ULTRA-SR Challenge: Assessment of Ultrasound Localization and TRacking Algorithms for Super-Resolution Imaging.

With the widespread interest and uptake of super-resolution ultrasound (SRUS) through localization and tracking of microbubbles, also known as ultrasound localization microscopy (ULM), many localization and tracking algorithms have been developed. ULM can image many centimeters into tissue in-vivo and track microvascular flow non-invasively with sub-diffraction resolution. In a significant community effort, we organized a challenge, Ultrasound Localization and TRacking Algorithms for Super-Resolution (ULTRA-SR). The aims of this paper are threefold: to describe the challenge organization, data generation, and winning algorithms; to present the metrics and methods for evaluating challenge entrants; and to report results and findings of the evaluation. Realistic ultrasound datasets containing microvascular flow for different clinical ultrasound frequencies were simulated, using vascular flow physics, acoustic field simulation and nonlinear bubble dynamics simulation. Based on these datasets, 38 submissions from 24 research groups were evaluated against ground truth using an evaluation framework with six metrics, three for localization and three for tracking. In-vivo mouse brain and human lymph node data were also provided, and performance assessed by an expert panel. Winning algorithms are described and discussed. The publicly available data with ground truth and the defined metrics for both localization and tracking present a valuable resource for researchers to benchmark algorithms and software, identify optimized methods/software for their data, and provide insight into the current limits of the field. In conclusion, Ultra-SR challenge has provided benchmarking data and tools as well as direct comparison and insights for a number of the state-of-the art localization and tracking algorithms.

PARP Inhibitors in Colorectal Malignancies: A 2023 Update.

BACKGROUND: Colorectal carcinoma (CRC) is one of the most common malignancies in the Western world, and metastatic disease is associated with a dismal prognosis. Poly-ADpribose polymerase (PARP) inhibitors gain increasing attention in the field of medical oncology, as they lead to synthetic lethality in malignancies with preexisting alterations in the DNA damage repair (DDR) pathway. As those alterations are frequently seen in CRC, a targeted approach through PARP inhibitors is expected to benefit these patients, both alone and in combination with other agents like chemotherapy, immunotherapy, antiangiogenics, and radiation. OBJECTIVE: This review article aims to better clarify the role of PARP inhibitors as a treatment option in patients with metastatic CRC with alterations in the DDR pathway. METHODS: We used the PubMed database to retrieve journal articles and the inclusion criteria were all human studies that illustrated the effective role of PARP inhibitors in patients with metastatic CRC with homologous repair deficiency (HRD) and the correct line of therapy. RESULTS: Current evidence supports the utilization of PARP inhibitors in CRC subgroups, as monotherapy and in combination with other agents. Up to now, data are insufficient to support a formal indication, and further research is needed. CONCLUSION: Efforts to precisely define the homologous repair deficiency (HRD) in CRC - and eventually the subgroup of patients that are expected to benefit the most - are also underway. REGISTRATION NUMBER: DOI: dx.doi.org/10.17504/protocols.io.dm6gp3ey8vzp/v1.

Identification of a Novel TSC2 c.170G>A Missense Variant: A Case Report and Elaboration on the Yield of Targeted Options against Tuberous Sclerosis Complex Manifestations.

