Post-Intensive Care Unit Multidisciplinary Approach in Patients with Severe Bilateral SARS-CoV-2 Pneumonia.

Background: Short and long-term sequelae after admission to the intensive care unit (ICU) for coronavirus disease 2019 (COVID-19) are to be expected, which makes multidisciplinary care key in the support of physical and cognitive recovery. Objective: To describe, from a multidisciplinary perspective, the sequelae one month after hospital discharge among patients who required ICU admission for severe COVID-19 pneumonia. Design: Prospective cohort study. Environment: Multidisciplinary outpatient clinic. Population: Patients with severe COVID-19 pneumonia, post- ICU admission. Methods: A total of 104 patients completed the study in the multidisciplinary outpatient clinic. The tests performed included spirometry, measurement of respiratory muscle pressure, loss of body cell mass (BCM) and BCM index (BCMI), general joint and muscular mobility, the short physical performance battery (SPPB or Guralnik test), grip strength with hand dynamometer, the six-minute walk test (6-MWT), the functional assessment of chronic illness therapy-fatigue scale (FACIT-F), the European quality of life-5 dimensions (EQ-5D), the Barthel index and the Montreal cognitive assessment test (MoCA). While rehabilitation was not necessary for 23 patients, 38 patients attended group rehabilitation sessions and other 43 patients received home rehabilitation. Endpoints: The main sequelae detected in patients were fatigue (75.96%), dyspnoea (64.42%) and oxygen therapy on discharge (37.5%). The MoCA showed a mean score compatible with mild cognitive decline. The main impairment of joint mobility was limited shoulder (11.54%) and shoulder girdle (2.88%) mobility; whereas for muscle mobility, lower limb limitations (16.35%) were the main dysfunction. Distal neuropathy was present in 23.08% of patients, most frequently located in lower limbs (15.38%). Finally, 50% of patients reported moderate limitation in the EQ-5D, with a mean score of 60.62 points (SD 20.15) in perceived quality of life. Conclusions: Our findings support the need for a multidisciplinary and comprehensive evaluation of patients after ICU admission for COVID-19 because of the wide range of sequelae, which also mean that these patients need a long-term follow-up. Impact on clinical rehabilitation: This study provides data supporting the key role of rehabilitation during the follow-up of severe patients, thus facilitating their reintegration in society and a suitable adaptation to daily living.

Results of a worldwide survey on the currently used histopathological diagnostic criteria for invasive lobular breast cancer.

Invasive lobular carcinoma (ILC) represents the second most common subtype of breast cancer (BC), accounting for up to 15% of all invasive BC. Loss of cell adhesion due to functional inactivation of E-cadherin is the hallmark of ILC. Although the current world health organization (WHO) classification for diagnosing ILC requires the recognition of the dispersed or linear non-cohesive growth pattern, it is not mandatory to demonstrate E-cadherin loss by immunohistochemistry (IHC). Recent results of central pathology review of two large randomized clinical trials have demonstrated relative overdiagnosis of ILC, as only ~60% of the locally diagnosed ILCs were confirmed by central pathology. To understand the possible underlying reasons of this discrepancy, we undertook a worldwide survey on the current practice of diagnosing BC as ILC. A survey was drafted by a panel of pathologists and researchers from the European lobular breast cancer consortium (ELBCC) using the online tool SurveyMonkey®. Various parameters such as indications for IHC staining, IHC clones, and IHC staining procedures were questioned. Finally, systematic reporting of non-classical ILC variants were also interrogated. This survey was sent out to pathologists worldwide and circulated from December 14, 2020 until July, 1 2021. The results demonstrate that approximately half of the institutions use E-cadherin expression loss by IHC as an ancillary test to diagnose ILC and that there is a great variability in immunostaining protocols. This might cause different staining results and discordant interpretations. As ILC-specific therapeutic and diagnostic avenues are currently explored in the context of clinical trials, it is of importance to improve standardization of histopathologic diagnosis of ILC diagnosis.

The influence of treatment sequence in the prognostic value of TMPRSS2-ERG as biomarker of taxane resistance in castration-resistant prostate cancer.

