Supermicrosurgery with perforator-to-perforator anastomoses for lower limb reconstructions - A systematic review and meta-analysis.

BACKGROUND: Supermicrosurgical flaps based on perforator-to-perforator microanastomoses have been described for lower limb reconstruction. This approach offers the benefit of raising short pedicles while sparing axial vessels, which effectively enables complex reconstructive techniques in comorbid patients at high risk of reconstructive failure. The aim of our study is to assess the surgical outcomes of perforator-to-perforator based flaps in comparison to conventional free flaps for reconstructions of the lower limb district, through a systematic review of literature and meta-analysis. METHODS: A search on PubMed, Embase, Cohrane, and Web of Science was performed between March-July 2022. No restrictions were placed on study date. Only English manuscripts were assessed. Reviews, short communications, letters, correspondence were excluded after reviewing their references for potentially relevant studies. A Bayesian approach was used to conduct the meta-analysis comparing flap-related outcomes. RESULTS: From 483 starting citations, 16 manuscripts were included for full-text analysis in the review, and three were included in the meta-analysis. Out of 1556 patients, 1047 received a perforator-to-perforator flap. Complications were reported in 119 flaps (11.4%), which included total flap failure in 71 cases (6.8%), partial flap failure in 47 cases (4.5%). Overall flap complications had a HR of 1.41 (0.94-2.11; 95% C.I.). Supermicrosurgical and conventional microsurgical reconstructions were not associated with statistically significant differences (p = .89). CONCLUSION: Our evidence supports the safety of surgical outcomes, with acceptable flap complication rates. Nevertheless, these findings are limited by poor overall quality which must be addressed and used to encourage higher-level evidence in the field.

A Case of Gastroallergic and Intestinal Anisakiasis in Italy: Diagnosis Based on Double Endoscopy and Molecular Identification.

Nematodes of the genus Anisakis (Rhabditida, Anisakidae) are zoonotic fish-borne parasites and cause anisakiasis, a disease with mild to severe acute or chronic gastrointestinal and allergic symptoms and signs. Anisakiasis can potentially lead to misdiagnosis or delay in diagnosis, and it has been suggested as a risk factor for gastrointestinal tumors. Here, we describe a case report of a 25-year-old woman who presented with gastrointestinal (abdominal pain, nausea, diarrhea) and allergic (diffuse skin rash) symptoms and reported ingestion of raw fish contaminated by worms. Gastro and colon endoscopy allowed the visualization and removal of nematodes and collection of bioptic tissue from ulcers and polyps. The removed nematodes were molecularly identified as Anisakis pegreffii. The patient was treated with chlorphenamine maleate, betamethasone, omeprazole, paracetamol, albendazole. We conclude that an upper endoscopy matched with a colonoscopy and molecular characterization of the pathogen yields the most reliable diagnosis and treatment for human anisakiasis, enabling the complete removal of the larvae and preventing chronic inflammation and damage.

Long-Term Host Immune Modulation Following Tisagenlecleucel Administration in Patients with Diffuse Large B-Cell Lymphoma and B-Lineage Acute Lymphoblastic Leukemia.

Background: Chimeric antigen receptor (CAR)-T cells represent a potentially curative strategy for patients with relapsed or refractory (R/R) B-cell malignancies. To elucidate a possible host immune activation following CAR-T-cell infusion, we investigated the effects of tisagenlecleucel administration on the patients' immune populations in 25 patients with R/R diffuse large B-cell lymphoma (DLBCL) and B-lineage acute lymphoblastic leukemia (B-ALL). Methods: The modulation of CAR-T cells over time, the numeric changes, as well as the cytokine production capability of different lymphocyte populations and circulating cytokine levels, were analyzed. Results: Our results confirmed the ability of tisagenlecleucel to control the disease, with an overall response observed in 84.6% of DLBCL and in 91.7% of B-ALL patients at 1-month post-infusion, and showed that most patients who subsequently relapsed could undergo further treatment. Interestingly, we could document a significant increase in CD3+, CD4+, CD8+, and NK cells over time, as well as a decrease in Treg cells, and an increased IFNγ and TNFα production by T lymphocytes. Conclusions: Taken together, our results indicate that in patients with DLBCL and B-ALL, the administration of tisagenlecleucel is capable of inducing a marked and prolonged in vivo modulation/reshaping of the host immune system, both in children and adults.

Evaluation of Bone Scan Index as a Prognostic Tool in Breast Cancer Patients with Bone Metastasis.

