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Abstract Background Although crackles on chest auscultation represent a fundamental component of the diagnostic suspect for fibrotic interstitial lung disease (ILD), their reliability has not been properly studied. We assessed the agreement among respiratory physicians on the presence and changes over time of audible crackles collected in a prospective longitudinal cohort of patients with fibrotic ILD. Methods Lung sounds were digitally recorded at baseline and after 12 months at eight anatomical sites. Nine respiratory physicians blindly assessed randomized couples of recordings obtained from the same anatomical site at different timepoints. The physicians indicated the presence of crackles in individual recordings and which recording from each couple eventually had more intense crackles. Fleiss’ kappa coefficient was used to measure inter- and intra-rater agreement. Results Fifty-two patients, mostly with a diagnosis of IPF (n = 40, 76.9%) were prospectively enrolled between October 2019 and May 2021. The final acoustic dataset included 702 single recordings, corresponding to 351 couples of recordings from baseline and 12-months timepoints. Kappa coefficient was 0.57 (95% CI 0.55–0.58) for the presence of crackles and 0.42 (95% CI 0.41–0.43) for acoustic change. Intra-rater agreement, measured for three respiratory physicians on three repeated assessments, ranged from good to excellent for the presence of crackles (κ = 0.87, κ = 0.86, κ = 0.79), and from moderate to good for acoustic change (κ = 0.75, κ = 0.76, κ = 0.57). Conclusions Agreement between respiratory physicians for the presence of crackles and acoustic change was acceptable, suggesting that crackles represent a reliable acoustic finding in patients with fibrotic ILD. Their role as a lung-derived indicator of disease progression merits further studies.

Abstract. Abdominoscrotal hydrocele (ASH) is a rare clinical finding comprising fluid collection between the layers of the tunica vaginalis, extending from the scrotum to the abdominal cavity. At present, there is no unique or recommended management for ASH, and different surgical treatments have been proposed. Despite an open surgical approach being the most common treatment, the use of laparoscopy has also previously been described. The most common intraoperative complication is devascularization of the testis due to damage to the spermatic cord, with consequent orchiectomy. We present a case of ASH treated with minimally invasive surgery, consisting of a right inguinotomy with puncture of the ASH by positioning a mono-J stent avoiding spermatic cord dissection and the risk of testis devascularization. Sclerotization of the hydrocelic sac with iodopovidone through a mono-J stent was performed with healing from ASH and preservation of testicular vascularization. Two months later, magnetic resonance imaging showed the presence of scar tissue replacing the previous ASH cavity.