BACKGROUND: Tuberous sclerosis complex (TSC) is a rare genetic disease that affects multiple organs and affects the quality of life. Mutations in TSC1 and TSC2 genes are causing dysregulations in the mammalian target of the rapamycin (mTOR) pathway, inducing mostly benign but also malignant tumors, including renal cell carcinoma (RCC). The diagnosis of TSC, based on established clinical and genetic criteria, is essential for the optimal surveillance and management of patients. CASE PRESENTATION: With the current report, we present the case of two sisters who were consequently diagnosed with early-stage chromophobe-like RCC, possibly familial given their young age. The younger sister also had a previous diagnosis of differentiated thyroid carcinoma, for which she had been treated properly. Genetic testing of both revealed the same heterozygous TSC2 variant that is currently regarded as a variant of unknown significance, while both patients did not fulfill the clinical criteria for the diagnosis of TSC. Owing to these data, we opted to manage and surveil both sisters as TSC patients, while we also considered the specific TSC2 variant to be pathogenic - but of low penetrance - based on clinical judgment and functional analyses. Furthermore, we discussed the implementation of mTOR inhibitors for the treatment of TSC complications. CONCLUSION: As novel pathogenic variants of TSC genes are constantly being explored, the identification of TSC variants of unknown significance in combination with absent clinical diagnostic criteria cannot exclude a TSC diagnosis. We support the implementation of clinical judgment in assisting the diagnosis of TSC, as well as the enrollment of patients in clinical trials due to the rarity of the disease.

Exploring Pragmatic Deficits in Relation to Theory of Mind and Executive Functions: Evidence from Individuals with Right Hemisphere Stroke.

Research investigating pragmatic deficits in individuals with right hemisphere damage focuses on identifying the potential mechanisms responsible for the nature of these impairments. Nonetheless, the presumed shared cognitive mechanisms that could account for these deficits have not yet been established through data-based evidence from lesion studies. This study aimed to examine the co-occurrence of pragmatic language deficits, Theory of Mind impairments, and executive functions while also exploring their associations with brain lesion sites. Twenty-five patients suffering from unilateral right hemisphere stroke and thirty-seven healthy participants were recruited for this study. The two groups were tested in pragmatics, Theory of Mind, and executive function tasks. Structural imaging data were also obtained for the identification of the lesion sites. The findings of this study suggest a potential convergence among the three aforementioned cognitive mechanisms. Moreover, we postulate a hypothesis for a neural circuitry for communication impairments observed in individuals with right hemisphere damage.

Unraveling the Thread of Aphasia Rehabilitation: A Translational Cognitive Perspective.

Translational neuroscience is a multidisciplinary field that aims to bridge the gap between basic science and clinical practice. Regarding aphasia rehabilitation, there are still several unresolved issues related to the neural mechanisms that optimize language treatment. Although there are studies providing indications toward a translational approach to the remediation of acquired language disorders, the incorporation of fundamental neuroplasticity principles into this field is still in progress. From that aspect, in this narrative review, we discuss some key neuroplasticity principles, which have been elucidated through animal studies and which could eventually be applied in the context of aphasia treatment. This translational approach could be further strengthened by the implementation of intervention strategies that incorporate the idea that language is supported by domain-general mechanisms, which highlights the impact of non-linguistic factors in post-stroke language recovery. Here, we highlight that translational research in aphasia has the potential to advance our knowledge of brain-language relationships. We further argue that advances in this field could lead to improvement in the remediation of acquired language disturbances by remodeling the rationale of aphasia-therapy approaches. Arguably, the complex anatomy and phenomenology of aphasia dictate the need for a multidisciplinary approach with one of its main pillars being translational research.

Moyamoya Disease: Clinical and Radiological Characteristics in Adult Greek Patients.

BACKGROUND AND PURPOSE: The aim of our study is to present, for the first time, the clinical, radiological, and neurocognitive characteristics of Greek adult patients with Moyamoya disease (MMD). METHODS: We analyzed prospectively collected data of 12 patients referred to our department from 2004 to 2019. All patients underwent a thorough diagnostic work up, including extensive clinical, neuroradiological, and neurocognitive assessment. RESULTS: Our study population consisted of 7 females and the median age at the time of the diagnosis was 43.5 years. No patient had a positive family history of the disease and roughly 50% were hypertensives. Ten patients presented with transient or permanent cerebrovascular ischemia and two patients suffered from hemorrhagic complications. The median NIHSS was 7.5 (0-23) and clinical status remained stable during follow-up with conservative treatment in most of the patients. The majority (83.3%) had bilateral disease confirmed by DSA. All lesions exclusively affected the anterior circulation, with 50% of patients presenting with stenoocclusive changes. No aneurysm or AVM were revealed. The most common neurocognitive deficits were in the executive and language domains. CONCLUSIONS: Our MMD patients had a later onset of the disease and an absence of familial occurrence. The most common manifestation was ischemia, transient or permanent, and all lesions affected the anterior circulation, whereas no vascular malformations (AVM, aneurysms) were demonstrated in brain imaging. These findings in Greek patients imply a probable different, Mediterranean phenotype.

