Prognostic value of specific KRAS mutations in patients with colorectal peritoneal metastases.

BACKGROUND: There is little evidence on KRAS mutational profiles in colorectal cancer (CRC) peritoneal metastases (PM). This study aims to determine the prevalence of specific KRAS mutations and their prognostic value in a homogeneous cohort of patients with isolated CRC PM treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. MATERIALS AND METHODS: Data were collected from 13 Italian centers, gathered in a collaborative group of the Italian Society of Surgical Oncology. KRAS mutation subtypes have been correlated with clinical and pathological characteristics and survival [overall survival (OS), local (peritoneal) disease-free survival (LDFS) and disease-free survival (DFS)]. RESULTS: KRAS mutations occurred in 172 patients (47.5%) out of the 362 analyzed. Two different prognostic groups of KRAS mutation subtypes were identified: KRASMUT1 (G12R, G13A, G13C, G13V, Q61H, K117N, A146V), median OS > 120 months and KRASMUT2 (G12A, G12C, G12D, G12S, G12V, G13D, A59E, A59V, A146T), OS: 31.2 months. KRASMUT2 mutations mainly occurred in the P-loop region (P < 0.001) with decreased guanosine triphosphate (GTP) hydrolysis activity (P < 0.001) and were more frequently related to size (P < 0.001) and polarity change (P < 0.001) of the substituted amino acid (AA). When KRASMUT1 and KRASMUT2 were combined with other known prognostic factors (peritoneal cancer index, completeness of cytoreduction score, grading, signet ring cell, N status) in multivariate analysis, KRASMUT1 showed a similar survival rate to KRASWT patients, whereas KRASMUT2 was independently associated with poorer prognosis (hazard ratios: OS 2.1, P < 0.001; DFS 1.9, P < 0.001; LDFS 2.5, P < 0.0001). CONCLUSIONS: In patients with CRC PM, different KRAS mutation subgroups can be determined according to specific codon substitution, with some mutations (KRASMUT1) that could have a similar prognosis to wild-type patients. These findings should be further investigated in larger series.

Prognostic factors in gastric cancer patients: a 10-year mono-institutional experience.

Introduction: Gastric cancer (GC) is one of the main causes of death from cancer globally. Long-term survival, especially in Western countries, remains dismal, with no significant improvements in recent years. Therefore, precise identification of clinical and pathological risk factors is crucial for prognosis, as it allows a better selection of patients suitable for oncologically radical treatments and contributes to longer survivals. Methods: We devised a retrospective observational longitudinal study over 10 years of experience with GC patients operated with curative intent. Results: Several factors were thoroughly investigated in a multivariate analysis to look for significance as independent risk factors for disease-free survival. Our results showed that only BMI, pTNM, and lymph node ratio expressed hazard ratios with implications for survival in our series of patients. Discussion: Although limited by the retrospective nature of the study, this is one of the few cancer reports from Northern Italy showing results over 10 years, which may in our view, have an impact on decision-making processes for multidisciplinary teams dedicated to the care of gastric cancer patients.

Genetic diversity and its impact on disease severity in respiratory syncytial virus subtype-A and -B bronchiolitis before and after pandemic restrictions in Rome.

OBJECTIVES: To scrutinize whether the high circulation of respiratory syncytial virus (RSV) observed in 2021-2022 and 2022-2023 was due to viral diversity, we characterized RSV-A and -B strains causing bronchiolitis in Rome, before and after the COVID-19 pandemic. METHODS: RSV-positive samples, prospectively collected from infants hospitalized for bronchiolitis from 2017-2018 to 2022-2023, were sequenced in the G gene; phylogenetic results and amino acid substitutions were analyzed. Subtype-specific data were compared among seasons. RESULTS: Predominance of RSV-A and -B alternated in the pre-pandemic seasons; RSV-A dominated in 2021-2022 whereas RSV-B was predominant in 2022-2023. RSV-A sequences were ON1 genotype but quite distant from the ancestor; two divergent clades included sequences from pre- and post-pandemic seasons. Nearly all RSV-B were BA10 genotype; a divergent clade included only strains from 2021-2022 to 2022-2023. RSV-A cases had lower need of O2 therapy and of intensive care during 2021-2022 with respect to all other seasons. RSV-B infected infants were more frequently admitted to intensive care units and needed O2 in 2022-2023. CONCLUSIONS: The intense RSV peak in 2021-2022, driven by RSV-A phylogenetically related to pre-pandemic strains is attributable to the immune debt created by pandemic restrictions. The RSV-B genetic divergence observed in post-pandemic strains may have increased the RSV-B specific immune debt, being a possible contributor to bronchiolitis severity in 2022-2023.