BACKGROUND: Bone metastatic involvement represents a leading cause of death in patients with advanced breast cancer (BC). At present, it is not clear whether the bone metastatic load might impact Overall Survival (OS) in patients with bone metastatic BC at diagnosis. For this purpose, we used the Bone Scan Index (BSI), which is a reproducible and quantitative expression of tumor load observed at bone scintigraphy. OBJECTIVE: The aim of this study was to associate BSI with OS in bone metastatic BC patients. METHODS: In this retrospective study, we enrolled BC patients with bone metastases at the scintigraphic bone scan performed for staging purposes. The BSI was calculated through the DASciS software, and statistical analysis was carried out. Other clinical variables relevant to OS analysis were taken into account. RESULTS: Of a total of 94 patients, 32% died. In most cases, the histotype was ductal infiltrating carcinoma. The median OS from diagnosis was 72 months (CI 95%: 62-NA). The univariate analysis with COX regression showed that only hormone therapy significantly correlates with OS (HR 0.417, CI 95%: 0.174-0.997, p < 0.049). As concerning BSI, the statistical analysis showed that it does not predict OS in BC patients (HR 0.960, 95% CI: 0.416-2.216, p < 0.924). CONCLUSION: Although the BSI significantly predicts OS in prostate cancer and in other tumors, we observed that the metastatic load of bone disease has not a key role in prognostic stratification in our population.

Bleeding and thrombotic events in atrial fibrillation patients with cancer: a systematic review and meta-analysis.

Atrial fibrillation (AF) and cancer are frequently coexisting in elderly patients. Pooled metanalytic data on the impact of cancer on clinical outcomes in AF patients are lacking. We performed a systematic review and meta-regression analysis of clinical studies retrieved from Medline (PubMed) and Cochrane (CENTRAL) databases according to PRISMA guidelines. Bleeding endpoints included any, major, gastrointestinal (GI) bleeding and intracranial haemorrhage (ICH). Cardiovascular (CV) endpoints included myocardial infarction (MI), ischemic stroke/systemic embolism (IS/SE), CV and all-cause death. PROSPERO registration number: CRD42022315678. We included 15 studies with 2,868,010 AF patients, of whom 479,571 (16.7%) had cancer. The pooled hazard ratio (HR) for cancer was 1.43 (95% confidence interval [95%CI] 1.42-1.44) for any bleeding, 1.27 (95% CI 1.26-1.29) for major bleeding, 1.17 (95% CI 1.14-1.19) for GI bleeding, and 1.07 (95% CI 1.04-1.11) for ICH. The risk of major bleeding increased with the proportion of breast cancer. Cancer increased the risk of all-cause death (HR 2.00, 95% CI 1.99-2.02) whereas no association with MI and CV death was found. Patients with AF and cancer were less likely to suffer from IS/SE (HR 0.91, 95% CI 0.89-0.94). Cancer complicates the clinical history of AF patients, mainly increasing the risk of bleeding. Further analyses according to the type and stage of cancer are necessary to better stratify bleeding risk in these patients.

Immuno-hematological monitoring after allogeneic stem cell transplantation: a single-center, prospective study of 104 patients.

BACKGROUND: The impact of ABO incompatibility on the outcome of hematopoietic stem cell transplantation (HSCT) is still debated. We report the results of a prospective, single-center study evaluating the impact of ABO mismatch on the development of immediate and late immuno-hematological complications, and the efficacy of the protocol used at the "Sapienza" University (Rome, Italy) to manage ABO incompatibility in patients undergoing HSCT. MATERIALS AND METHODS: From January 2013 to December 2016, we prospectively analyzed all patients undergoing HSCT. Graft manipulation or desensitization strategies were used according to ABO incompatibility, donor sex and donor transfusion history. Red blood cell and platelet transfusions were given based on immunohematological features. RESULTS: From January 2013 to December 2016, 104 consecutive patients underwent HSCT from a matched related donor (29.81%), matched unrelated donor (53.58%), cord blood (1.9%) or haploidentical donor (14.42%). Forty-nine patients (47%) were ABO-identical and 55 (53%) ABO-incompatible (23 major, 25 minor, 7 bidirectional). Donor engraftment, graft failure or other complications did not differ between ABO compatible or incompatible patients. ABO incompatibility did not show a significant impact on graft-versus-host disease, overall survival or disease-free survival. Factors associated with the need for prolonged red blood cell support were ABO incompatibility (p=0.0395), HLA disparity between donor and recipient (p=0.004) and the onset of hemorrhagic cystitis (p=0.015). In multivariate analysis HLA disparity was the only statistically significant condition (p=0.004). DISCUSSION: ABO incompatibility does not represent a barrier to allogeneic HSCT. It is, however, associated with prolonged transfusion requirements. Close immunohematological monitoring, as a shared standard procedure, allows appropriate transfusion support to be provided and limits post-HSCT immuno-hematological complications.

