadoblastoma, the precursor of an invasive GCT in dysgenetic gonads. In GCTs, it was generally not expressed in seminoma and dysgerminoma, but was found in the vast majority of non-seminoma cells. beta-catenin was found in the cytoplasm of fetal germ cells at all gestational ages and in spermatogenesis in post-pubertal testes. It was also present in CIS/ITGCNU and gonadoblastoma. Whereas seminomas and dysgerminoma were negative, non-seminoma cells were frequently found to express beta-catenin. Expression of both factors therefore reflects the degree of differentiation of these tumours. No differences for either E-cadherin or beta-catenin were observed between samples of tumours resistant or sensitive to chemotherapy, and E-cadherin expression did not correlate with vascular invasion. E-cadherin and beta-catenin therefore play a role in both normal and malignant germ cell development and differentiation that warrants further investigation, but they seem to be of limited value as predictive or prognostic factors in GCTs.

Binding of protein kinase B to the plakin family member periplakin.

The serine/threonine kinase protein kinase B (PKB/c-Akt) acts downstream of the lipid kinase phosphoinositide 3-kinase (PI3K) and functions as an essential mediator in many growth-factor-induced cellular responses such as cell cycle regulation, cell survival and transcriptional regulation. PI3K activation generates 3'-phosphorylated phosphatidylinositol lipids (PtdIns3P) and PKB activation requires PtdIns3P-dependent membrane translocation and phosphorylation by upstream kinases. However PKB activation and function is also regulated by interaction with other proteins. Here we show binding of PKB to periplakin, a member of the plakin family of cytolinker proteins. Interaction between PKB and periplakin was mapped to part of the pleckstrin homology (PH) domain of PKB, which is probably not involved in lipid binding, and indeed binding to periplakin did not affect PKB activation. We therefore investigated the possibility that periplakin may act as a scaffold or localization signal for PKB. In cells endogenous periplakin localizes to different cellular compartments, including plasma membrane, intermediate filament structures, the nucleus and mitochondria. Overexpression of the C-terminal part of periplakin, encompassing the PKB binding region, results in predominant intermediate filament localization and little nuclear staining. This also resulted in inhibition of nuclear PKB signalling as indicated by inhibition of PKB-dependent Forkhead transcription factor regulation. These results suggest a possible role for periplakin as a localization signal in PKB-mediated signalling.

Involvement of the Fas/FasL pathway in the pathogenesis of germ cell tumours of the adult testis.

Induction of apoptosis by Fas ligand (FasL) of Fas-containing cells is a known mechanism involved in the eradication of inappropriate cells during normal development. Alterations of the Fas/FasL pathway have been found in various types of cancer, leading to circumvention of attack of the tumour by the immune system. An alternative way to circumvent eradication by induction of apoptosis is through changes in the downstream inhibitors. For example, Fas-associating phosphatase-1 (Fap-1) binds directly to the Fas receptor and results in a block of the downstream signalling. To shed more light on the role of the Fas/FasL pathway in the development of human testicular germ cell tumours of the adult testis, this study investigated the presence of Fas, FasL, Fap-1, HLA class I and II molecules, CD45 (lymphocyte marker), and CD57 [natural killer (NK) cell marker] by immunohistochemistry on frozen sections of 41 cases of seminomas, non-seminomas, and spermatocytic seminomas. Every germ cell tumour was positive for Fap-1 and negative for HLA classes I and II, like their non-malignant cells of origin. The infiltrating lymphocytes, predominantly present in seminomas, showed consistently positive staining for Fas and CD45, but not for Fap-1. No Fas was found on NK cells. All seminomas and non-seminomas (except teratomas), including their precursor stages, carcinoma in situ, intratubular seminoma and intratubular non-seminoma, showed positive staining for FasL, but not for Fas. Teratoma showed no staining for FasL and was positive for Fas. In contrast, both Fas and FasL were detectable on spermatocytic seminoma. These data indicate a different regulation of the Fas/FasL system in seminoma and spermatocytic seminoma, supporting a separate pathogenesis for these germ cell-derived tumours. The presence of Fap-1 in all histological variants of germ cell tumours might be related to the consistently positive staining in cells of the germ lineage. This study indicates that production of FasL by the germ cell tumour cells might be involved in the early development of these types of adult testicular cancer by inducting apoptosis of Fas-positive, Fap-1-negative tumour-infiltrating lymphocytes.