Preliminary results of a program for the implementation of laparoscopic colorectal surgery in an Italian comprehensive cancer center during the COVID-19 pandemic.

Despite operative benefit and oncological non-inferiority, videolaparoscopic (VLS) colorectal surgery is still relatively underutilized. This study analyzes the results of a program for the implementation of VLS colorectal surgery started in an Italian comprehensive cancer center shortly before COVID-19 outbreak. A prospective database was reviewed. The study period was divided in four phases: Phase-1 (Open surgery), Phase-2 (Discretional phase), Phase-3 (VLS implementation phase), and Phase-4 (VLS consolidation phase). Formal surgical and perioperative protocols were adopted from Phase-3. Postoperative complications were scored by the Clavien-Dindo classification. 414 surgical procedures were performed during Phase-1, 348 during Phase-2, 360 during Phase-3, and 325 during Phase-4. In the four phases, VLS primary colorectal resections increased from 11/214 (5.1%), to 55/163 (33.7%), 85/151 (57.0%), and 109/147 (74.1%), respectively. The difference was statistically significant (P < 0.001). All-type VLS procedures were 16 (3.5%), 61 (16.2%), 103 (27.0%), and 126 (38.6%) (P < 0.001). Conversions to open surgery of attempted laparoscopic colorectal resections were 17/278 in the overall series (6.1%), and 12/207 during Phase-3 and Phase-4 (4.3%). Severe (grades IIIb-to-V) postoperative complications of VLS colorectal resections were 9.1% in Phase-1, 12.7% in Phase-2, 12.8% in Phase-3, and 5.3% in Phase-4 (P = 0.677), with no significant differences with open resections in each of the four phases: 9.4% (P = 0.976), 11.1% (P = 0.799), 13.8% (P = 1.000), and 8.3% (P = 0.729). Despite the difficulties deriving from the COVID-19 outbreak, our experience suggests that volume of laparoscopic colorectal surgery can be significantly and safely increased in a specialized surgical unit by means of strict operative protocols.

Role of poorly differentiated cluster in gastric cancer: is it a new prognosis factor?

BACKGROUND: Poorly differentiated Clusters (PDCs) of tumor cells composed of more than five elements have been recently described in gastrointestinal cancers and correlate with a worse prognosis. Our study aims to investigate PDC occurrence in a series of patients with gastric cancer and correlate it with lymph node status and clinical outcome. MATERIAL AND METHODS: 50 patients were included in the study; PDCs count was graduated as G1, G2, and G3 according to Ueno classification (PDCs count at 20× <5, 5-9 and ≥10 respectively). We collected several clinicopathologic variables such as tumor location, pTNM stage, vascular or perineural invasion, and lymph-node ratio for each case. RESULTS: The presence of PDCs was related to vascular invasion (p < .013) and recurrence event (p < .027). When the population was categorized according to the number of PDCs, a significant correlation was found with the presence of lymph node metastasis (p < .000), the Lymph Node Ratio (p < .002), WHO stage at the diagnosis (p < .000) and vascular invasion (p < .001). At the univariate and multivariate analysis, PDCs were found as an independent risk factor for recurrence (HR 1.94; CI 95% 1.209-3.121; p < .006 and HR 0.401; CI 95% 0.187-0.862; p < .017 respectively). The Kaplan-Meier curves for OS and DFS showed a significant association between PDCs and shorter time to recurrence or survival. CONCLUSION: PDC is a strong prognostic factor in gastric cancer, easily detectable, and feasible. As far as we know, this is the first report in Literature of a strong correlation between PDC and survival in patients with operated gastric cancer.

Strong impact of sarcopenia as a risk factor of survival in resected gastric cancer patients: first Italian report of a Bicentric study.