TMPRSS2-ERG expression in blood has been correlated with low docetaxel benefit in metastatic castration-resistant prostate cancer (mCRPC). This multicenter study aimed to prospectively asses its role as a taxane-resistance biomarker in blood and retrospectively in tumors, exploring also the impact of prior abiraterone/enzalutamide (A/E) in patients and in vitro. TMPRSS2-ERG was tested by quantitative reverse-transcription PCR. We included 204 patients (137 blood and 124 tumor samples) treated with taxanes. TMPRSS2-ERG expression was correlated with prostate-specific antigen (PSA)-progression-free survival (PFS), radiological-PFS (RX-PFS), and overall survival (OS). Independent association with survival was evaluated by multivariate Cox modeling. In vitro ERG knockdown and combinatorial and sequential experiments with enzalutamide and docetaxel were performed in VCaP cells. Prior A/E (HR 1.8, 95% CI 1.2-2.8) and blood TMPRSS2-ERG detection (HR 2, 95% CI 1.1-3.7) were independently associated to lower PSA-PFS. In patients without prior A/E, blood and tumor TMPRSS2-ERG independently predicted lower PSA-PFS (HR 3.3, 95% CI 1.4-7.9 and HR 1.8, 95% CI 1.02-3.3, respectively) to taxanes. When prior A/E was administered, TMPRSS2-ERG was not associated with outcome. There was a significant interaction between blood TMPRSS2-ERG and prior A/E related to PSA-PFS (p = 0.032) and RX-PFS (p = 0.009). In vitro stable ERG inhibition did not sensitize VCaP cells to docetaxel. Concomitant enzalutamide and taxanes were synergistic, but prior enzalutamide reduced docetaxel cytotoxicity in VCaP cells. Enzalutamide induced the expression of neuroendocrine markers and reduced that of E-cadherin. We conclude that prior hormone-therapy may influence taxanes response and TMPRSS2-ERG prognostic value. Thus, multiple and sequential biomarkers are needed in CRPC follow-up evaluation.

Neoadjuvant Systemic Therapy in Breast Cancer: Association of Contrast-enhanced MR Imaging Findings, Diffusion-weighted Imaging Findings, and Tumor Subtype with Tumor Response.

Purpose To investigate the performance of tumor subtype and various magnetic resonance (MR) imaging parameters in the assessment of tumor response to neoadjuvant systemic therapy (NST) in patients with breast cancer and to outline a model of pathologic response, considering pathologic complete response (pCR) as the complete absence of any residual invasive cancer or ductal carcinoma in situ (DCIS). Materials and Methods This was an institutional review board-approved retrospective study, with waiver of the need to obtain informed consent. From November 2009 to December 2014, 111 patients with histopathologically confirmed invasive breast cancer who were undergoing NST were included (mean age, 54 years; range, 27-84 years). Breast MR imaging was performed before and after treatment. Presence of late enhancement was assessed. Apparent diffusion coefficients (ADCs) were obtained by using two different methods. ADC ratio (mean posttreatment ADC/mean pretreatment ADC) was calculated. pCR was defined as absence of any residual invasive cancer or DCIS. Multivariate regression analysis and receiver operating characteristic analysis were performed. Results According to their immunohistochemical (IHC) profile, tumors were classified as human epidermal growth factor receptor 2 (HER2) positive (n = 51), estrogen receptor (ER) positive/HER2 negative (n = 40), and triple negative (n = 20). pCR was achieved in 19% (21 of 111) of cases; 86% of them were triple-negative or HER2-positive subtypes. Absence of late enhancement at posttreatment MR imaging was significantly associated with pCR (area under the curve [AUC], 0.85). Mean ADC ratio significantly increased when pCR was achieved (P < .001). A κ value of 0.479 was found for late enhancement (P < .001), and the intraclass correlation coefficient for ADCs was 0.788 (P < .001). Good correlation of ADCs obtained with the single-value method and those obtained with the mean-value methods was observed. The model combining the IHC subtype, ADC ratio, and late enhancement had the highest association with pathologic response, achieving an AUC of 0.92 (95% confidence interval: 0.86, 0.97). Conclusion Triple-negative or HER2-positive tumors showing absence of late enhancement and high ADC ratio after NST are associated with pCR. © RSNA, 2016 Online supplemental material is available for this article.

Patterns of somatic uniparental disomy identify novel tumor suppressor genes in colorectal cancer.

