Unraveling noncoding DNA variants and epimutations: a paradigm shift in hereditary cancer research.

Exhaustive efforts have been dedicated to uncovering genomic aberrations linked to cancer susceptibility. Noncoding sequence variants and epigenetic alterations significantly influence gene regulation and could contribute to cancer development. However, exploring noncoding regions in hereditary cancer susceptibility demands cutting-edge methodologies for functionally characterizing genomic discoveries. Additionally, comprehending the impact on cancer development of variants in noncoding DNA and the epigenome necessitates integrating diverse data through bioinformatic analyses. As novel technologies and analytical methods continue to advance, this realm of research is rapidly gaining traction. Within this mini-review, we delve into future research domains concerning aberrations in noncoding DNA regions, such as pseudoexons, promoter variants and cis-epimutations.

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A Comprehensive Review on the Role of Lurbinectedin in Soft Tissue Sarcomas.

OPINION STATEMENT: Soft tissue sarcoma (STS), a substantial group of aggressive and rare tumors with tissue heterogeneity, is infrequently represented in clinical trials with an urgent necessity for newer treatment options. Lurbinectedin, an analog of trabectedin, is currently approved, in various countries, as a single agent, for the treatment of patients with relapsed small cell lung cancer (SCLC). However, preclinical and phase I and phase II trials have demonstrated the efficacy of lurbinectedin in different tumor types, including STS. The better understanding of the pathophysiology and evolution of STS as well as the mechanism of action of lurbinectedin in addition to the available data regarding the activity of this drug in this subset of patients will pave the way to newer therapeutic options and strategies.

Experience with second-line trabectedin in daily clinical practice: case studies.

As a recommended second-line option for advanced soft tissue sarcoma, trabectedin can provide the necessary balance between long-term tumor control and preserved quality of life. Three case studies illustrate the long-lasting responses that patients can achieve with second-line trabectedin. A female patient with metastatic leiomyosarcoma maintained disease control for 2 years with trabectedin (× 41 cycles) with excellent tolerability and no relevant adverse events. At the time of writing, a male patient with a metastatic solitary fibrous tumor was asymptomatic after 30 cycles of trabectedin and treatment was ongoing. A young male patient with a recurrent, nonresectable, retroperitoneal myxoid/round cell liposarcoma was able to continue his sporting activities (triathlons) over 2 years with trabectedin (× 14 cycles) plus watchful waiting.

Non-branched microcysts of the pancreas on MR imaging of patients with pancreatic tumors who had pancreatectomy may predict the presence of pancreatic intraepithelial neoplasia (PanIN): a preliminary study.

PURPOSE: To evaluate whether pancreatic parenchymal abnormalities on magnetic resonance imaging (MRI) are associated with pancreatic intraepithelial neoplasia (PanIN) on histology. MATERIALS AND METHODS: Retrospective study approved by institutional review board. One hundred patients (48 men, 52 women; mean age, 53.2 ± 16.29 [SD]) underwent MRI before pancreatectomy for pancreatic tumors analyzed by two independent observers blinded to histopathological results for the presence of non-communicating microcysts and pancreatic atrophy (global or focal) beside tumors. MRI findings were compared to histopathological findings of resected specimens. Interobserver agreement was calculated. The association between parenchymal abnormalities and presence of PanIN was assessed by uni- and multivariate analyses. RESULTS: PanIN was present in 65/100 patients (65%). The presence of microcysts on MRI had a sensitivity of 52.3% (34/65 [95%CI, 51.92-52.70%]), a specificity of 77.1% (27/35 [95%CI, 76.70-77.59]), and accuracy of 61% (61/100 95%CI [50.7-70.6]) for the diagnosis of PanIN while global atrophy had a sensitivity of 24.6% (16/6 [95%CI, 24.28-24.95]) and a specificity of 97.1% (34/35 [95%CI, 96.97-97.32%]). In multivariate analysis, the presence of microcysts (OR, 3.37 [95%CI, 1.3-8.76]) (p = 0.0127) and global atrophy (OR, 9.79 [95%CI, 1.21-79.129]) (p = 0.0324) were identified as independent predictors of the presence of PanIN. The combination of these two findings was observed in 10/65 PanIN patients and not in patients without PanIN (p = 0.013 with an OR of infinity [95%CI, 1.3-infinity]) and was not discriminant for PanIN-3 and lower grade (p = 0.22). Interobserver agreement for the presence of microcysts was excellent (kappa = 0.92), and for the presence of global atrophy, it was good (kappa = 0.73). CONCLUSION: The presence of non-communicating microcysts on pre-operative MRI can be a significant predictor of PanIN in patients with pancreatic tumors. KEY POINTS: • In patients with pancreatic tumors who had partial pancreatectomy, MR non-communicating pancreatic microcysts have a 52.3% sensitivity, a 77.1% specificity, and a 61% accuracy for the presence of PanIN with univariate and with an odds ratio of 3.37 with multivariate analyses. • The association of global atrophy and non-communicating microcysts increases the predictive risk of PanIN.