BACKGROUND: Approximately 15-20% of advanced gastric and gastro-oesophageal junction cancers overexpress HER2. In DESTINY-Gastric01, the HER2-targeted antibody-drug conjugate trastuzumab deruxtecan improved response and overall survival versus chemotherapy in patients from Japan and South Korea with locally advanced or metastatic HER2-positive gastric or gastro-oesophageal junction cancer whose disease progressed after two lines of previous therapy including trastuzumab. Here, we report primary and updated analyses of the single-arm, phase 2 DESTINY-Gastric02 trial, which aimed to examine trastuzumab deruxtecan in patients living in the USA and Europe. METHODS: DESTINY-Gastric02 is a single-arm, phase 2 study in adult patients from 24 study sites in the USA and Europe (Belgium, Spain, Italy, and the UK). Eligible patients were aged at least 18 years and had an Eastern Cooperative Oncology Group performance status of 0 or 1, pathologically documented unresectable or metastatic gastric or gastro-oesophageal junction cancer, progressive disease on or after first-line therapy with a trastuzumab-containing regimen, with at least one measurable lesion per Response Evaluation Criteria in Solid Tumours (version 1.1), and centrally confirmed HER2-positive disease on a postprogression biopsy. Patients were given 6·4 mg/kg of trastuzumab deruxtecan intravenously every 3 weeks until disease progression, withdrawal by patient, physician decision, or death. The primary endpoint was confirmed objective response rate by independent central review. The primary endpoint and safety were assessed in the full analysis set (ie, participants who received at least one dose of study drug). Here, we report the primary analysis of this study, with a data cutoff of April 9, 2021, and an updated analysis, with a data cutoff of Nov 8, 2021. This trial is registered with ClinicalTrials.gov, NCT04014075, and is ongoing. FINDINGS: Between Nov 26, 2019, and Dec 2, 2020, 89 patients were screened and 79 were enrolled and subsequently treated with trastuzumab deruxtecan (median age 60·7 years [IQR 52·0-68·3], 57 [72%] of 79 were male, 22 [28%] were female, 69 [87%] were White, four [5%] were Asian, one [1%] was Black or African American, one [1%] was Native Hawaiian or Pacific Islander, one had missing race, and three [4%] were other races). At the primary analysis (median follow-up 5·9 months [IQR 4·6-8·6 months]), confirmed objective response was reported in 30 (38% [95% CI 27·3-49·6]) of 79 patients, including three (4%) complete responses and 27 (34%) partial responses, as assessed by independent central review. As of data cutoff for the updated analysis (median follow-up 10·2 months [IQR 5·6-12·9]), a confirmed objective response was reported in 33 (42% [95% CI 30·8-53·4]) of 79 patients, including four (5%) complete responses and 29 (37%) partial responses, as assessed by independent central review. The most common grade 3 or worse treatment-emergent adverse events were anaemia (11 [14%]), nausea (six [8%]), decreased neutrophil count (six [8%]), and decreased white blood cell count (five [6%]). Drug-related serious treatment-emergent adverse events occurred in ten patients (13%). Deaths determined to be associated with study treatment occurred in two patients (3%) and were due to interstitial lung disease or pneumonitis. INTERPRETATION: These clinically meaningful results support the use of trastuzumab deruxtecan as second-line therapy in patients with HER2-positive advanced gastric or gastro-oesophageal junction cancer. FUNDING: Daiichi Sankyo and AstraZeneca.

BACKGROUND: In the randomized, controlled, phase III KEYNOTE-061 trial, second-line pembrolizumab did not significantly prolong overall survival (OS) versus paclitaxel in patients with PD-L1-positive (combined positive score ≥1) advanced gastric/gastroesophageal junction (G/GEJ) cancer but did elicit a longer duration of response and offered a favorable safety profile. This prespecified exploratory analysis was conducted to evaluate associations between tumor gene expression signatures and clinical outcomes in the phase III KEYNOTE-061 trial. METHODS: Using RNA sequencing data obtained from formalin-fixed, paraffin-embedded baseline tumor tissue samples, we evaluated the 18-gene T-cell-inflamed gene expression profile (TcellinfGEP) and 10 non-TcellinfGEP signatures (angiogenesis, glycolysis, granulocytic myeloid-derived suppressor cell (gMDSC), hypoxia, monocytic MDSC (mMDSC), MYC, proliferation, RAS, stroma/epithelial-to-mesenchymal transition/transforming growth factor-β, WNT). The association between each signature on a continuous scale and outcomes was analyzed using logistic (objective response rate (ORR)) and Cox proportional hazards regression (progression-free survival (PFS) and OS). One-sided (pembrolizumab) and two-sided (paclitaxel) p values were calculated for TcellinfGEP (prespecified α=0.05) and the 10 non-TcellinfGEP signatures (multiplicity-adjusted; prespecified α=0.10). RESULTS: RNA sequencing data were available for 137 patients in each treatment group. TcellinfGEP was positively associated with ORR (p=0.041) and PFS (p=0.026) for pembrolizumab but not paclitaxel (p>0.05). The TcellinfGEP-adjusted mMDSC signature was negatively associated with ORR (p=0.077), PFS (p=0.057), and OS (p=0.033) for pembrolizumab, while the TcellinfGEP-adjusted glycolysis (p=0.018), MYC (p=0.057), and proliferation (p=0.002) signatures were negatively associated with OS for paclitaxel. CONCLUSIONS: This exploratory analysis of tumor TcellinfGEP showed associations with ORR and PFS for pembrolizumab but not for paclitaxel. TcellinfGEP-adjusted mMDSC signature was negatively associated with ORR, PFS, and OS for pembrolizumab but not paclitaxel. These data suggest myeloid-driven suppression may play a role in resistance to PD-1 inhibition in G/GEJ cancer and support a strategy of considering immunotherapy combinations which target this myeloid axis. TRIAL REGISTRATION NUMBER: NCT02370498.