Assessment of Resistance Mechanisms and Clinical Implications in Patients with KRAS Mutated-Metastatic Breast Cancer and Resistance to CDK4/6 Inhibitors.

Despite therapeutic improvements, resistance to palbociclib is a growing clinical challenge which is poorly understood. This study was conducted in order to understand the molecular mechanisms of resistance to palbociclib, and to identify biomarkers to predict who will take advantage from cyclin-dependent kinase 4/6 inhibitors (CDK4/6i). A total of about a thousand blood samples were collected from 106 patients with hormone receptor positive (HR+) human epidermal growth factor receptor 2 (HER2) negative metastatic breast cancer who received palbociclib in combination with fulvestrant as the first-line metastatic therapy enrolled in this study. The genotyping of their plasma cell-free DNA was studied, including serial plasma samples. Collectively, our findings identify the appearance of KRAS mutations leading to palbociclib resistance acquisition within 6 months, and provide critical information for the prediction of therapeutic responses in metastatic breast cancer. By monitoring KRAS status through liquid biopsy, we could predict who will take advantage from the combination of palbociclib and fulvestrant, offering highly-individualized treatment plans, thus ensuring the best patient quality of life.

Relapsed/refractory diffuse large B-cell lymphoma patients. A multicenter retrospective analysis of eligibility criteria for car-T cell therapy.

Anti-CD19 chimeric antigen receptor (CAR) T cells represent the first approved third-line therapy associated with long-term remissions in patients with refractory/relapsed (R/R) diffuse large B-cell lymphoma (DLBCL). Eligibility criteria to identify patients who can successfully receive CAR-T are still debated. For this reason, the aim of this study was to identify factors influencing eligibility and define a realistic patient estimate. Of 1100 DLBCL patients, 137 were included. Based on the Juliet trial inclusion criteria, only 64 patients (46.7%) would be eligible. Median overall survival (OS) was 8.04 months in eligible vs 3.23 in non-eligible patients (p < 0.001). Multivariate analysis identified stage III-IV (p = 0.017) and ECOG ≥2 (p < 0.001) as significant independent prognostic factors for OS. Moreover, only 64/1100 (5.8%) DLBCL patients would be truly eligible for CAR-T. Our real-life data confirm that with a  longer waiting time patients with advanced stage and poor ECOG are less likely to be eligible for CAR-T cell infusion.

Validation of the 3-variable prognostic score (3-PS) in mCRPC patients treated with 223Radium-dichloride: a national multicenter study.

OBJECTIVE: Radium-223 (223Ra) has been approved for treatment in patients with metastatic castration-resistant prostatic cancer (mCRPC) and bone metastasis. This α-emitting radionuclide has a beneficial effect on pain and is also capable to increase overall survival (OS). Several studies evaluated the prognostic value of different biomarkers at baseline, such as serum values, imaging parameters or pain. To date, however, clinicians lack a validated and simple system to assess which patients will most likely benefit from 223Ra treatment. The 3-variable prognostic score (3-PS), proposed in a single-center study in 2017 classifies patients in five prognostic groups with a specific OS. This study aims to validate the 3-PS in a larger multicenter population. METHODS: Four hundred and thirty mCRPC patients treated with 223Ra from six different centers were analyzed. The 3-PS score consists of the collection of baseline hemoglobin, prostatic specific antigen and Eastern cooperative oncology group performance status and was initially applied to the whole population (total group). The score was then validated on the 338 patient's subgroup (clean group) obtained by subtracting the 92 patients enrolled for the original study of the 3-PS score. This purified group served as further validation evidence. RESULTS: Statistical analysis showed that the 3-PS score was valid on the total group as well as in the clean group as the AUC estimated (0.74) falls within the CI of the AUC calculated on the validation sample (95% CI 0.66-0.82). CONCLUSION: This study confirms the validity of the 3-PS score for mCRPC patients. This score is simple, noninvasive and affordable and can be easily used to select patients that will most probably complete 223Ra treatment. In addition, this tool provides an exact estimate of life expectancy in terms of OS.

Baseline quality of life predicts overall survival in patients with mCRPC treated with 223Ra-dichloride.