Colorectal cancer (CRC) is characterized by specific patterns of copy number alterations (CNAs), which helped with the identification of driver oncogenes and tumor suppressor genes (TSGs). More recently, the usage of single nucleotide polymorphism arrays provided information of copy number neutral loss of heterozygosity, thus suggesting the occurrence of somatic uniparental disomy (UPD) and uniparental polysomy (UPP) events. The aim of this study is to establish an integrative profiling of recurrent UPDs/UPPs and CNAs in sporadic CRC. Our results indicate that regions showing high frequencies of UPD/UPP mostly coincide with regions typically involved in genomic losses. Among them, chromosome arms 3p, 5q, 9q, 10q, 14q, 17p, 17q, 20p, 21q and 22q preferentially showed UPDs/UPPs over genomic losses suggesting that tumor cells must maintain the disomic state of certain genes to favor cellular fitness. A meta-analysis using over 300 samples from The Cancer Genome Atlas confirmed our findings. Several regions affected by recurrent UPDs/UPPs contain well-known TSGs, as well as novel candidates such as ARID1A, DLC1, TCF7L2 and DMBT1. In addition, VCAN, FLT4, SFRP1 and GAS7 were also frequently involved in regions of UPD/UPP and displayed high levels of methylation. Finally, sequencing and fluorescence in situ hybridization analysis of the gene APC underlined that a somatic UPD event might represent the second hit to achieve biallelic inactivation of this TSG in colorectal tumors. In summary, our data define a profile of somatic UPDs/UPPs in sporadic CRC and highlights the importance of these events as a mechanism to achieve the inactivation of TSGs.

Amyloidosis of the Breast: Three Different and Unusual Presentations of a Rare Entity.

BACKGROUND: Amyloidosis involving the breast is a rare finding and it may present as a solitary mass called 'amyloid tumor'. According to the largest case series, the amyloid deposits are usually of the AL type (commonly x03BA; light chain). METHODS: We report 3 cases diagnosed at our institution in the period from 2000 to 2015. Radiological, histological and immunohistochemical studies were performed. RESULTS AND CONCLUSIONS: Together with a case presenting in a patient with multiple myeloma, we describe 2 unique presentations including 1 associated with CREST syndrome in a patient with a previous history of breast carcinoma and another, also associated with cancer, with transthyretin deposits in a woman with a TTR gene mutation and a family history of familial amyloidotic polyneuropathy. These cases are an example of the vast heterogeneity of this disorder regarding its clinical presentation, the type of amyloid deposits and other diseases associated with breast amyloidosis.

Histopathological Study of a Mummified Eye and Optic Nerve from a Strangled Peruvian Mummy.

We present the histopathological findings of a naturally mummified eye from the Peruvian Lambayeque culture (900-1,200 AD), in which rehydration, light microscopy, and scanning electron microscopy allowed a detailed analysis of several eye tissues including the eyelids, sclera, and optic nerve, the latter showing evidence of hemorrhage likely related to the documented strangulation as the cause of death. We conclude that histopathological analysis of rehydrated mummified tissues can provide valuable information from fragile eye structures including the optic nerve, and these findings can be useful from a forensic point of view.

Validation study of a noninvasive urine test for diagnosis and prognosis assessment of bladder cancer: evidence for improved models.

PURPOSE: We validated the performance of our previously reported test for bladder cancer based on urine gene expression patterns using an independent cohort. We also ascertained whether alternative models could achieve better accuracy. MATERIALS AND METHODS: Gene expression patterns of the previously reported 48 genes, including the 12 + 2 genes of the signature, were analyzed by TaqMan® arrays in an independent set of 207 urine samples. We pooled all samples analyzed to date to obtain a larger training set of 404 and used it to search for putative improved new models. RESULTS: Our 12 + 2 gene expression signature had overall 80% sensitivity with 86% specificity (AUC 0.914) to discriminate between bladder cancer and control samples. It had 75% sensitivity and 75% specificity (AUC 0.83) to predict tumor aggressiveness in the validation set of urine samples. After grouping all samples 3 new signatures for diagnosis containing 2, 5 and 10 genes, respectively, and 1 containing 6 genes for prognosis were designed. Diagnostic performance of the 2, 5, 10 and 12-gene signatures was maintained or improved in the enlarged sample set (AUC 0.913, 0.941, 0.949 and 0.944, respectively). Performance to predict aggressiveness was also improved in the 14 and 6-gene signatures (AUC 0.855 and 0.906, respectively). CONCLUSIONS: This validation study confirms the accuracy of the 12 + 2 gene signature as a noninvasive tool for assessing bladder cancer. We present improved models with fewer genes that must be validated in future studies.