Older melanoma patients aged 75 and above retain responsiveness to anti-PD1 therapy: results of a retrospective single-institution cohort study.

INTRODUCTION: The utility of immunotherapy in elderly melanoma patients is debated. We aimed in this study to evaluate the efficacy and tolerability of immunotherapy among elderly patients. METHOD: This is a retrospective single-institution cohort study. Patients aged 75 years and above who had been treated with nivolumab, pembrolizumab or ipilimumab for advanced or metastatic melanoma, were included. Patients and disease characteristics were collected using electronic medical records. Objective response was determined according to the immune-related response criteria. Drug-related toxicities (DRT) were graded according to the CTCAE v4.03. RESULTS: 99 patients were included with a mean age of 80 years (SD = 4). One patient received nivolumab and ipilimumab combination, but died because of drug-related diverticulitis. Median PFS on pembrolizumab, nivolumab or ipilimumab were equal to 11.9 (95% CI 5.4-18.4), 1.4 (95% CI 0.01-2.8), and 2.8 months (95% CI 2.6-3), respectively, while objective response rates were equal to 51.6, 12.5, and 17.3%, respectively. Median OS was not reached in patients who received only pembrolizumab, 8.7 months in the ipilimumab only group, and 23 months in patients receiving several immune therapies sequentially. Pembrolizumab, nivolumab, and ipilimumab grade 3-4 DRT rates were equal to 24.2, 62.5, and 32.7% respectively, while discontinuation rates were equal to 43.5, 62.5, and 28.8%, respectively. CONCLUSIONS: Our study suggests that immunotherapy is effective and well tolerated in the elderly. The PFS on pembrolizumab was greater than expected, a finding that needs to be investigated further.

The role of palliative care in the last month of life in elderly cancer patients.

INTRODUCTION: One major health care issue encountered in elderly cancer patients is the alteration of the quality of life. The purpose of our study is to evaluate the administration of chemotherapy in the last month of life (CLML) and to evaluate the impact of the palliative care consult (PCC) in the elderly patients. METHODS: We conducted a retrospective observational study that included elderly patients diagnosed with an end-stage cancer and who were deceased between the 1st of January 2012 and the 31st of December 2015. Patient medical records were reviewed for patients' characteristics and management during the last month of life. RESULTS: This study enrolled 231 patients that fulfilled the eligibility criteria. CLML was administered in 91 patients (39.4 %) among which 43 patients (47.3 %) had their treatment within the last 2 weeks of life. Seventy-seven patients (33.3 %) had a palliative care consult (PCC) with a median duration of follow up of 13 days (range 2-56 days). Overall, PCC failed to decrease CLML administration, the duration of hospitalization, and ICU admissions. However, CLML administration decreased by 69 % among patients that had their PCC before receiving treatment (OR = 0.31; 95 % CI 0.15-0.63). PCC also led to a change in the pattern of treatment administered in the last month of life with less cytotoxic therapy (OR = 0.27 CI 95 % 0.09-0.9, p = 0.02) and higher rates of oral agents being prescribed (OR = 3.8; 95 % CI 1.3-11.3, p = 0.014). CONCLUSION: Our elderly patients seem to receive aggressive management similar to the general oncology population. Early PCC was shown throughout our results to decrease the aggressiveness of cancer treatment in elderly patients which seems to improve the quality of care of our patients.