OBJECTIVE: The prognostic value of baseline clinical parameters in predicting the survival prolonging effect of radium-223-dichloride (223Ra)-therapy in metastatic castration resistant prostate cancer (mCRPC) patients is still an open issue. The aim of this study was investigating the impact of baseline quality of life (QoL) on overall survival (OS) in mCRPC patients treated with 223Ra. The present study also evaluated the trend of patient-reported QoL during both 223Ra-treatment and post-therapy follow-up period. MATERIALS AND METHODS: One hundred and seventy-three consecutive mCRPC patients treated with 223Ra were included in this prospective study. Quality of life was assessed through EORTC QLQ-C30 and QLQ-BM22 questionnaires and 2264 questionnaires were evaluated. Other baseline variables relevant to the OS analysis have been considered. Data were summarized using descriptive statistics, univariate and multivariate analysis with Cox model. A principal component analysis (PCA) on the questionnaires' results compiled at baseline was performed to reduce the data to a one-dimensional score. Joint models for survival and longitudinal data were finally used in order to evaluate the relationship between the time-depended QoL scores and OS. RESULTS: On multivariate analysis, baseline patients' hemoglobin (Hb), total alkaline phosphatase (tALP), and two EORTC QLQ-C30 items, physical functioning (HR=0.970,CI=0.960-0.980, P<0.001) and dyspnea (HR=0.992,CI=0.986-0.999, P=0.023), were significantly associated with OS. In the resulting model of the multivariate analysis performed after PCA, baseline patients' Hb, tALP and QoL-score were independent significant predictors of OS (QoL-score: HR=0.995-95%CI=0.992 - 0.998, P=0.001). The OS analysis stratified by score of baseline QoL, showed a median OS of 8 (95%CI=6-11) and 16 (95%CI=12-24) months for scores respectively below and above the cut-off value (log-rank-P<0.001). The joint model showed a significant deterioration of QoL-score during both 223Ra-therapy and follow-up period (P<0.001). CONCLUSION: Baseline QoL is a significant predictor of OS, meaning that patients with better pretreatment QoL are more likely to obtain a marked survival prolonging effect from 223Ra.

Standardized EEG analysis to reduce the uncertainty of outcome prognostication after cardiac arrest.

PURPOSE: Post-resuscitation guidelines recommend a multimodal algorithm for outcome prediction after cardiac arrest (CA). We aimed at evaluating the prevalence of indeterminate prognosis after application of this algorithm and providing a strategy for improving prognostication in this population. METHODS: We examined a prospective cohort of comatose CA patients (n = 485) in whom the ERC/ESICM algorithm was applied. In patients with an indeterminate outcome, prognostication was investigated using standardized EEG classification (benign, malignant, highly malignant) and serum neuron-specific enolase (NSE). Neurological recovery at 3 months was dichotomized as good (Cerebral Performance Categories [CPC] 1-2) vs. poor (CPC 3-5). RESULTS: Using the ERC/ESICM algorithm, 155 (32%) patients were prognosticated with poor outcome; all died at 3 months. Among the remaining 330 (68%) patients with an indeterminate outcome, the majority (212/330; 64%) showed good recovery. In this patient subgroup, absence of a highly malignant EEG by day 3 had 99.5 [97.4-99.9] % sensitivity for good recovery, which was superior to NSE < 33 µg/L (84.9 [79.3-89.4] % when used alone; 84.4 [78.8-89] % when combined with EEG, both p < 0.001). Highly malignant EEG had equal specificity (99.5 [97.4-99.9] %) but higher sensitivity than NSE for poor recovery. Further analysis of the discriminative power of outcome predictors revealed limited value of NSE over EEG. CONCLUSIONS: In the majority of comatose CA patients, the outcome remains indeterminate after application of ERC/ESICM prognostication algorithm. Standardized EEG background analysis enables accurate prediction of both good and poor recovery, thereby greatly reducing uncertainty about coma prognostication in this patient population.

Coronary atherosclerosis in apparently healthy master athletes discovered during pre-PARTECIPATION screening. Role of coronary CT angiography (CCTA).