SAMHD1 expression is a surrogate marker of immune infiltration and determines prognosis after neoadjuvant chemotherapy in early breast cancer.

PURPOSE: The lack of validated surrogate biomarkers is still an unmet clinical need in the management of early breast cancer cases that do not achieve complete pathological response after neoadjuvant chemotherapy (NACT). Here, we describe and validate the use of SAMHD1 expression as a prognostic biomarker in residual disease in vivo and in vitro. METHODS: SAMHD1 expression was evaluated in a clinical cohort of early breast cancer patients with stage II-III treated with NACT. Heterotypic 3D cultures including tumor and immune cells were used to investigate the molecular mechanisms responsible of SAMHD1 depletion through whole transcriptomic profiling, immune infiltration capacity and subsequent delineation of dysregulated immune signaling pathways. RESULTS: SAMHD1 expression was associated to increased risk of recurrence and higher Ki67 levels in post-NACT tumor biopsies of breast cancer patients with residual disease. Survival analysis showed that SAMHD1-expressing tumors presented shorter time-to-progression and overall survival than SAMHD1 negative cases, suggesting that SAMHD1 expression is a relevant prognostic factor in breast cancer. Whole-transcriptomic profiling of SAMHD1-depleted tumors identified downregulation of IL-12 signaling pathway as the molecular mechanism determining breast cancer prognosis. The reduced interleukin signaling upon SAMHD1 depletion induced changes in immune cell infiltration capacity in 3D heterotypic in vitro culture models, confirming the role of the SAMHD1 as a regulator of breast cancer prognosis through the induction of changes in immune response and tumor microenvironment. CONCLUSION: SAMHD1 expression is a novel prognostic biomarker in early breast cancer that impacts immune-mediated signaling and differentially regulates inflammatory intra-tumoral response.

Dynamic contrast-enhanced MRI reveals the extent and the microvascular pattern of breast ductal carcinoma in situ.

To report the role of magnetic resonance imaging (MRI) in assessing the extent of breast ductal carcinoma in situ (DCIS). To assess whether the microvascularity pattern in DCIS correlates with magnetic resonance enhancement. Eighty-five histologically proven DCIS (77 pure DCIS, eight microinvasive DCIS) were prospectively studied with MRI. The morphology of magnetic resonance enhancement and the kinetic curve was recorded. Histopathologically, intraductal lesions were classified according to Van Nuys score. Tumor microvascularity was immunohistochemically assessed in a subset of 24 DCIS evaluating the number of microvessels, microvascularity area, and microvascularity pattern (diffuse or periductal). On the mammogram, 74% of DCIS appeared as microcalcifications. On MRI, 70% of DCIS showed enhancement. Non-mass-like uptake was observed in 78% of cases. The mean size of nonenhancing carcinomas was significantly lower than that of enhancing carcinomas (p = 0.033). The diffuse pattern was more frequent than the periductal pattern. A significant relationship between the morphology of MR enhancement and the microvascularity pattern was observed (p = 0.036); thus, 90% of DCIS showing segmental enhancement on MRI displayed a diffuse pattern while all DCIS with ductal enhancement showed a periductal pattern. There was a significant relationship between the maximum area of microvascularity and the vascular pattern (p = 0.015); periductal patterns showed larger areas than diffuse patterns. The lesion size was significantly larger as the Van Nuys score increased (p < 0.001) and was also related to the number of microvessels (p = 0.012). The mean area of microvascularity of DCIS was significantly larger as the Van Nuys score increased (p = 0.02). Breast MRI helps depict the extent of DCIS and reveals its microvascular pattern.

Impact of Prolonged Ischemia on the Immunohistochemical Expression of Programmed Death Ligand 1 (PD-L1).