DESTINY-CRC01 (NCT03384940) was a multicenter, open-label, phase 2 trial assessing the efficacy and safety of trastuzumab deruxtecan (T-DXd) in patients with HER2-expressing metastatic colorectal cancer (mCRC) that progressed after ≥2 prior regimens; results of the primary analysis are published. Patients received T-DXd 6.4 mg/kg every 3 weeks and were assigned to either: cohort A (HER2-positive, immunohistochemistry [IHC] 3+ or IHC 2+/in situ hybridization [ISH]+), cohort B (IHC 2+/ISH-), or cohort C (IHC 1+). Primary endpoint was objective response rate (ORR) by independent central review in cohort A. Secondary endpoints included ORR (cohorts B and C), duration of response, disease control rate, progression-free survival, overall survival, pharmacokinetics, and safety of T-DXd. 86 patients were enrolled (53 in cohort A, 15 in cohort B, and 18 in cohort C). Results of the primary analysis are published, reporting an ORR of 45.3% in cohort A. Here, we report the final results. No responses occurred in cohorts B or C. Median progression-free survival, overall survival, and duration of response were 6.9, 15.5, and 7.0 months, respectively. Overall serum exposure (cycle 1) of T-DXd, total anti-HER2 antibody, and DXd were similar regardless of HER2 status. Most common grade ≥3 treatment-emergent adverse events were decreased neutrophil count and anemia. Adjudicated drug-related interstitial lung disease/pneumonitis occurred in 8 patients (9.3%). These findings support the continued exploration of T-DXd in HER2-positive mCRC.

Psychosis is a characterizing feature of many mental disorders that dramatically affects human thoughts and perceptions, influencing the ability to distinguish between what is real and what is not. Both genetic and environmental factors, such as stressful events or drug use, play a pivotal role in the development of symptomatology and therefore changes in the epigenome may be of relevance in modeling a psychotic phenotype. According to the well-documented dysregulation of endocannabinoid and dopaminergic system genes in schizophrenia, we investigated DNA methylation cannabinoid type 1 receptor (CNR1) and dopamine D2 receptor (DRD2) genes in saliva samples from psychotic subjects using pyrosequencing. The epigenetic mark was significantly higher and directly correlated for both genes in psychotic subjects compared to healthy controls. We also showed that these DNA methylation levels were lower in psychotic subjects reporting current delta-9-tetrahydrocannabinol (THC) consumption, a well-known risk factor for developing psychosis throughout the lifespan, resembling those of controls at least for the DRD2 gene. Overall, our data confirm the key role of CNR1 and DRD2 gene regulation in psychosis and suggest DNA methylation levels at specific CpG sites as potential biomarkers, but just in those psychotic subjects not consuming THC.