Role of P53 and MDM2 in treatment response of human germ cell tumors.

PURPOSE: Testicular germ cell tumors (TGCTs) of adolescents and adults are very sensitive to systemic treatment. The exquisite chemosensitivity of these cancers has been attributed to a high level of wild-type P53. MATERIALS AND METHODS: To clarify the role of P53 in treatment sensitivity and resistance of TGCTs, we performed immunohistochemistry and Western blotting analysis on a series of 39 fresh-frozen primary TGCTs before therapy (unselected series). In a series of formalin-fixed paraffin-embedded TGCTs of patients with fully documented clinical course, including treatment-sensitive (n = 17) and -resistant (n = 18) tumors, P53 status was assessed by immunohistochemistry and mutation analysis. In addition, the involvement of MDM2, a P53 antagonist, was investigated by immunohistochemistry, reverse transcriptase polymerase chain reaction, and in situ hybridization. RESULTS: Immunohistochemistry demonstrated absence of staining for P53 in 36%, 41%, and 17% of the unselected, responding, and nonresponding TGCTs, respectively. Of the positive TGCTs, most tumors, ie, 49%, 41%, and 33%, showed 1% to 10% positive nuclei. This overall low level of P53 was confirmed by Western blotting. Mutation analysis revealed only one silent P53 mutation in one of the responding patients. All embryonal carcinomas were homogeneously positive for MDM2, encoded by the full length mRNA, while a heterogeneous pattern was found for the other histologic components. Amplification of MDM2 was detected in one out of 12 embryonal carcinomas. CONCLUSION: Although our results are in line with previous findings of the presence of wild-type P53 in TGCTs, they show that a high level of P53 does not relate directly to treatment sensitivity of these tumors, and inactivation of P53 is not a common event in the development of cisplatin resistance.

[Hypertensive emergencies. Clinical evaluation and therapeutic methods]. / Crisi ipertensive. Inquadramento clinico e indirizzi terapeutici.

Hypertensive crisis may be defined as a condition characterized by a sudden rise in blood pressure, of varying length, that can damage arteries, arteriolas, and capillary vessels, producing impairment of end-organs. Hypertensive crises may occur under different clinical conditions, for this reason it is necessary to classify them according to their clinical context. Hypertensive crises are generally classified as hypertensive emergencies or urgencies on the basis of the clinical evaluation and according to the level of blood pressure and the presence of acute or ongoing end-organ damage. Hypertensive emergencies are conditions characterized by a great rise in blood pressure in the presence of acute or ongoing end-organ damages. A severe elevation of blood pressure is considered an emergency if there is an evidence of rapid or progressive damage to the central nervous system and myocardial, or renal deterioration. These are situations in which greatly elevated blood pressure must be lowered within one hour in order to reduce actual risk for the patient. Hypertensive urgencies are conditions in which severe elevations in blood pressure do not cause immediate end-organ damages but should be controlled within 24 hours in order to reduce potential risk for the patient. This group includes accelerated hypertension, severe elevation of blood pressure with minimal end-organ damages and no impending complications. In order to formulate a correct therapeutic plan and make the best use of the powerful antihypertensive drugs at our disposal, it is therefore necessary to distinguish hypertensive emergencies from hypertensive urgencies.

[The prevention of bacterial endocarditis]. / Profilassi delle endocarditi batteriche.

The paper examines the prevention of bacterial endocarditis in risk patients undergoing outpatient treatment. The hypothesis of possible bacteremia provoked by either diagnostic or therapeutic surgery should be carefully assessed. For this purpose antibiotic prophylaxis should be commenced, using different methods and doses according to the type of patient, in association with hygienic and behavioural norms which the specialist will recommend and monitor.