Antibodies targeting programmed death receptor 1 or programmed death ligand 1 (PD-L1) have become a standard of care to treat different cancers; for some of these tumors, there is a correlation between tissue expression of PD-L1 and response rates in patients. Although most of the analytical challenges in the evaluation of PD-L1 expression have been standardized, preanalytical issues have been less explored. The objective of this study was to evaluate the impact of time of ischemia on the performance of 2 commonly used antibodies against PD-L1. Sixteen tonsillectomy samples were kept in ischemia for <30 minutes from sample obtention (control) and 1, 3, 6, 12, and 24 hours at room temperature before formalin fixation and paraffin embedding. Selected areas were inserted into TMA paraffin recipient blocks stained with SP142 and SP263 antibodies and evaluated by 2 blind observers. The proportion of suboptimally stained samples was significantly higher for samples with cold ischemia times 6 hours or over ( P <0.0001). False-negative results were 25% in samples exposed to 6 hours of ischemia and raised to 34% for samples remaining in ischemia for 12 or 24 hours. When all observations were pooled, SP142 provided suboptimal results in 24% of observations and SP263 in 12.5%; this is a statistically significant difference ( P =0.042). In conclusion, the quality of staining for PD-L1 in tonsil samples varies with the time of cold ischemia. The SP142 antibody presented a significantly lower tolerance to prolonged cold ischemia than SP263. These results reveal the relevance of controlled preanalytical processing of samples.

Pre- and Post-Neoadjuvant Clinicopathological Parameters Can Help in the Prognosis and the Prediction of Response in HER2+ and Triple Negative Breast Cancer.

Neoadjuvant treatment (NAT) is one of the most widely used options for HER2+ and triple negative (TN) early breast cancer (BC). Since around half of the patients treated with NAT do not achieve a pathologically complete response (pCR), biomarkers to predict resistance are urgently needed. The correlation of clinicopathological factors with pCR was studied in 150 patients (HER2 = 81; TN = 69) and pre- and post-NAT differences in tumour biomarkers were compared. Low estrogen receptor (ER) expression, high tumour-infiltrating lymphocytes (TILs) and low cT-stage were associated with pCR in HER2+ tumours (p = 0.022; p = 0.032 and p = 0.005, respectively). Furthermore, ER expression was also associated with residual cancer burden (RCB; p = 0.046) in the HER2+ subtype. Similarly, pre-NAT, low progesterone receptor expression (PR; 1-10%) was associated with higher RCB (p < 0.001) in TN tumours. Only clinical and pathological T-stage (cpT-stage) had prognostic capacity in HER2+ tumours, whereas pre-NAT cpT-stage and post-NAT TILs had this capacity for the prognosis of TN tumours. We conclude that ER and PR expression may help predict response to NAT in HER2 and TN BC and should be taken into account in residual tumours. Also, changes observed in the phenotype after NAT suggest the need to reevaluate biomarkers in surviving residual tumour cells.

The current clinical practice for management of post-infarction ventricular septal rupture: a European survey.

Aims: Many historical and recent reports showed that post-infarction ventricular septal rupture (VSR) represents a life-threatening condition and the strategy to optimally manage it remains undefined. Therefore, disparate treatment policies among different centres with variable results are often described. We analysed data from European centres to capture the current clinical practice in VSR management. Methods and results: Thirty-nine centres belonging to eight European countries participated in a survey, filling a digital form of 38 questions from April to October 2022, to collect information about all the aspects of VSR treatment. Most centres encounter 1-5 VSR cases/year. Surgery remains the treatment of choice over percutaneous closure (71.8% vs. 28.2%). A delayed repair represents the preferred approach (87.2%). Haemodynamic conditions influence the management in almost all centres, although some try to achieve patients stabilization and delayed surgery even in cardiogenic shock. Although 33.3% of centres do not perform coronarography in unstable patients, revascularization approaches are widely variable. Most centres adopt mechanical circulatory support (MCS), mostly extracorporeal membrane oxygenation, especially pre-operatively to stabilize patients and achieve delayed repair. Post-operatively, such MCS are more often adopted in patients with ventricular dysfunction. Conclusion: In real-life, delayed surgery, regardless of the haemodynamic conditions, is the preferred strategy for VSR management in Europe. Extracorporeal membrane oxygenation is becoming the most frequently adopted MCS as bridge-to-operation. This survey provides a useful background to develop dedicated, prospective studies to strengthen the current evidence on VSR treatment and to help improving its currently unsatisfactory outcomes.