Unravelling brain connectivity patterns in body dysmorphic disorder during decision-making on visual illusions: A graph theoretical approach.

Body dysmorphic disorder (BDD) is characterized by an excessive preoccupation with perceived defects in physical appearance, and is associated with compulsive checking. Visual illusions are illusory or distorted subjective perceptions of visual stimuli, which are induced by specific visual cues or contexts. While previous research has investigated visual processing in BDD, the decision-making processes involved in visual illusion processing remain unknown. The current study addressed this gap by investigating the brain connectivity patterns of BDD patients during decision-making about visual illusions. Thirty-six adults - 18 BDD (9 female) and 18 healthy controls (10 female) - viewed 39 visual illusions while their EEG was recorded. For each image, participants were asked to indicate (1) whether they perceived the illusory features of the images; and (2) their degree of confidence in their response. Our results did not uncover group-level differences in susceptibility to visual illusions, supporting the idea that higher-order differences, as opposed to lower-level visual impairments, can account for the visual processing differences that have previously been reported in BDD. However, the BDD group had lower confidence ratings when they reported illusory percepts, reflecting increased feelings of doubt. At the neural level, individuals with BDD showed greater theta band connectivity while making decisions about the visual illusions, likely reflecting higher intolerance to uncertainty and thus increased performance monitoring. Finally, control participants showed increased left-to-right and front-to-back directed connectivity in the alpha band, which may suggest more efficient top-down modulation of sensory areas in control participants compared to individuals with BDD. Overall, our findings are consistent with the idea that higher-order disruptions in BDD are associated with increased performance monitoring during decision-making, which may be related to constant mental rechecking of responses.

Is the Patient Actually Failing on Enzalutamide? A Case Report and Issues to Consider in Enzalutamide-Resistant Oligoprogressive Metastatic Castrate-Resistant Prostate Cancer.

BACKGROUND: Metastatic castrate-resistant prostate cancer (mCRPC) is a challenging disease, especially in heavily pretreated patients. Androgen pathway inhibitors have contributed to a notable improvement in the overall survival and quality of life in patients with mCRPC during the last decade. Still, a considerable percentage of patients are unable to draw benefits from this drug category and are deprived of a treatment that offers limited toxicity and preserves a good quality of life. The mechanisms leading to this pre-existing or acquired resistance, as well as the possible strategies to overcome this resistance have been put at the center of scientists' attention. CASE PRESENTATION: With the present report we present the case of a 70-year-old patient with mCRPC, who was apparently an enzalutamide non-responder, but a multimodal approach with enzalutamide continuation and irradiation to his symptomatic oligoprogressive disease converted him to a responder with clinical, biochemical and imaging response; furthermore, we discuss the existing data providing evidence for the use of metastasis-directed therapy in combination with androgen pathway inhibitors in order to overcome drug resistance in patients with oligoprogressive disease. CONCLUSION: A considerable proportion of patients with oligometastatic or oligoprogressive prostate cancer who seem not to respond to androgen pathway inhibitors, such as enzalutamide, due to preexisting or acquired resistance, could benefit from MDT with a multimodal treatment approach. This strategy allows androgen pathway inhibitor continuation beyond biochemical progression and delays the switch to next-line systemic treatment.

Immune checkpoint inhibitors and combinations with other agents in cholangiocarcinoma.