Gastric cancer (GC) accounts for 4% of all cancers in Europe. Sarcopenia is a complex syndrome characterized by a loss of muscle mass and function associated with age, often present in neoplastic patients. Recently, several studies have shown a significant association between sarcopenia and poor prognosis in various pathological conditions. The current observational retrospective study investigates the association between sarcopenia and overall survival (OS) and recurrence-free survival (RFS) in patients with GC undergoing up-front surgery with curative intent. Resected GC patients' clinical records and CT images were retrospectively assessed. The preoperative CT calculation of the skeletal muscle index (SMI) at L3 level allowed us to categorize patients as sarcopenic or not. Kaplan-Meyer and univariate and multivariate Cox regression analyses were performed to determine the difference in survival and presence of independent prognostic factors. Fifty-five patients, 28 male and 27 female, out of 298 studied for gastric cancer were enrolled in the current study from two cancer referral centers in Italy. The preoperative CT calculation of the SMI at L3 level allowed us to identify 39 patients with and 16 without sarcopenia. A statistically significant difference between the sarcopenic and non-sarcopenic groups was observed in both OS and RFS (p < 0.023; p < 0.006). Moreover, sarcopenia was strongly correlated to a higher risk of recurrence in univariate and multivariate analysis (p < 0.02). Sarcopenia can be considered a critical risk factor for survival in patients with resectable GC treated with up-front surgery. Identifying sarcopenic patients at the time of diagnosis would direct selection of patients who could benefit from early nutritional and/or physical treatments able to increase their muscle mass and possibly improve the prognosis. More extensive multicenter studies are needed to address this issue.

Síndrome autoinmune inducido por inyección cosmética de ácido hialurónico / Autoimmune syndrome induced by cosmetic injection of hyaluronic acid

El síndrome autoinmune/inflamatorio inducido por adyuvantes (ASIA) es una condición en la cual la exposición a un adyuvante lleva a una respuesta inmune aberrante dando como resultado signos y síntomas de enfermedades autoinmunes. Se presenta el caso de una paciente con artritis y púrpura palpable luego de inyección labial de ácido hialurónico.

Autoimmune/inflammatory syndrome induced by adjuvant (ASIA) is a condition in which exposure to an adjuvant leads to an aberrant immune response resulting in signs and symptoms of autoimmune diseases. We present the case of a patient with arthritis and palpable purpura after hyaluronic acid lip injection.

Co-administration of H-ferritin-doxorubicin and Trastuzumab in neoadjuvant setting improves efficacy and prevents cardiotoxicity in HER2 + murine breast cancer model.

Neoadjuvant chemotherapy has been established as the standard of care for HER2-positive breast cancer since it allows cancer down-staging, up to pathological complete response. The standard of care in the neoadjuvant setting for HER2-positive breast cancer is a combination of highly cytotoxic drugs such as anthracyclines and the anti-HER2 monoclonal antibody. Despite this cocktail allows a pathological complete response in up to 50%, their co-administration is strongly limited by intrinsic cardiotoxicity. Therefore, only a sequential administration of anthracyclines and the anti-HER2 treatment is allowed. Here, we propose the anthracycline formulation in H-Ferritin nanocages as promising candidate to solve this unmet clinical need, thanks to its capability to increase anthracyclines efficacy while reducing their cardiotoxicity. Treating a murine model of HER2-positive breast cancer with co-administration of Trastuzumab and H-Ferritin anthracycline nanoformulation, we demonstrate an improved tumor penetration of drugs, leading to increased anticancer efficacy and reduced of cardiotoxicity.

Establishment and Morphological Characterization of Patient-Derived Organoids from Breast Cancer.