BACKGROUND: Pre-participation screening (PPS) of athletes aged over 35 years (master athletes, MA) is a major concern in Sports Cardiology. In this population, sports-related sudden cardiac death is rare but usually due to coronary atherosclerosis (CA). Coronary CT Angiography (CCTA) has changed the approach to diagnosis/management of CA, but its role in this context still needs to be assessed. METHODS AND RESULTS: We retrospectively examined 167 MA who underwent CCTA in our hospital since 2006, analyzing symptoms, stress-test ECG, cardiovascular risk profiles (SCORE) and CCTA findings. Among the whole enrolled population, 153 (91.6%) MA underwent CCTA for equivocal/positive stress-test ECG with/without symptoms, 13 (7.8%) just for clinical symptoms, 1 (0.6%) for the family history. The CCTA showed the presence of CA in 69 MA (41.3%), congenital coronary anomalies (anomalous origin or deep myocardial bridge) in 8 (4.8%), both in 7 (4.2%). A negative CCTA was observed in 83 MA (49.7%). The risk-SCORE (age, hypertension, hypercholesterolemia, smoking) was a good indicator for the presence of moderate/severe CA on CCTA. However, mild/moderate CA was present in 17.8% of MA clinically stratified at a low risk-SCORE. CONCLUSION: While coronary angiography is more indicated in athletes with positive stress-test ECG and high clinical risk, the CCTA may be useful in the evaluation of MA with an abnormal stress test ECG and/or clinical symptoms engaged in competitive sports with a high cardiovascular involvement. Age, gender, presence of symptoms and clinical risk-SCORE assessment may help sports physicians and cardiologists to decide whether to request a CCTA or not.

Locally advanced squamous cell carcinoma of the head and neck: A systematic review and Bayesian network meta-analysis of the currently available treatment options.

BACKGROUND: There are still many unresolved questions in the management of locally advanced Head and Neck Cancer (HNC). Many chemotherapeutic drugs and radiotherapy fractionation schemes are available and not all have been evaluated in head-to-head clinical trials. This systematic review and Bayesian network meta-analysis aims to compare the available treatment strategies and chemotherapeutic options for locally advanced HNC. METHODS: We performed a search on bibliography databases, trials registries and meetings proceedings for published and unpublished randomized trials from January 1st 2000 to December 1st 2017. Trials had to compare systemic interventions and radiotherapy (RT) approaches for locally advanced, non-metastatic HNC. Trials recruiting patients whose surgery was the first treatment option, sample size less than 20 per arm or that did not use randomization for treatment allocation were excluded from the analysis. Summary estimates on Overall survival (OS), Progression-free survival (PFS) and toxicity outcomes (grade 3-4 mucositis and neutropenia) were extracted from the included studies on a predefined database sheet. Bias was assessed through the Chocrane risk of bias assessment tool. We performed a set of pair-wise meta-analyses using a random effect model. We also performed a random effect network meta-analysis under a Bayesian framework. FINDINGS: From the 57 included trials, including 15,723 patients, was possible to conduct analysis on 26 treatments for OS, 22 treatments for PFS and 10 treatments for toxicity. In terms of OS Concurrent chemoradiotherapy (CCRT) with cisplatin (HR 0.70, 95% CrI [credible interval] 0.62-0.78) and cetuximab on top of CCRT (HR 0.7, 95% CrI 0.5-0.97) are clearly superior to conventional RT alone. Induction chemotherapy (IC) with cisplatin and fluorouracil (HR 0.74, 95% CrI 0.52-0.95), IC with docetaxel, cisplatin, fluorouracil (HR 0.55, 95% CrI 0.54-0.89) and IC with paclitaxel, cisplatin, fluorouracil (HR 0.55, 95% CrI 0.34-0.89) before CCRT are all superior to conventional RT. CCRT with cisplatin is also superior to altered fractionation RT (HR 0.74, 95% CrI 0.64-0.84). Altered fractionation RT is not superior to conventional RT (HR 0.95, 95% CrI 0.85-1.06). Regarding PFS, CCRT with cisplatin (HR 0.72, 95% CrI 0.63-0.83), cisplatin and fluorouracil (HR 0.67, 95% CrI 0.5-0.88), carboplatin (HR 0.63, 95% CrI 0.46-0.87), carboplatin and fluorouracil (HR 0.75, 95% CrI 0.56-1), IC with cisplatin and fluorouracil (HR 0.59, 95% CrI 0.45-0.78), IC with docetaxel, cisplatin and fluorouracil (HR 0.53, 95% CrI 0.41-0.68) and IC with paclitaxel, cisplatin and fluorouracil (HR 0.59, 95% CrI 0.35-0.99) are superior to conventional RT and altered fractionation RT. IC with docetaxel, cisplatin and fluorouracil shows a significant superiority against CCRT with cisplatin (HR 0.73 95% CrI 0.58-0.92). Altered fractionation RT is not superior to conventional RT (HR 0.91, 95% CrI 0.81-1.02). Altered fractionation increases the risk of developing grade 3-4 mucositis compared to conventional RT (OR 3.74 95% 1.64-8.67) INTERPRETATION: CCRT with cisplatin remains the gold standard of treatment. Taxane based IC regimens may have a impact on locally advanced disease. Altered fractionation RT is inferior to CCRT and also does not seem to be meaningfully better than conventionally fractionated RT alone. Its role in locally advanced disease should be reevaluated.