Cholangiocarcinoma consists of a heterogeneous group of malignancies with generally poor prognoses. Immunotherapy has emerged in the treatment landscape of many tumors, offering survival benefits, but data regarding the use of immunotherapy for cholangiocarcinoma remain vague. In this review, the authors analyze differences in the tumor microenvironment and various immune escape mechanisms and discuss available immunotherapy combinations with other agents among completed and ongoing clinical trials, such as chemotherapy, targeted agents, antiangiogenic drugs, local ablative therapies, cancer vaccines, adoptive cell therapy and PARP and TGF-ß inhibitors. Ongoing research to identify appropriate biomarkers is warranted.

Cholangiocarcinomas are a group of rare tumors. Survival time is limited, due to late diagnosis and advanced symptoms. The small number of patients makes it difficult to carry out clinical trials and find new medicines. Another issue is that there are many different subtypes of this tumor. Each one requires a different approach. Despite these setbacks, new treatment choices have appeared. Medicines that stimulate the immune system to fight cancer cells have changed the current treatment landscape for many tumor types and are very promising in cholangiocarcinomas.

Investigating Aphasia Recovery: Demographic and Clinical Factors.

Post-stroke language recovery remains one of the main unresolved topics in the field of aphasia. In recent years, there have been efforts to identify specific factors that could potentially lead to improved language recovery. However, the exact relationship between the recovery of particular language functions and possible predictors, such as demographic or lesion variables, is yet to be fully understood. In the present study, we attempted to investigate such relationships in 42 patients with aphasia after left hemisphere stroke, focusing on three language domains: auditory comprehension, naming and speech fluency. Structural imaging data were also obtained for the identification of the lesion sites. According to our findings, patients demonstrated an overall improvement in all three language domains, while no demographic factor significantly contributed to aphasia recovery. Interestingly, specific lesion loci seemed to have a differential effect on language performance, depending on the time of testing (i.e., acute/subacute vs. chronic phase). We argue that this variability concerning lesion-deficit associations reflects the dynamic nature of aphasia and further discuss possible explanations in the framework of neuroplastic changes during aphasia recovery.

Silent Pauses and Speech Indices as Biomarkers for Primary Progressive Aphasia.

Background and Objectives: Recent studies highlight the importance of investigating biomarkers for diagnosing and classifying patients with primary progressive aphasia (PPA). Even though there is ongoing research on pathophysiological indices in this field, the use of behavioral variables, and especially speech-derived factors, has drawn little attention in the relevant literature. The present study aims to investigate the possible utility of speech-derived indices, particularly silent pauses, as biomarkers for primary progressive aphasia (PPA). Materials and Methods: We recruited 22 PPA patients and 17 healthy controls, from whom we obtained speech samples based on two elicitation tasks, i.e., cookie theft picture description (CTP) and the patients' personal narration of the disease onset and course. Results: Four main indices were derived from these speech samples: speech rate, articulation rate, pause frequency, and pause duration. In order to investigate whether these indices could be used to discriminate between the four groups of participants (healthy individuals and the three patient subgroups corresponding to the three variants of PPA), we conducted three sets of analyses: a series of ANOVAs, two principal component analyses (PCAs), and two hierarchical cluster analyses (HCAs). The ANOVAs revealed significant differences between the four subgroups for all four variables, with the CTP results being more robust. The subsequent PCAs and HCAs were in accordance with the initial statistical comparisons, revealing that the speech-derived indices for CTP provided a clearer classification and were especially useful for distinguishing the non-fluent variant from healthy participants as well as from the two other PPA taxonomic categories. Conclusions: In sum, we argue that speech-derived indices, and especially silent pauses, could be used as complementary biomarkers to efficiently discriminate between PPA and healthy speakers, as well as between the three variants of the disease.

Bayesian semi-parametric modeling of covariance matrices for multivariate longitudinal data.