BACKGROUND: Patient-derived organoids (PDO) technology represents an emerging tool for the study of tumor biology and drug responsiveness, thus being useful to design personalized medicine approaches. Despite several studies and clinical trials are ongoing using PDO from colorectal and pancreatic cancer, only few research papers have been published exploiting PDO from breast cancer. Here, we have developed a new protocol to establish PDO from surgical and biopsy samples. Furthermore, we have set up also the methodologies adopted for culture and morphological evaluations. RESULTS: Surgical and core biopsy specimens collected from 33 patients with diagnosis of breast cancer have been processed using the protocols here described obtaining PDO from cancerous and healthy mammary tissue (when available) in a quick and easy way with good yields. The more critical aspects influencing the yield were the characteristic of the tissue of origin (healthy vs tumor tissue) and the amount of material obtained after enzymatic digestion process. Success rate from healthy samples was about 20,83%, while this percentage was higher in samples from cancer tissue (i.e. 87,5%). Also the morphological characterization of breast cancer PDO by brightfield and transmission electron microscopy has been reported. CONCLUSIONS: Despite obtaining some organoids from a surgical or biopsy specimen is not a difficult procedure, the establishment of a stable organoid line able to grow and replicate, suitable for long-term biobank storage, is not so obvious. A novel, simple and quick procedure to obtain PDO from surgical and biopsy samples is here proposed to achieve high success rate .

H-Ferritin-nanocaged olaparib: a promising choice for both BRCA-mutated and sporadic triple negative breast cancer.

Poly(ADP-ribose) polymerase (PARP) inhibitors represent a promising strategy toward the treatment of triple-negative breast cancer (TNBC), which is often associated to genomic instability and/or BRCA mutations. However, clinical outcome is controversial and no benefits have been demonstrated in wild type BRCA cancers, possibly due to poor drug bioavailability and low nuclear delivery. In the attempt to overcome these limitations, we have developed H-Ferritin nanoformulated olaparib (HOla) and assessed its anticancer efficacy on both BRCA-mutated and non-mutated TNBC cells. We exploited the natural tumor targeting of H-Ferritin, which is mediated by the transferrin receptor-1 (TfR1), and its physiological tropism toward cell nucleus. TNBC cell lines over-expressing TfR-1 were successfully recognized by H-Ferritin, displaying a fast internalization into the cells. HOla induced remarkable cytotoxic effect in cancer cells, exhibiting 1000-fold higher anticancer activity compared to free olaparib (Ola). Accordingly, HOla treatment enhanced PARP-1 cleavage, DNA double strand breaks and Ola delivery into the nuclear compartment. Our findings suggest that H-Ferritin nanoformulation strongly enhances cytotoxic efficacy of Ola as a stand-alone therapy in both BRCA-mutated and wild type TNBC cells, by promoting targeted nuclear delivery.

Preoperative localization and surgical margins in conservative breast surgery.

Breast-conserving surgery (BCS) is the treatment of choice for early breast cancer. The adequacy of surgical margins (SM) is a crucial issue for adjusting the volume of excision and for avoiding local recurrences, although the precise definition of an adequate margins width remains controversial. Moreover, other factors such as the biological behaviour of the tumor and subsequent proper systemic therapies may influence the local recurrence rate (LRR). However, a successful BCS requires preoperative localization techniques or margin assessment techniques. Carbon marking, wire-guided, biopsy clips, radio-guided, ultrasound-guided, frozen section analysis, imprint cytology, and cavity shave margins are commonly used, but from the literature review, no single technique proved to be better among the various ones. Thus, an association of two or more methods could result in a decrease in rates of involved margins. Each institute should adopt its most congenial techniques, based on the senologic equipe experience, skills, and technologies.

[Manual handling of loads in the hotel trade: the experience of the ASL (Local Health Unit) Milan]. / La movimentazione manuale dei carichi nel comparto alberghiero: l'esperienza della ASL di Milano.

UNLABELLED: There are over 400 hotels in Milan with a guest capacity of about 62,000 and employing more than 10,000 workers. In 2008/09 the Occupational Health and Safety Service of A.S.L. Milano (Local Health Unit) carried out research into the hotel trade to ascertain the development of this commercial sector, also in view of EXPO 2015. OBJECTIVES: The aim of the project was to improve hygiene and safety conditions and carry out preventive measures. A specific purpose was to study manual handling of loads and repetitive movements risk. METHOD: The study covered 30 hotels and 7 temporary staff cooperatives. We acquired the Risk Evaluation Document, the Health Surveillance Programme and Registers of Labour Accidents to analyze manual handling of loads and repetitive movements. In the investigations and assessments on hotels we used currently available scientific tools--NIOSH Lifting Index, Push and Pulling Analysis, OC.R.A. Check-List--to study risks related to handling loads and upper limb mechanical overload, which revealed a specific occupational risk that requires a fresh approach to prevention and safety in the entire sector. RESULTS: Chambermaid: LI (Range): 0.57-2.75; Push and Pulling Actions: Fi 0.66-Fm 1.5 and Fi 0.76-Fm 1.33 respectively; OC.R.A. Check-List: 21. Porter: LI (Range): 0.77-3.75. Maintenance staff LI (Range): 0.57-2.75. CONCLUSIONS: The study highlighted the presence of risk due to manual handling of loads and repetitive movements in porters, maintenance personnel and particularly in chambermaids that up to now have been poorly assessed by safety experts. Analysis of the information contained in the registers of labour accidents suggests that a significant number of accidents can be related to muscular-skeletal disorders that affect especially cleaning, portering and kitchen staff