Abstract Background Biliary tract cancers (BTCs) are rare and lethal cancers, with a 5-year survival inferior to 20%(1–3). The only potential curative treatment is surgical resection. However, despite complex surgical procedures that have a remarkable risk of postoperative morbidity and mortality, the 5-year survival rate after radical surgery (R0) is 20–40% and recurrence rates are up to ~ 75%(4–6). Up to ~ 40% of patients relapse within 12 months after resection, and half of these patient will recur systemically(4–6). There is no standard of care for neoadjuvant chemotherapy (NAC) in resectable BTC, but retrospective reports suggest its potential benefit (7, 8). Methods PURITY is a no-profit, multicentre, randomized phase II/III trial aimed at evaluating the efficacy of the combination of gemcitabine, cisplatin and nabpaclitaxel (GAP) as neoadjuvant treatment in patients with resectable BTC at high risk for recurrence. Primary objective of this study is to evaluate the efficacy of neoadjuvant GAP followed by surgery as compared to upfront surgery, in terms of 12-month progression-free survival for the phase II part and of progression free survival (PFS) for the phase III study. Key Secondary objectives are event free survival (EFS), relapse-free survival, (RFS), overall survival (OS), R0/R1/R2 resection rate, quality of life (QoL), overall response rate (ORR), resectability. Safety analyses will include toxicity rate and perioperative morbidity and mortality rate. Exploratory studies including Next-Generation Sequencing (NGS) in archival tumor tissues and longitudinal ctDNA analysis are planned to identify potential biomarkers of primary resistance and prognosis. Discussion Considering the poor prognosis of resected BTC experiencing early tumor recurrence and the negative prognostic impact of R1/R2 resections, PURITY study is based on the rationale that NAC may improve R0 resection rates and ultimately patients’ outcomes. Furthermore, NAC should allow early eradication of microscopic distant metastases, undetectable by imaging but already present at the time of diagnosis and avoid mortality and morbidity associated with resection for patients with rapid progression or worsening general condition during neoadjuvant therapy. The randomized PURITY study will evaluate whether patients affected by BTC at high risk from recurrence benefit from a neoadjuvant therapy with GAP regimen as compared to immediate surgery. Trial registration PURITY is registered at ClinicalTrials.gov (NCT06037980) and EuCT(2023–503295-25–00).

Abstract Mechanically exfoliated multilayer WS2 flakes are used as the channel of field effect transistors for low-power photodetection in the visible and near-infrared (NIR) spectral range. The electrical characterization as a function of the temperature reveals devices with n-type conduction and slightly different Schottky barriers at the drain and source contacts. The WS2 phototransistors can be operated in self-powered mode, yielding both a current and a voltage when exposed to light. The spectral photoresponse in the visible and the NIR ranges shows a high responsivity (4.5 μA/W) around 1250 nm, making the devices promising for telecommunication applications.

ABSTRACTMineral oil-derived lubricants, extracted from fossil fuels, account for approximately 90% of the lubricant market. A large proportion of these lubricants end up in the environment through usage, spillage, and disposal, leading to contamination of aquatic systems, ecosystems, and agricultural lands. To address this, new regulations were released (e.g. Vessel General Permit 2013) to promote the use of Environmentally Acceptable Lubricants (EALs) over conventional, toxic, non-biodegradable mineral oils. Today, the range of EAL is limited, particularly affecting the maritime sector. Since 2013, the variety and effectiveness of EALs have improved, but further advancements and cost reductions are essential. This study focuses on developing sustainable bio-based additives from microbial processes to enhance EALs. These additives, sourced through fermentation, avoid using fossil fuels and do not require arable land, preserving water resources and food production areas. The research reveals that yeast, high in sulfur and phosphorus, and microbial oils, mainly carboxylic acids, effectively stabilize EAL formulations, reducing friction and wear in water-based lubricants. Microbial oils are superior in reducing friction, while yeast offers better wear protection. This study opens the possibility of incorporating various bio-based products into EALs, providing a sustainable, environmentally friendly option.

Abstract The family of 2D chalcogenide semiconductors has been growing rapidly. Metal monochalcogenides, for instance, can enable new possibilities in functional electronics and optoelectronics. A Gallium Selenide (GaSe) thin flake is used to fabricate a back gated field effect transistor (FET) with n‐type conduction behavior and wide hysteresis at the ambient conditions. The device shows high mobility up to 28 cm2 V−1 s−1 with Ion/Ioff ratio over 103. Under the laser exposure, the device shows a decrease in the threshold voltage and a left‐shift of the transfer characteristic with a slight increase in the current. The transfer characteristic exhibits a hysteretic behavior with hysteresis width linearly dependent on the applied gate voltage. Moreover, the GaSe‐based FET shows a photo response with a photoresponsivity of 475 mAW−1 and detectivity of 4.6 × 1012 Jones. The photocurrent rise and decay times are 0.1 and 1.3 s, respectively. Furthermore, the GaSe FET device can be used as a performant memory device with well separated states and memory window enhanced by the laser exposure, confirming an optoelectronic memory class.