The article develops marginal models for multivariate longitudinal responses. Overall, the model consists of five regression submodels, one for the mean and four for the covariance matrix, with the latter resulting by considering various matrix decompositions. The decompositions that we employ are intuitive, easy to understand, and they do not rely on any assumptions such as the presence of an ordering among the multivariate responses. The regression submodels are semi-parametric, with unknown functions represented by basis function expansions. We use spike-slap priors for the regression coefficients to achieve variable selection and function regularization, and to obtain parameter estimates that account for model uncertainty. An efficient Markov chain Monte Carlo algorithm for posterior sampling is developed. The simulation study presented investigates the gains that one may have when considering multivariate longitudinal analyses instead of univariate ones, and whether these gains can counteract the negative effects of missing data. We apply the methods on a highly unbalanced longitudinal dataset with four responses observed over a period of 20 years.

Trimodality treatment in gastric and gastroesophageal junction cancers: Current approach and future perspectives.

Gastric and gastroesophageal junction (GEJ) cancers represent an aggressive group of malignancies with poor prognosis even when diagnosed in relatively early stage, with an increasing incidence both in Asia and in Western countries. These cancers are characterized by heterogeneity as a result of different pathogenetic mechanisms as shown in recent molecular analyses. Accordingly, the understanding of phenotypic and genotypic correlations/classifications has been improved. Current therapeutic strategies have also advanced and moved beyond surgical extirpation alone, with the incorporation of other treatment modalities, such as radiation and chemotherapy (including biologics). Chemoradiotherapy has been used as postoperative treatment after suboptimal gastrectomy to ensure local disease control but also improvement in survival. Preoperative chemoradiotherapy/chemotherapy has been employed to increase the chance of a successful R0 resection and pathologic complete response rate, which is associated with improved long-term outcomes. Several studies have defined various chemotherapy regimens to accompany radiation (before and after surgery). Recently, addition of immunotherapy after trimodality of gastroesophageal cancer has produced an advantage in disease-free interval. Targeted agents used in the metastatic setting are being investigated in the early setting with mixed results. The aim of this review is to summarize the existing data on trimodality approaches for gastric and GEJ cancers, highlight the remaining questions and present the current research effort addressing them.

Perforated appendicitis induced by pembrolizumab: a case report and review of the literature.

Monoclonal antibodies against programmed cell death protein 1 (PD-1) and PD-1 ligand 1 (PD-L1) are the main representatives in the field of immunotherapy and their indications are constantly increasing in medical oncology and hematology during the last decade. They are associated with long-lasting responses and an acceptable toxicity profile, although they may infrequently cause life-threatening complications requiring prolonged hospitalization or urgent interventions. With the current report, we present the case of a 75-year-old woman diagnosed with stage IV lung adenocarcinoma, who developed acute abdominal pain without preceding symptomatology while on pembrolizumab-pemetrexed maintenance treatment. A contained rupture of the appendix was found, for which she was managed conservatively. Subsequent endoscopic as well as histopathological findings from biopsies obtained via colonoscopy associated the clinical and imaging findings with grade 4 immune-mediated colitis. Interestingly, high-grade colitis is more frequent with anti-CTLA-4 agents in comparison to anti-PD-1 agents; moreover, most cases of anti-PD-1-mediated colitis present with preceding symptomatology (like diarrhea or vomiting), while cases or colonic perforation are extremely rare if ever described.

High grade neuroendocrine carcinoma of the breast, first line and maintenance immunotherapy.

Small cell carcinomas (SCCs) are poorly differentiated neuroendocrine tumors that arise predominantly in the lung and gastrointestinal tract (GIT). Neuroendocrine carcinomas can occur in a variety of extrapulmonary sites throughout the body, including breast, larynx, GIT, prostate, urinary bladder, ovary and cervix. This is a case report of a 55-year-old Asian female patient with metastatic high-grade neuroendocrine carcinoma of unknown origin that responded notably to off-label nivolumab maintenance treatment after first-line carboplatin - etoposide chemotherapy and radiation. After 2 years of nivolumab after platinum-based chemotherapy results from PET-CT showed no residual disease and we proceeded to mastectomy.

The Effects of Different Hormones on Supraventricular and Ventricular Premature Contractions in Healthy Premenopausal Women.