Biomarkers vs conventional histological analysis to detect lymph node micrometastases in bladder cancer: a real improvement?

UNLABELLED: Study Type - Therapy (case series) Level of Evidence 4. What's known on the subject? and What does the study add? Muscle invasive bladder cancer has a mortality rate at 5 years of 50%, despite radical therapy, as a result of tumour progression and dissemination. This suggests that half of patients have disseminated disease at the time of diagnosis, which is not detected by the staging techniques currently used. The prognostic factors (histological grade and tumour stage) and current staging techniques do not discriminate between those patients who will be cured with surgical treatment and those who will die from metastatic spread. New diagnostic and prognostic tools that complement the existing methods and provide a proper assessment of carcinoma invading bladder muscle are therefore essential. Molecular staging techniques using specific biomarkers have been applied in various solid tumours to determine the presence of missed tumour cells in lymph nodes (LNs) during routine pathological examination. These techniques could identify patients with LN micrometastases who may potentially benefit from early treatment with chemotherapy. This study compares the performance of conventional histological analysis and molecular biomarkers in detecting bladder cancer LN micrometastases and predicting patient's clinical outcome. The study found that, even though a clear trend to a worse outcome was shown in those patients who became node-positive after molecular analysis, no statistical differences were found in cancer-specific and recurrence-free survival analysis between those patients who were negative by histology but positive by molecular analysis and those who were negative by both techniques. We concluded that molecular analysis of LN spreading in bladder cancer has a better detection rate than conventional histological examination. OBJECTIVE: • To improve the sensitivity of histological examination in detecting occult lymph node (LN) dissemination of bladder cancer using gene expression analysis. PATIENTS AND METHODS: • We carried out a retrospective study that included 504 formalin-fixed paraffin-embedded LNs from 90 patients with muscle invasive bladder cancer and 35 controls. • Gene expression values of two molecular biomarkers (FXYD3 and KRT20) were analysed using reverse transcription real-time quantitative PCR (RT-qPCR). • Molecular results were compared with histological status and patients' clinical outcomes. RESULTS: • Of the 90 patients analysed, 16 were positive and 74 were negative by histological analysis. Of these 74, 19 were classified as positive using RT-qPCR. • Significant differences in cancer-specific (P= 0.011) and recurrence-free (P= 0.009) survival were found between the three patient groups (patients positive by both techniques, patients negative by both techniques, and patients negative by histological but positive by molecular analysis). • A significant difference was not found between histologically negative but molecularly positive patients and patients who were negative by both techniques, but a clear trend to a worse outcome was found in those patients who became node-positive after molecular analysis. CONCLUSIONS: • The analysis of FXYD3 and KRT20 could improve current pathological examination for the detection of micrometastases in LNs. • Further and more extensive studies will determine the real prognostic value of such LN micrometastases.

Conventional and digital Ki67 evaluation and their correlation with molecular prognosis and morphological parameters in luminal breast cancer.

Digital counting methods were developed to decrease the high intra- and inter-observer variability of immunohistochemical markers such as Ki67, with most presenting a good correlation coefficient (CC). Since Ki67 is one of the major contributors to Oncotype DX, it is conceivable that Ki67 expression and the recurrence score (RS) obtained by the multigene panel are positively correlated. We decided first to test to what extent conventional and digital Ki67 quantification methods correlate in daily practice and, second, to determine which of these methods correlates better with the prognostic capacity of the Oncotype DX test. Both Ki67 evaluations were performed in 89 core biopsies with a diagnosis of estrogen receptor (ER) positive HER2-negative breast cancer (BC). Cases were, thus, classified twice for surrogate subtype: first by conventional analysis and then by digital evaluation. The Oncotype RS was obtained in 55 cases that were subsequently correlated to Ki67 evaluation by both methods. Conventional and digital Ki67 evaluation showed good concordance and correlation (CC = 0.81 (95% CI 0.73-0.89)). The correlation of Oncotype DX risk groups and surrogate derived subtypes was slightly higher for the digital technique (rs = 0.46, p < 0.01) compared to the conventional method (rs = 0.39, p < 0.01), even though both were statistically significant. In conclusion, we show that digital evaluation could be an alternative to conventional counting, and also has advantages for predicting the risk established by the Oncotype DX test in ER-positive BC. This study also supports the importance of an accurate Ki67 analysis which can influence the decision to submit ER-positive HER2-negative BC to prognostic molecular platforms.

