Navigating the landscape of liver cancer management: Study designs in clinical trials and clinical practice.

Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer death worldwide and its prognosis is highly heterogeneous, being related not only to tumour burden but also to the severity of underlying chronic liver disease. Moreover, advances in systemic therapies for HCC have increased the complexity of patient management. Randomised-controlled trials represent the gold standard for evidence generation across all areas of medicine and especially in the oncology field, as they allow for unbiased estimates of treatment effect without confounders. Observational studies have many problems that could reduce their internal and external validity. However, large prospective (well-conducted) observational real-world studies can detect rare adverse events or monitor the occurrence of long-term adverse events. How best to harness real world data, which refers to data generated from the routine care of patients, and real-world 'evidence', which is the evidence generated from real-world data, represents an open challenge. In this review article, we aim to provide an overview of the benefits and limitations of different study designs, particularly focusing on randomised-controlled trials and observational studies, to address important and not fully resolved questions in HCC research.

Single versus multiple reoperations for recurrent intracranial meningiomas.

PURPOSE: To identify the risk factors and management of the multiple recurrences and reoperations for intracranial meningiomas. METHODS: Data of a neurosurgical series of 35 patients reoperated on for recurrent intracranial meningiomas were reviewed. Analyzed factors include patient age and sex, tumor location, extent of resection, WHO grade, Ki67-MIB1 and PR expression at initial diagnosis, time to recurrence; pattern of regrowth, extent of resection, WHO grade and Ki67-MIB1 at first recurrence were also analyzed. All these factors were stratified into two groups based on single (Group A) and multiple reoperations (Group B). RESULTS: Twenty-four patients (69%) belonged to group A and 11 (31%) to group B. The age < 65 years, male sex, incomplete resection at both initial surgery and first reoperation, and multicentric-diffuse pattern of regrowth at first recurrence are risk factors for multiple recurrences and reoperations. In group B, the WHO grade and Ki67-MIB1 increased in further recurrences in 54% and 64%, respectively. The time to recurrence was short in 7 cases (64%), whereas 4 patients (36%) further recurred after many years. Eight patients (73%) are still alive after 7 to 22 years and 2 to 4 reoperations. CONCLUSION: The extent of resection and the multicentric-diffuse pattern of regrowth at first recurrence are the main risk factors for multiple recurrences and reoperations. Repeated reoperations might be considered even in patients with extensive recurrent tumors before the anaplastic transformation occurs. In such cases, even partial tumor resections followed by radiation therapy may allow long survival in good clinical conditions.

Different prognostic values of KRAS exon 2 submutations and BRAF V600E mutation in microsatellite stable (MSS) and unstable (MSI) stage III colon cancer: an ACCENT/IDEA pooled analysis of seven trials.

BACKGROUND: The prognostic value of KRAS and BRAFV600E mutations in stage III colon cancer (CC) remains controversial and has never been clearly analyzed in patients with microsatellite instability-high (MSI-H) tumors due to sample size limitations. Data are also lacking for KRAS submutations and prognosis. PATIENTS AND METHODS: We examined clinicopathological variables and prognosis in patients with surgically resected stage III CC who participated in seven clinical trials from the ACCENT/IDEA databases. Associations between KRAS exon 2 and BRAFV600E mutations and time to recurrence (TTR), overall survival (OS), and survival after recurrence (SAR) were assessed using a Cox model. We also analyzed the prognostic value of KRAS exon 2 submutations. RESULTS: Among 8460 patients, 11.4% had MSI-H status. In the MSI-H group, BRAFV600E, KRAS exon 2 mutants, and double-wild-type statuses were detected in 40.6%, 18.1%, and 41.3%, respectively, whereas and in the microsatellite stable (MSS) group, these were detected in 7.7%, 38.6%, and 53.8%, respectively. In the MSS group, 5-year TTR rates of 61.8%, 66.3%, and 72.9% were observed among patients with BRAFV600E, KRAS exon 2 mutants, and those who were DWT, respectively [adjusted hazard ratio (HR) = 1.58 and 1.31, both P < 0.001]. In the MSI-H group, 5-year TTR rates did not differ significantly among the mutated subgroups. Similar results were found for OS. However, survival after relapse was significantly shorter in the KRAS exon 2- and BRAFV600E-mutated patients in both MSS (adjusted HR = 2.06 and 1.15; both P < 0.05) and MSI-H (adjusted HR = 1.99 and 1.81; both P < 0.05) groups. In the MSS group, KRAS exon 2 mutations were associated with TTR, but only p.G12C, p.G12D, and p.G13D were associated with poor outcomes after disease recurrence. CONCLUSIONS: Testing for both KRAS and BRAFV600E mutations in stage III patients should be considered as they can better define individual patient prognosis, and may also enable patient selection for (neo)adjuvant trials dedicated to specific molecular subtypes with poor prognosis.