IntroductionSurgical-related injuries are frequent, in fact the reported percentage of musculoskeletal disorders in surgeons is between 47% and 87%. These conditions are caused by long periods of standing, incorrect postures, repeated movements, little rest between operations, the lack of integrated operator rooms, the correct number and arrangement of monitors and the use of non-ergonomic instruments. This survey aims to assess the Italian overview both highlighting how prevalent surgical-related injury is in our surgeons and whether there is an operating room ergonomics education program in Italian surgical specialty schools.MethodsAn anonymous questionnaire was designed through SurveyMonkey© web application. This survey was composed of 3 different sections concerning the general characteristics of the participants, their surgical background and any training performed, and any injuries or ailments related to the surgical activity. The survey was carried out in the period 1th of December 2022 and the 6th of February 2023.ResultsAt the close of our survey, 300 responses were collected. Among the participants, the two most represented specialties were Gynecology and Obstetrics (42.3%) and General Surgery (39.7%) and surgeons were mainly employed in the Northern regions of Italy (54.8%). Analyzing the participants’ background, 61.7% of the respondents had laparoscopic training during their training and only 53.1% had a pelvic trainer during their residency. In accordance with 98.7% of the respondents, during surgery we have the feeling of being in an uncomfortable position that causes discomfort or muscle pain, and regarding the frequency of these discomforts, the majority of our study population experiences these problems monthly (46.2%), while in 29.6% it is experienced weekly, 12.1% annually and finally 12.1% daily. The surgical approach that is most correlated with these disorders is laparoscopy (62.7%) while the one that causes the least discomfort is robotic surgery (1.4%). These discomforts cause 43.9% of our population to take a break or do short exercises to reduce pain during surgery, and the body areas most affected are the back (61.6%), neck (40.6%) and shoulders (37.8%).ConclusionDespite this, our survey allows us to highlight some now-known gaps present in the surgical training program of our schools and the lack of protection toward our surgeons during their long career.

Abstract Background Research suggests that interpersonal dysfunction may be central to borderline personality disorder (BPD), and that the relationships of people with BPD are particularly impaired. Further, the significant others of people with BPD exhibit elevated psychological problems but little access to mental healthcare. Despite this, most BPD interventions are delivered individually and do not routinely incorporate significant others. This manuscript presents the first case series of Sage, a 12-session manualized intervention for people with borderline personality disorder (BPD) and their intimate partners with three targets: a) BPD severity, b) relationship conflict, and c) intimate partner mental health. Findings Five couples of people with BPD with frequent suicidal/self-injurious behavior or high suicidal ideation and their intimate partners received Sage. Measures of Sage targets as well as tertiary outcomes were administered at pre-, mid-, and post-intervention. Four out of five dyads completed Sage, with high intervention satisfaction ratings. Improvements were generally demonstrated in BPD severity, suicidal ideation, and suicidal behavior/self-injury. Half of dyads exhibited improvements in conflict, and additional improvements in mental health outcomes for dyad members were demonstrated. One dyad exhibited poor outcomes and speculations regarding this are offered. Conclusions Findings provide proof of concept of Sage as an intervention that can improve BPD and other mental health outcomes in those with BPD and their intimate partners. Incorporating intimate partners into BPD treatment may optimize and expedite its outcomes. However, further testing is needed. Trial registration This project was pre-registered at Clinicaltrials.gov (Identifier: [NCT04737252]).