SERUM INSULIN-LIKE GROWTH FACTOR 1 IN LEBANESE SCHOOLCHILDREN AND ITS RELATION TO VITAMIN D AND FERRITIN LEVELS.

OBJECTIVE: The aims of our study were to establish reference values for insulin-like growth factor 1 (IGF-1) in Lebanese schoolchildren and to evaluate the relationship between IGF-1 and age, sex, body mass index (BMI), vitamin D, and ferritin. METHODS: This cross-sectional study included 952 Lebanese schoolchildren (495 boys and 457 girls) aged 8 to 18 years. Blood samples were taken from children attending 10 schools with different socio-economic status (SES). Chemiluminescent immunoassays were used for IGF-1, 25 hydroxyvitamin D (25(OH)D), testosterone, and ferritin measurements. RESULTS: The mean age was 13.46 ± 2.80 with no significant difference according to sex. IGF-1 was correlated with age in both sexes (P<.0001); it was higher in girls compared to boys (P = .007) and peaked at the ages of 14 and 12 for boys and girls, respectively. For each age group, the median IGF-1 value was higher compared to the values provided by the kit. IGF-1 was significantly correlated with BMI in boys (r = 0.16, P<.0001) but not girls. In both sexes, IGF-1 was inversely correlated with 25(OH)D and ferritin values. After adjustment for age, BMI, and height, the correlation between IGF-1 and 25(OH)D disappeared, whereas the relationship with ferritin persisted (P<.001 for boys, P = .002 for girls). For both sexes, multivariate regression analysis revealed independent associations between IGF-1 and height, Tanner stage, and ferritin. An association was also noted in boys for BMI and testosterone. CONCLUSION: Our results showed higher and earlier peak IGF-1 values in the pediatric Lebanese population compared to western populations. In addition, an independent inverse relationship was observed between IGF-1 and ferritin. Further studies are needed to identify the reason(s) underlying these results. ABBREVIATIONS: BMI = body mass index CRP = C-reactive protein CV = coefficient of variation GH = growth hormone IGF-1 = insulin-like growth factor 1 25(OH)D = 25 hydroxyvitamin D SES = socio-economic status TSH = thyroid-stimulating hormone.

PULMONARY ARTERY ACCELERATED FLOW REVEALING HODGKIN'S LYMPHOMA.

We present a case in which transthoracic echocardiography was the first diagnostic tool to suspect mediastinal Hodgkin's lymphoma by revealing a change in the hemodynamic of left pulmonary artery flow, and it was used as a follow-up method for monitoring treatment efficacy by demonstrating a normalization of pulmonary artery hemodynamics.

Could contrast-enhanced CT detect STEMI prior to electrocardiogram?

We present here a case in which contrast-enhanced computed tomography (CT) was the first diagnostic tool to detect myocardial hypoperfusion in a patient with atypical symptoms and normal electrocardiogram (ECG) on admission. An ST-segment elevation was detected thereafter on a second ECG realized several minutes after CT with raised troponin levels. Percutaneous coronary intervention was performed after failure of thrombolysis and confirmed occlusion of the left anterior descending artery. Further studies are needed to evaluate the role of high-resolution contrast-enhanced CT with or without coronary angiography in the workup of suspected myocardial infarction in the setting of a normal ECG.

Reversibility of hyperhidrosis post axillary depilatory laser.