Safety of ethanolic kava extract: Results of a study of chronic toxicity in rats.

BACKGROUND: Recently, potential liver toxicity was discussed with the intake of kava extract preparations (Piper methysticum) as anxiolytic drugs. The aim of this study was to test chronic toxicity in rats by oral application of an ethanolic kava full extract. METHODS: Wistar rats of both sexes were fed 7.3 or 73 mg/kg body weight of ethanolic kava extract for 3 and 6 months. The animals were examined for changes in body weight, hematological and liver parameters, and macroscopical and microscopical histological changes in the major organs. RESULTS: No signs of toxicity could be found. CONCLUSIONS: The results are in accordance with the medical experience regarding the use of kava preparations and the long tradition of kava drinking in the South Pacific island states. Specifically, the results do not back the suspicion of potential liver toxicity.

Anatomy and imaging of lumbar plexus.

Sensory and motor innervation of the whole lower limb is due to lumbo-sacral-plexus that arises from the spinal roots L1-S3. The whole lower limb can be blocked from its origin to the foot for surgical procedures or for postoperative analgesia. Single or continuous lumbar plexus blockade can be an alternative to general anesthesia and central block in elective and traumatic hip or femur repair, for knee surgery and for postoperative analgesia. To understand the relative plexus depth and the relationship between the plexus and the closer structure in order to avoid complicance, the aid of imaging technique such as CT-scan, MRI and ultrasounds can be considered.

[Postpartum hemorrhage]. / L'emorragia del postpartum.

Postpartum hemorrhage, frequently due to uterine atony, is an important cause of maternal death and morbidity. The knowledge of causes, of antenatal and intrapartum risk factors and of physiopathological changes in hemodynamics and coagulation during pregnancy are essential for the management of the condition. At the present time, many efforts are made to organize a multidisciplinary approach to this complication of delivery involving clinical and laboratory staffs, since the rapid correction of hypovolemia, the diagnosis and treatment of defective coagulation, the surgical and pharmacological control of bleeding are mandatory. Several medical options have been developed and the surgical management includes traditional and newer conservative procedures with variable success rates. The developments in the treatment of postpartum hemorrhage may reduce hysterectomy that is to be considered the last resort to resolve the hemorrhage in some cases. In the modern management of postpartum hemorrhage protocols and guidelines should be available in every delivery room.

Pharmacological studies on the sedative and hypnotic effect of Kava kava and Passiflora extracts combination.

Kava kava extract, Passiflora extract and a combination of both extracts, administered to mice, caused a significant decrease of the amphetamine-induced hypermotility and significant prolongation of sleeping phase induced by subcutaneous injection of barbiturates. Due to a synergism of both extracts, simultaneously administered the pharmacologically registered effect in both in vivo experiments was found to be superior over the sum of the single separately administered extracts.

Dexamethasone improves vascular hyporeactivity induced by LPS in vivo by modulating ATP-sensitive potassium channels activity.