Quantum computers are inherently affected by noise. While in the long term, error correction codes will account for noise at the cost of increasing physical qubits, in the near term, the performance of any quantum algorithm should be tested and simulated in the presence of noise. As noise acts on the hardware, the classical simulation of a quantum algorithm should not be agnostic on the platform used for the computation. In this paper, we apply the recently proposed noisy gates approach to efficiently simulate noisy optical circuits described in the dual rail framework. The evolution of the state vector is simulated directly, without requiring the mapping to the density matrix framework. Notably, we test the method on both the gate-based and measurement-based quantum computing models, showing that the approach is very versatile. We also evaluate the performance of a photonic variational quantum algorithm to solve the MAX-2-CUT problem. In particular we design and simulate an ansatz, which is resilient to photon losses up to p∼10^{−3} making it relevant for near-term applications.

A rising demand for prosthetic-driven jaw reconstruction is encountered in maxillo-facial surgery. The free scapula flap is a workhorse of cervico-facial reconstructions, but an implant-based prosthetic rehabilitation on this flap is a debated topic. A systematic review of the papers on this subject has been conducted on Embase, MEDLINE, and Cochrane libraries following PRISMA guidelines, in order to analyze the results described in the literature. A total of nine papers were eligible for inclusion, with 83 scapula flaps overall being used for an implant-based prosthetic rehabilitation. The mandible was the reconstructed jaw in 58.0% of the cases. Overall, 249 implants were positioned (mean 3.0 implant per flap) with a 3.6% implant failure rate. In 95.2% of the cases, delayed rehabilitation was performed. Radiotherapy and the timing of implant placement did not seem to influence implant failure. Only two papers analyzed the quality of life following the rehabilitation, highlighting a functional improvement. Scapula-based implant-prosthetic rehabilitation is a feasible technique that can also benefit from the new CAD/CAM technologies and digital workflows. Nonetheless, further studies focused on this topic and on its impact on the quality of life are needed in order to analyze risk factors and to optimize the outcomes.

One of the major problems related to climate change is the increase in land area affected by higher salt concentrations and desertification. Finding economically and environmentally friendly sustainable solutions that effectively mitigate salt stress damage to plants is of great importance. In our work, some natural products and microbial biocontrol agents were evaluated for their long-term effectiveness in reducing salt stress in lettuce (Lactuca sativa L. var. romana) plants. Fourteen different treatments applied to soil pots, with and without salt stress, were analyzed using biometric (leaf and root length and width), physiological (chlorophyll and proline content), and morphological (microscopic preparations) techniques and NGS to study the microbial communities in the soil of plants subjected to different treatments. Under our long-term experimental conditions (90 days), the results showed that salt stress negatively affected plant growth. The statistical analysis showed a high variability in the responses of the different biostimulant treatments. Notably, the biocontrol agents Papiliotrema terrestris (strain PT22AV), Bacillus amyloliquefaciens (strain B07), and Rahnella aquatilis (strain 36) can act as salt stress mitigators in L. sativa. These findings suggest that both microbial biocontrol agents and certain natural products hold promise for reducing the adverse effects of salt stress on plants.