Hyperhidrosis and bromhidrosis were lately reported as novel side effects of laser-assisted removal of axillary hair. The goal of our study was to evaluate the reversibility of these two side effects. An observational, single-center cohort study included over a 30-month screening period 30 patients with newly reported hyperhidrosis and/or bromhidrosis related to axillary depilatory laser. After 26 weeks of follow-up, each patient was assessed for spontaneous reversibility. A 12-week duration treatment with topical aluminum chloride was evaluated in patients with persisting hyperhidrosis. Hyperhidrosis was assessed using the Hyperhidrosis Disease Severity Scale (HDSS). Spontaneous reversibility was observed in 20% of patients. In total, 23 out of 30 patients recovered normal axillary transpiration either spontaneously or after treatment. Mean HDSS score was significantly lower in the treated group. It appears that axillary hyperhidrosis and bromhidrosis, secondary to laser depilation, reverse either spontaneously or after using topical antiperspirant.

UGT1A1 Testing in Breast Cancer: should it become routine practice in patients treated with antibody-drug conjugates?

The use of genetic testing to personalize therapeutic strategies in cancer is rapidly evolving and thus changing the landscape of treatment of oncologic patients. The UGT1A1 gene is an important component for the metabolism and glucoronidation of certain drugs, including irinotecan and sacituzumab govitecan (SG); therefore, various UGT1A1 polymorphisms leading to decreased function of the UGT1A1 enzyme may lead to increased risk of treatment-related side effects. Testing for UGT1A1 polymorphism is not routinely adopted in clinical practice; that is due to the lack of concise studies and recommendations concerning the clinical relevance of this test and its impact on the quality of life of cancer patients. The knowledge regarding UGT1A1 polymorphism and its clinical relevance will be reviewed in this article, as well as the published literature on the association between UGT1A1 polymorphism and the toxicity risk of irinotecan as well as sacituzumab govitecan. The current recommendations and guidelines on UGT1A1 testing will be discussed in detail in the hopes of providing guidance to oncologists in their clinical practice.

Development of Novel Models of Aggressive Variants of Castration-resistant Prostate Cancer.

BACKGROUND: Genomic studies have identified new subsets of aggressive prostate cancer (PCa) with poor prognosis (eg, neuroendocrine prostate cancer [NEPC], PCa with DNA damage response [DDR] alterations, or PCa resistant to androgen receptor pathway inhibitors [ARPIs]). Development of novel therapies relies on the availability of relevant preclinical models. OBJECTIVE: To develop new preclinical models (patient-derived xenograft [PDX], PDX-derived organoid [PDXO], and patient-derived organoid [PDO]) representative of the most aggressive variants of PCa and to develop a new drug evaluation strategy. DESIGN, SETTING, AND PARTICIPANTS: NEPC (n = 5), DDR (n = 7), and microsatellite instability (MSI)-high (n = 1) PDXs were established from 51 patients with metastatic PCa; PDXOs (n = 16) and PDOs (n = 6) were developed to perform drug screening. Histopathology and treatment response were characterized. Molecular profiling was performed by whole-exome sequencing (WES; n = 13), RNA sequencing (RNA-seq; n = 13), and single-cell RNA-seq (n = 14). WES and RNA-seq data from patient tumors were compared with the models. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Relationships with outcome were analyzed using the multivariable chi-square test and the tumor growth inhibition test. RESULTS AND LIMITATIONS: Our PDXs captured both common and rare molecular phenotypes and their molecular drivers, including alterations of BRCA2, CDK12, MSI-high status, and NEPC. RNA-seq profiling demonstrated broad representation of PCa subtypes. Single-cell RNA-seq indicates that PDXs reproduce cellular and molecular intratumor heterogeneity. WES of matched patient tumors showed preservation of most genetic driver alterations. PDXOs and PDOs preserve drug sensitivity of the matched tissue and can be used to determine drug sensitivity. CONCLUSIONS: Our models reproduce the phenotypic and genomic features of both common and aggressive PCa variants and capture their molecular heterogeneity. Successfully developed aggressive-variant PCa preclinical models provide an important tool for predicting tumor response to anticancer therapy and studying resistance mechanisms. PATIENT SUMMARY: In this report, we looked at the outcomes of preclinical models from patients with metastatic prostate cancer enrolled in the MATCH-R trial (NCT02517892).