Biological Difference between L858R and Exon 19 Deletion Contributes to Recurrence-Free Survival of Resected Non-Small Cell Lung Cancer.

INTRODUCTION: The differences in biological characteristics among different genotypes of classical EGFR mutations have not been clarified. This study aimed to clarify the clinical and biological differences between L858R and 19 deletion in NSCLC. METHODS: We analyzed a cohort of 191 consecutive cases of surgically resected NSCLC harboring EGFR driver mutations (L858R or 19 deletion) in which curative resection was performed in Aichi Cancer Center Hospital, Nagoya, Japan, from January 2006 to September 2021 and in which recurrence subsequently developed. We also subjected 61 surgically resected NSCLC specimens harboring EGFR driver mutations (L858R or 19 deletion) to an RNA sequencing analysis. RESULTS: In patients with stage I disease, the median time to recurrence did not differ to a statistically significant extent between the types of EGFR mutations; however, among those with stage II and III disease, the median time to recurrence in patients with the L858R genotype tended to be shorter in comparison to those with 19 deletion (log-rank test, p = 0.47 and 0.46, respectively). In comparison to 19 deletion tumors, L858R tumors had higher cytological malignancy (e.g., mitotic ability) and showed stronger immunogenicity. CONCLUSION: L858R and 19 deletion tumors are likely to have a slight difference in the time to recurrence. They suggest that even in EGFR driver tumors, which are treated as the same disease category, the biological characteristics of the tumors are different, which may leave room for innovations in postoperative treatment and treatment at recurrence.

An exploration of immunohistochemistry-based prognostic markers in patients undergoing curative resections for colon cancer.

BACKGROUND: The immune system recognizes and destroys cancer cells. However, cancer cells develop mechanisms to avoid detection by expressing cell surface proteins. Specific tumour cell surface proteins (e.g. HLA-G, PD-L1, CDX2) either alone or in combination with the relative presence of immune cells (CD3 and CD8 positive T-cells) in the tumour tissue may describe the cancer cells' ability to escape eradication by the immune system. The aim was to investigate the prognostic value of immunohistochemical markers in patients with colon cancer. METHODS: We conducted a retrospective study including patients diagnosed with pT3 and pT4 colon cancers. Immunohistochemical staining with HLA-G, PD-L1, CDX2, CD3, and CD8 was performed on tissue samples with representation of the invasive margin. PD-L1 expression in tumour cells and immune cells was reported conjointly. The expression of CD3 and CD8 was reported as a merged score based on the expression of both markers in the invasive margin and the tumour centre. Subsequently, a combined marker score was established based on all of the markers. Each marker added one point to the score when unfavourable immunohistochemical features was present, and the score was categorized as low, intermediate or high depending on the number of unfavourable stains. Hazard ratios for recurrence, disease-free survival and mortality were calculated. RESULTS: We included 188 patients undergoing colon cancer resections in 2011-2012. The median follow-up was 41.7 months, during which 41 (21.8%) patients had recurrence and 74 (39.4%) died. In multivariable regression analysis positive HLA-G expression (HR = 3.37, 95%CI [1.64-6.93]) was associated with higher recurrence rates, while a preserved CDX2 expression (HR = 0.23, 95%CI [0.06-0.85]) was associated with a lower risk of recurrence. An intermediate or high combined marker score was associated with increased recurrence rates (HR = 20.53, 95%CI [2.68-157.32] and HR = 7.56, 95%CI [1.06-54.16], respectively). Neither high expression of PD-L1 nor high CD3-CD8 score was significantly associated with recurrence rates. Patients with a high CD3-CD8 score had a significantly longer DFS and OS. CONCLUSIONS: In tumour cells, expression of HLA-G and loss of CDX2 expression were associated with cancer recurrence. In addition, a combination of certain tumour tissue biomarkers was associated with colorectal cancer recurrence.