Modulation of DNA Damage Response by SAM and HD Domain Containing Deoxynucleoside Triphosphate Triphosphohydrolase (SAMHD1) Determines Prognosis and Treatment Efficacy in Different Solid Tumor Types.

SAMHD1 is a deoxynucleotide triphosphate (dNTP) triphosphohydrolase with important roles in the control of cell proliferation and apoptosis, either through the regulation of intracellular dNTPs levels or the modulation of the DNA damage response. However, SAMHD1's role in cancer evolution is still unknown. We performed the first in-depth study of SAMHD1's role in advanced solid tumors, by analyzing samples of 128 patients treated with chemotherapy agents based on platinum derivatives and/or antimetabolites, developing novel in vitro knock-out models to explore the mechanisms driving SAMHD1 function in cancer. Low (or no) expression of SAMHD1 was associated with a positive prognosis in breast, ovarian, and non-small cell lung cancer (NSCLC) cancer patients. A predictive value was associated with low-SAMHD1 expression in NSCLC and ovarian patients treated with antimetabolites in combination with platinum derivatives. In vitro, SAMHD1 knock-out cells showed increased γ-H2AX and apoptosis, suggesting that SAMHD1 depletion induces DNA damage leading to cell death. In vitro treatment with platinum-derived drugs significantly enhanced γ-H2AX and apoptotic markers expression in knock-out cells, indicating a synergic effect of SAMHD1 depletion and platinum-based treatment. SAMHD1 expression represents a new strong prognostic and predictive biomarker in solid tumors and, thus, modulation of the SAMHD1 function may constitute a promising target for the improvement of cancer therapy.

Transfusion-transmitted arboviruses: Update and systematic review.

BACKGROUND: The detection of the first cases of transfusion-transmitted West Nile virus in 2002 posed a new challenge for transfusion safety. Institutions like the World Health Organization have stated that blood transfusion centers need to know the epidemiology of the different emerging infectious agents and their impact on blood transfusion. The aim of the study is to review the published cases of arbovirus transmission through transfusion of blood or blood components and to analyze their main clinical and epidemiological characteristics. MATERIAL AND METHODS: Systematic literature searches were conducted in MEDLINE, Embase and Scopus. Pairs of review authors selected a variety of scientific publications reporting cases of transfusion-transmitted arboviruses. Main clinical and epidemiological characteristics were reviewed of the cases described. The study protocol was registered in PROSPERO CRD42021270355. RESULTS: A total of 74 cases of transfusion-transmitted infections were identified from 10 arboviruses: West Nile virus (n = 42), dengue virus (n = 18), Zika virus (n = 3), yellow fever vaccine virus (n = 3), tick-borne encephalitis virus (n = 2), Japanese encephalitis virus (n = 2), Powassan virus (n = 1), St. Louis encephalitis virus (n = 1), Ross River virus (n = 1) and Colorado tick fever virus (n = 1). The blood component most commonly involved was red blood cells (N = 35, 47.3%; 95% confidence interval [CI] 35.9% to 58.7%). In 54.1% (N = 40; 95% CI: 42.7%-65.47%) of the cases, the recipient was immunosuppressed. Transmission resulted in death in 18.9% (N = 14; 95% CI: 10.0%-27.8%) of the recipients. In addition, 18 additional arboviruses were identified with a potential threat to transfusion safety. DISCUSSION: In the last 20 years, the number of published cases of transfusion-transmitted arboviruses increased notably, implicating new arboviruses. In addition, a significant number of arboviruses that may pose a threat to transfusion safety were detected. In the coming years, it is expected that transmission of arboviruses will continue to expand globally. It is therefore essential that all responsible agencies prepare for this potential threat to transfusion safety.

DigiPatICS: Digital Pathology Transformation of the Catalan Health Institute Network of 8 Hospitals-Planification, Implementation, and Preliminary Results.