Overview of the role of liquid biopsy in cancer management.

With the emergence of novel targeted therapeutic options in early-stage and advanced-stage malignancies, researchers have shifted their focus on developing personalized treatment plans through molecular profiling. Circulating tumor DNA (ctDNA) is a cell-free DNA (ctDNA) fragment, originating from tumor cells, and circulating in the bloodstream as well as biological fluids. Over the past decade, many techniques were developed for liquid biopsies through next-generation sequencing. This alternative non-invasive biopsy offers several advantages in various types of tumors over traditional tissue biopsy. The process of liquid biopsy is considered minimally invasive and therefore easily repeatable when needed, providing a more dynamic analysis of the tumor cells. Moreover, it has an advantage in patients with tumors that are not candidates for tissue sampling. Besides, it offers a deeper understanding of tumor burden as well as treatment response, thereby enhancing the detection of minimal residual disease and therapeutic guidance for personalized medicine. Despite its many advantages, ctDNA and liquid biopsy do have some limitations. This paper discusses the basis of ctDNA and the current data available on the subject, as well as its clinical utility. We also reflect on the limitations of using ctDNA in addition to its future perspectives in clinical oncology and precision medicine.

Synergic prognostic value of 3D CT scan subcutaneous fat and muscle masses for immunotherapy-treated cancer.

BACKGROUND: Our aim was to explore the prognostic value of anthropometric parameters in a large population of patients treated with immunotherapy. METHODS: We retrospectively included 623 patients with advanced non-small cell lung cancer (NSCLC) (n=318) or melanoma (n=305) treated by an immune-checkpoint-inhibitor having a pretreatment (thorax-)abdomen-pelvis CT scan. An external validation cohort of 55 patients with NSCLC was used. Anthropometric parameters were measured three-dimensionally (3D) by a deep learning software (Anthropometer3DNet) allowing an automatic multislice measurement of lean body mass, fat body mass (FBM), muscle body mass (MBM), visceral fat mass (VFM) and sub-cutaneous fat mass (SFM). Body mass index (BMI) and weight loss (WL) were also retrieved. Receiver operator characteristic (ROC) curve analysis was performed and overall survival was calculated using Kaplan-Meier (KM) curve and Cox regression analysis. RESULTS: In the overall cohort, 1-year mortality rate was 0.496 (95% CI: 0.457 to 0.537) for 309 events and 5-year mortality rate was 0.196 (95% CI: 0.165 to 0.233) for 477 events. In the univariate Kaplan-Meier analysis, prognosis was worse (p<0.001) for patients with low SFM (<3.95 kg/m2), low FBM (<3.26 kg/m2), low VFM (<0.91 kg/m2), low MBM (<5.85 kg/m2) and low BMI (<24.97 kg/m2). The same parameters were significant in the Cox univariate analysis (p<0.001) and, in the multivariate stepwise Cox analysis, the significant parameters were MBM (p<0.0001), SFM (0.013) and WL (0.0003). In subanalyses according to the type of cancer, all body composition parameters were statistically significant for NSCLC in ROC, KM and Cox univariate analysis while, for melanoma, none of them, except MBM, was statistically significant. In multivariate Cox analysis, the significant parameters for NSCLC were MBM (HR=0.81, p=0.0002), SFM (HR=0.94, p=0.02) and WL (HR=1.06, p=0.004). For NSCLC, a KM analysis combining SFM and MBM was able to separate the population in three categories with the worse prognostic for the patients with both low SFM (<5.22 kg/m2) and MBM (<6.86 kg/m2) (p<0001). On the external validation cohort, combination of low SFM and low MBM was pejorative with 63% of mortality at 1 year versus 25% (p=0.0029). CONCLUSIONS: 3D measured low SFM and MBM are significant prognosis factors of NSCLC treated by immune checkpoint inhibitors and can be combined to improve the prognostic value.