Background and Objectives: The effects of gender differences on cardiac parameters have been well-established. In this study, we aimed to evaluate the possible associations of plasma levels of different sex hormones with premature atrial or ventricular contractions in premenopausal women. Materials and Methods: We conducted a prospective study which included women in late reproductive age who presented with palpitations during an eight-month period. A 12-lead electrocardiography, a transthoracic echocardiogram, blood samples, and 24-hour rhythm Holter were conducted on the third day of the menstrual cycle. Results Overall, 93 healthy premenopausal women with a median age of 42 years were enrolled. QTc interval was within normal limits in all patients. The 24 h range of premature atrial contractions (PACs) and premature ventricular contractions (PVCs) was 0-6450 and was 0-21,230, respectively. The median number of PVCs was 540 and the median number of PACs was 212, respectively. In total, 51 patients (54.8%) had a frequency of PVCs > 500/24 h and 37 patients (39.8%) had a frequency of PACs > 500/24 h, respectively. No statistically significant association was shown between any hormone and the frequency of PACs. Regarding PVCs, patients with a PVCs frequency > 500/24 h had higher estradiol levels compared to patients with PVCs less than 500/24 h (median 60 pg/mL versus 42 pg/mL, p = 0.02, OR: 1.01). No association was found between PVCs and other hormones. Conclusions: In premenopausal healthy women, higher estradiol levels are independently associated with increased PVCs. This suggests that estradiol in late reproductive stages may exert proarrhythmic effects.

Central neurotoxicity induced by trastuzumab emtansine (T-DM1): a case report.

Trastuzumab emtansine (T-DM1) is a human epidermal growth factor receptor 2 (Her2) - targeted antibody-drug conjugate that is approved for patients previously treated with trastuzumab and a taxane for Her2-positive advanced breast cancer and those who have progressed within 6 months of completion of adjuvant chemotherapy, as well as for patients with residual invasive Her2-positive disease after the completion of adjuvant chemotherapy. Peripheral neuropathy is a common adverse event; however, ocular events have also been described. With the current report we present the case of a 67-year old woman who developed transient grade 2-3 blurred vision after the first T-DM1 infusion, which was complicated with grade 2 diplopia causing vertigo after the second infusion. After extended investigation, this symptomatology was attributed to central neurotoxicity, and gradually resolved after T-DM1 discontinuation.

Immunotherapy for cholangiocarcinoma: a 2021 update.

Cholangiocarcinoma (CCA) is a rare malignancy with generally dismal prognosis. Immunotherapy has revolutionized the management of cancer patients during the last decade, offering durable responses with an acceptable safety profile, but there are still no significant advances regarding CCA. Novel immunotherapeutic methods, such as cancer vaccines, oncolytic viruses, adoptive cell therapy and combinations of immune checkpoint inhibitors with other agents are currently under investigation and may improve prognosis. Efforts to find robust biomarkers for response are also ongoing. In this review, we discuss the rationale for the use of immunotherapy in CCA and available clinical data. Ongoing trials will also be presented, as well as key findings from each study.

Case Report: Combination of Olaparib With Chemotherapy in a Patient With ATM-Deficient Colorectal Cancer.

Poly-ADP ribose polymerase (PARP) inhibitors are constantly increasing in their indications for use as anti-cancer treatment in various neoplasms, the majority of which are linked with BRCA deficiency. Preclinical data support the investigation of PARP inhibitors in other neoplasms exhibiting "BRCAness" or homologous recombination deficiency (HRD) as monotherapy as well as in combination with chemotherapy. With the current report we present the case of a heavily pretreated 55-year-old male patient diagnosed with stage IV ATM-deficient CRC, who was effectively treated with an off-label olaparib-irinotecan combination after exhaustion of all available treatment choices; furthermore, we discuss the existing data providing evidence for the use of PARP inhibitors in ATM-deficient CRC and encourage the implementation of next-generation sequencing (NGS) in patients with no other available treatment options.