Complete digital pathology transformation for primary histopathological diagnosis is a challenging yet rewarding endeavor. Its advantages are clear with more efficient workflows, but there are many technical and functional difficulties to be faced. The Catalan Health Institute (ICS) has started its DigiPatICS project, aiming to deploy digital pathology in an integrative, holistic, and comprehensive way within a network of 8 hospitals, over 168 pathologists, and over 1 million slides each year. We describe the bidding process and the careful planning that was required, followed by swift implementation in stages. The purpose of the DigiPatICS project is to increase patient safety and quality of care, improving diagnosis and the efficiency of processes in the pathological anatomy departments of the ICS through process improvement, digital pathology, and artificial intelligence tools.

Prognostic Impact of Change in Nutritional Risk on Mortality and Heart Failure After Transcatheter Aortic Valve Replacement.

BACKGROUND: Limited data are available regarding change in the nutritional status after transcatheter aortic valve replacement (TAVR). This study evaluated the prognostic impact of the change in the geriatric nutritional risk index following TAVR. METHODS: TAVR patients were analyzed in a prospective and observational study. To analyze the change in nutritional status, geriatric nutritional risk index of the patients was calculated on the day of TAVR and at 3-month follow-up. The impact of the change in nutritional risk index after TAVR on all-cause mortality, heart failure hospitalization (HF-h), and the composite of all-cause death and HF hospitalization was analyzed using the Cox Proportional Hazards model. RESULTS: Four hundred thirty-three patients were included. After TAVR, 68.4% (n=182) patients with baseline nutritional risk improved compared with 31.6% (n=84) who remained at nutritional risk. The change from no-nutritional risk to nutritional risk after TAVR occurred in 15.0% (n=25), while 85.0% (n=142) remained without risk of malnutrition. During follow-up, 157 (36.3%) patients died and 172 patients (39.7%) were hospitalized due to HF. Patients who continued to be at nutritional risk had a higher risk of mortality (hazard ratio [HR], 2.10 [95% CI, 1.30-3.39], P=0.002), HF-h (HR, 1.97 [95% CI, 1.26-3.06], P=0.000), and the composite of death and HF-h (HR, 2.0 [95% CI, 1.37-2.91], P<0.001). The change to non-nutritional risk after TAVR significantly impacted mortality (HR, 0.48 [95% CI, 0.30-0.78], P=0.003), HF-h (HR, 0.50 [95% CI, 0.34-0.74], P=0.001), and the composite outcome (HR, 0.44 [95% CI, 0.32-0.62], P<0.001). CONCLUSIONS: Remaining at nutritional risk after TAVR confers a poor prognosis and is associated with an increased risk of mortality and HF-h, while the change from risk of malnutrition to non-nutritional risk after TAVR was associated with a halving of the risk of mortality and HF-h. Further studies are needed to identify whether patients at nutritional risk would benefit from nutritional intervention during processes of care of TAVR programs.

EML4-ALK rearrangement in non-small cell lung cancer and non-tumor lung tissues.

A fusion gene, echinoderm microtubule associated protein like 4-anaplastic lymphoma kinase (EML4-ALK), with transforming activity has recently been identified in a subset of non-small cell lung cancer (NSCLC), but its pathogenetic, diagnostic, and therapeutic roles remain unclear. Both frequency and type of EML4-ALK transcripts were investigated by reverse transcription PCR in 120 frozen NSCLC specimens from Italy and Spain; non-neoplastic lung tissues taken far from the tumor were used as controls. In cases carrying the fusion transcript, we determined EML4-ALK gene and protein levels using fluorescence in situ hybridization, Western blotting, and immunoprecipitation. We also analyzed ALK protein levels in paraffin samples from 662 NSCLC specimens, including the 120 cases investigated in the molecular studies. EML4-ALK transcripts (variants 1 and 3) were detected in 9 of 120 NSCLC samples but were not specific for NSCLC since they were also found in non-cancerous lung tissues taken far from the tumor. Notably, no transcripts were detected in matching tumor samples from these patients. Fluorescence in situ hybridization analysis of cases expressing EML4-ALK transcripts showed that only a minority of cells harbored the EML4-ALK gene. None of these cases was found to express the EML4-ALK protein as examined by immunohistochemistry, Western blotting, and immunoprecipitation. The EML4-ALK transcript cannot be regarded as a specific diagnostic tool for NSCLC. Our results show therefore that the causal role and value of EML4-ALK as a therapeutic target remain to be defined.