Genomic Profiling of Metastatic Castration-Resistant Prostate Cancer Samples Resistant to Androgen Receptor Pathway Inhibitors.

PURPOSE: The androgen receptor axis inhibitors (ARPI; e.g., enzalutamide, abiraterone acetate) are administered in daily practice for men with metastatic castration-resistant prostate cancer (mCRPC). However, not all patients respond, and mechanisms of both primary and acquired resistance remain largely unknown. EXPERIMENTAL DESIGN: In the prospective trial MATCH-R (NCT02517892), 59 patients with mCRPC underwent whole-exome sequencing (WES) and/or RNA sequencing (RNA-seq) of samples collected before starting ARPI. Also, 18 patients with mCRPC underwent biopsy at time of resistance. The objectives were to identify genomic alterations associated with resistance to ARPIs as well as to describe clonal evolution. Associations of genomic and transcriptomic alterations with primary resistance were determined using Wilcoxon and Fisher exact tests. RESULTS: WES analysis indicated that no single-gene genomic alterations were strongly associated with primary resistance. RNA-seq analysis showed that androgen receptor (AR) gene alterations and expression levels were similar between responders and nonresponders. RNA-based pathway analysis found that patients with primary resistance had a higher Hedgehog pathway score, a lower AR pathway score and a lower NOTCH pathway score than patients with a response. Subclonal evolution and acquisition of new alterations in AR-related genes or neuroendocrine differentiation are associated with acquired resistance. ARPIs do not induce significant changes in the tumor transcriptome of most patients; however, programs associated with cell proliferation are enriched in resistant samples. CONCLUSIONS: Low AR activity, activation of stemness programs, and Hedgehog pathway were associated with primary ARPIs' resistance, whereas most acquired resistance was associated with subclonal evolution, AR-related events, and neuroendocrine differentiation. See related commentary by Slovin, p. 4323.

Perioperative risk factors associated with delayed graft function following deceased donor kidney transplantation: A retrospective, single center study.

BACKGROUND: There is an abundant need to increase the availability of deceased donor kidney transplantation (DDKT) to address the high incidence of kidney failure. Challenges exist in the utilization of higher risk donor organs into what appears to be increasingly complex recipients; thus the identification of modifiable risk factors associated with poor outcomes is paramount. AIM: To identify risk factors associated with delayed graft function (DGF). METHODS: Consecutive adults undergoing DDKT between January 2016 and July 2017 were identified with a study population of 294 patients. The primary outcome was the occurrence of DGF. RESULTS: The incidence of DGF was 27%. Under logistic regression, eight independent risk factors for DGF were identified including recipient body mass index ≥ 30 kg/m2, baseline mean arterial pressure < 110 mmHg, intraoperative phenylephrine administration, cold storage time ≥ 16 h, donation after cardiac death, donor history of coronary artery disease, donor terminal creatinine ≥ 1.9 mg/dL, and a hypothermic machine perfusion (HMP) pump resistance ≥ 0.23 mmHg/mL/min. CONCLUSION: We delineate the association between DGF and recipient characteristics of pre-induction mean arterial pressure below 110 mmHg, metabolic syndrome, donor-specific risk factors, HMP pump parameters, and intraoperative use of phenylephrine.

Role of microRNAs in the predisposition to gastrointestinal malignancies.

MicroRNAs (miRNAs) are highly deregulated in cancer and play a role in the initiation of tumorigenesis. Recently, miRNAs have attracted attention in gastrointestinal (GI) cancers. Single nucleotide polymorphisms (SNPs) could affect the genes involved in each step of miRNA biosynthesis. Several meta-analyses of case-control studies have assessed the association between miRNA "pathway" gene-SNPs (including biosynthesis regulators and binding sites) and susceptibility to GI cancers. We present in this mini-review the current knowledge on the association between miRNAs "pathway" genes and GI cancer predisposition. The interaction between miRNA/regulators/binding site-SNPs and environmental as well as genomic factors is an interesting field that should be exploited in future studies.