(1) Septic shock represents an important risk factor for patients critically ill. This pathology has been largely demonstrated to be a result of a myriad of events. Glucocorticoids represent the main pharmacological therapy used in this pathology. (2) Previously we showed that ATP-sensitive potassium (KATP) channels are involved in delayed vascular hyporeactivity in rats (24 h after Escherichia coli lipopolysaccharide (LPS) injection). In LPS-treated rats, we observed a significant hyporeactivity to phenylephrine (PE) that was reverted by glybenclamide (GLB), and a significant increase in cromakalim (CRK)-induced hypotension. (3) We evaluated the effect of dexamethasone (DEX 8 mg kg-1 i.p.) whether on hyporeactivity to PE or on hyperreactivity to CRK administration, in vivo, in a model of LPS (8 x 106 U kg-1 i.p.)-induced endotoxemia in urethane-anaesthetised rats. (4) DEX treatment significantly reduced, in a time-dependent manner, the increased hypotensive effect induced by CRK in LPS-treated rats. This effect was significantly (P<0.05) reverted by the glucocorticoid receptor antagonist RU38486 (6.6 mg kg-1 i.p.). (5) GLB-induced hypertension (40 mg kg-1 i.p.), in LPS-treated rats, was significantly inhibited by DEX if administered at the same time of LPS. (6) Simultaneous administration of DEX and LPS to rats completely abolished the hyporeactivity to PE observed after 24 h from LPS injection. (7) In conclusion, our results suggest that the beneficial effect of DEX in endotoxemia could be ascribed, at least in part, to its ability to interfere with KATP channel activation induced by LPS. This interaction may explain the improvement of vascular reactivity to PE, mediated by DEX, in LPS-treated rats, highlighting a new pharmacological activity to the well-known anti-inflammatory properties of glucocorticoids.

Anaesthesia for shock wave therapy in musculoskeletal disorders: a preliminary report.

The potential for using external applied energy to rectify or ameliorate musculoskeletal disorders has been explored for decades. A shock wave is a pressure disturbance: tissue effect is cavitation, producing microtrauma or microfracture and haematoma formation, inducing, as to date is thought, increase in vascularization, increased soft callus and faster enchondral ossification. Anaesthesiological interest in this field is focused in non-union or delayed osseous union, joint stiffness or osteochondrosis and femoral head necrosis in adults. Actually, because of the pain associated with high energy extracorporeal shock wave therapy on bones, anaesthesia is necessary, but, since almost all patients have no complaint after treatment, there is no need of postoperative analgesia. Therefore, short duration anaesthetic techniques and agents should be preferred. Loco-regional anaesthesia or general anaesthesia are both suitable to the purpose. Fifty patients have been treated nowadays in our Institution with shock wave therapy needing anaesthesia. 18 patients (36%) received general anaesthesia. Since patient's stay in hospital was expected to be short, short duration agents have been used, avoiding those causing unpleasent side effects, first emesis. We used Propofol or Remifentanil by continuous infusion, titrated to maintain stable haemodynamics and an appropriate level of anaesthesia. The short duration of action of Propofol depends on its rapid elimination, whereas Remifentanil undergoes rapid biotransformation to minimally active metabolites. 32 patients (64%) received regional anaesthesia. We avoided long acting agents or high concentration drugs. Spinal blocks have been performed with 0.5% hyperbaric bupivacaine; brachial plexus blocks, sciatic-femoral blocks and an epidural block have been performed with 0.5-1% xylocaine or 1% mepivacaine. Shock Wave Therapy has been done during a 3-day hospital stay. With suitable anaesthesiological treatment and preparation, almost all patients could be treated as outpatients or with an overnight hospital stay.

Corpus callosum agenesis, multiple cysts, skin defects, and subtle ocular abnormalities with a de novo mutation [45,XX,der(5), t(5;;14) (pter;q11.2)].

We report on a 2-year-old girl with a de novo mutation [45,XX,der(5),t(5;14) (pter;q11.2)] with corpus callosum agenesis, multiple cysts (cerebral and cardiac), subtle eye abnormalities, and at least two different skin defects, strongly indicating neuroectodermal involvement, as a neuromuscular choristoma (hamartoma) and an eccrine hamartoma. Fluorescent in situ hybridization with different single-locus probes showed that chromosome 5 has a very small deletion, confined to a region composed of repetitive sequences. By contrast, the long (q) arm of chromosome 14 seems to be much more involved in the rearrangement, with partial monosomy spanning from the centromere to the D14S72 and D14S261 loci. The extent of the deleted region of chromosome 14 is approximately 16 cM. To our knowledge, this is the smallest reported deletion involving the chromosome 14q11.2 region to be associated with a developmental disorder resulting in variable eye, skin, and brain anomalies. We suggest that a new syndrome, mimicking in some ways the MLS phenotype, is caused by a deletion in the chromosome 14q11.2 region.