Abstract Background First‐line nivolumab plus chemotherapy and nivolumab plus ipilimumab both demonstrated significant overall survival (OS) benefit versus chemotherapy in previously untreated patients with advanced esophageal squamous cell carcinoma (ESCC) in the CheckMate 648 trial, leading to approvals of both nivolumab‐containing regimens in many countries. We report longer‐term follow‐up data. Methods This open‐label, phase III trial (NCT03143153) enrolled adults with previously untreated, unresectable, advanced, recurrent, or metastatic ESCC. Patients were randomized 1:1:1 to nivolumab plus chemotherapy, nivolumab plus ipilimumab, or chemotherapy. Primary endpoints were OS and progression‐free survival (PFS) by blinded independent central review. Hierarchical testing was performed first in patients with tumor cell programmed death ligand 1 (PD‐L1) expression of ≥1% and then in the overall population. Results A total of 970 patients were randomly assigned. After 29 months of minimum follow‐up, nivolumab plus chemotherapy continued to demonstrate improvement in OS versus chemotherapy (hazard ratio [HR] = 0.59 [95% CI: 0.46–0.76]) in patients with tumor cell PD‐L1 expression of ≥1% and in the overall population (HR = 0.78 [95% CI: 0.65–0.93]) and with nivolumab plus ipilimumab versus chemotherapy (HR = 0.62 [95% CI: 0.48–0.80]) in patients with tumor cell PD‐L1 expression of ≥1% and in the overall population (HR = 0.77 [95% CI: 0.65–0.92]). In patients with tumor cell PD‐L1 expression of ≥1%, nivolumab plus chemotherapy demonstrated PFS benefit versus chemotherapy (HR = 0.67 [95% CI: 0.51–0.89]); PFS benefit was not observed with nivolumab plus ipilimumab versus chemotherapy (HR = 1.04 [95% CI: 0.79–1.36]). Among all treated patients (n = 936), Grade 3–4 treatment‐related adverse events were reported in 151 (49%, nivolumab plus chemotherapy), 105 (32%, nivolumab plus ipilimumab), and 110 (36%, chemotherapy) patients. Conclusions Nivolumab plus chemotherapy and nivolumab plus ipilimumab continued to demonstrate clinically meaningful OS benefit versus chemotherapy with no new safety signals identified with longer follow‐up, further supporting use as first‐line standard treatment options for patients with advanced ESCC.

O artigo apresenta o desenvolvimento e a análise de resultados do projeto Macunaíma, caso aplicado de IA utilizada para a criação de roteiros e de storyboards, que une narrativa, áudio e imagens geradas automaticamente. Tecnicamente, foram utilizados modelos de IA para geração de texto (ChatGPT) e imagem (Stable Diffusion), com uma interface web que permite a interação do usuário. As dimensões de Coesão Temporal da Narrativa, Coesão Cinematográfica da cena e Coesão Gráfica foram verificadas, assim como foi criado um protótipo de visualização de dados para identificar as narrativas geradas e direções de aprimoramentos da ferramenta. Apontamos o uso de visualização de dados como crucial na análise destes modelos complexos, em especial pela quantidade de informação envolvida.

PurposeIn GI cancers, anaplastic lymphoma kinase (ALK) rearrangements are extremely less frequent than in non-small-cell lung cancer but may be important to offer personalized strategies of treatment in selected patients. Data about the activity and efficacy of ALK inhibitors (ALKi) in GI cancers are scarce.Materials and methodsWe assembled a clinical and molecular international data set of pretreated patients with metastatic or nonresectable cancers of GI primary tumor origin with documented ALK rearrangement treated with at least one line of ALKi. Measurable disease as per RECIST 1.1 was required for response analysis.ResultsPrimary tumor sites were distributed as follows: 5 (38%) pancreas, 3 (23%) right colon, and 1 (8%) for each one of gastric, duodenal, rectal, left colon, and biliary tract sites. Seven patients (54%) were treated with alectinib, 5 (38%) with crizotinib, and 1 (8%) with entrectinib. After disease progression, five patients (38%) received a subsequent ALKi treatment line, and at the time of data cutoff date, treatment was still ongoing in two patients. Five of 12 evaluable patients (41%) achieved a partial response to first-line ALKi, five patients (41%) had stable disease, and 2 (17%) had progressive disease. No complete responses were registered. At a median follow-up of 39.6 months (interquartile range: 19.8-59.5), the median progression-free survival was 5.0 months (95% CI, 3.68 to no response) and the median overall survival was 9.3 months (95% CI, 5.46 to no response).ConclusionTreatment with ALKi provides remarkable responses and clinical benefit in pretreated patients with ALK fusion-positive GI malignancies. Despite the rarity, ALK rearrangements represent an important therapeutic target in individual pretreated patients with GI solid tumors. Further work providing prospective clinical validation of this target is needed.