The survival after recurrence of colorectal cancer: a retrospective study focused on time to recurrence after curative resection.

PURPOSE: The significance of the duration of the recurrence-free survival after curative resection for colorectal cancer remains unclear. The purpose was to reveal the association between time to recurrence after surgery and the survival after recurrence. METHODS: Patients with stage II and III colorectal cancer who underwent curative resection between 2007 and 2015 were retrospectively reviewed (n = 645). Patients with recurrence after surgery (n = 133) were divided into 2 groups: early recurrence (within 13 months after surgery, n = 63) and late recurrence (more than 13 months after surgery, n = 70). The overall survival after recurrence and clinicopathological features were compared between early recurrence, late recurrence, and without recurrence groups. RESULTS: The overall survival after recurrence was significantly shorter in patients with early recurrence occurring at less than 13 months (hazard ratio: 1.70, p = 0.03). A high preoperative CA19-9 level (odds ratio [OR]: 2.38, p = 0.03), venous invasion (OR: 2.26, p = 0.03), and the absence of adjuvant chemotherapy (OR: 2.08, p = 0.04) were independently correlated with early recurrence. CONCLUSION: Early recurrence was associated with a poor prognosis after recurrence. Venous invasion correlated with early recurrence. Adjuvant chemotherapy may reduce the risk of early recurrence. These results indicate the importance of prudent surveillance and the aggressive application of adjuvant chemotherapy.

High recurrence rate in patients with juvenile-onset respiratory papillomatosis and its risk factors.

PURPOSE: To identify the recurrence rate and risk factors for recurrence in patients with juvenile-onset recurrent respiratory papillomatosis (JORRP). METHODS: A retrospective review was performed for all JORRP patients who underwent surgery between 2002 and 2019 at our institution. The demographic characteristics and clinical parameters were recorded. Kaplan-Meier estimates and Cox proportional hazards models were used to analyze the rate of recurrence and its risk factors. RESULTS: Our study included 721 patients. The cumulative recurrence rates at 1, 5, and 10 postoperative years following initial surgery were 74.2%, 90.0%, and 94.3%, respectively. Age at diagnosis younger than 4.5 years (HR = 2.380, 95% CI [1.169-4.846], P = 0.017), high Derkay anatomical score (HR = 1.136, 95% CI [1.043-1.236], P = 0.003) and HPV type 11 infection (HR = 2.947, 95% CI [1.326-6.551], P = 0.008) were independent risk factors for recurrence. Adjuvant therapy with interferon was less likely to recur (HR = 0.237, 95% CI [0.091-0.616], P = 0.003). Additionally, gender, tracheotomy, mode of delivery, parity, expression of Ki-67, HPV vaccination, and surgical treatment method were not independently associated with recurrence (P > 0.05). CONCLUSION: Age at diagnosis younger than 4.5 years, high Derkay anatomical score and HPV type 11 infection were associated with an increased risk for recurrence in patients with JORRP. Adjuvant therapy with interferon may reduce the risk of recurrence.

Real-world treatment patterns and effectiveness outcomes in patients with early-stage triple-negative breast cancer.

Background: This retrospective, observational study examined real-world treatment patterns and effectiveness outcomes in 450 patients with stage II-IIIB early-stage triple-negative breast cancer treated in the community oncology setting. Methods: Kaplan-Meier methods were used to evaluate event-free survival (EFS), time to recurrence and overall survival (OS). Cox regression models were used to evaluate predictors of EFS and OS by pathological complete response (pCR) status. Results: Among patients receiving neoadjuvant systemic therapy only, pCR was a predictor of EFS and OS. Conclusion: These results highlight the unmet need for therapies that improve outcomes for patients with early-stage triple-negative breast cancer including increasing rates of pCR among patients receiving neoadjuvant therapy.

Lay abstract This study included 450 patients with early-stage triple-negative breast cancer treated in the USA at community oncology practices. Patients were female, 18 years or older, diagnosed with stage II, IIIA or IIIB breast cancer between March 2008 and March 2016, and the breast cancer was determined to be triple negative (i.e., negative for estrogen receptors, progesterone receptors and excess HER2 protein). The study looked at the treatments received, whether those treatments worked and the response to treatment at the time of surgery. The study findings align with findings from other studies that complete response in tissue samples is associated with improved clinical outcomes. Triple-negative breast cancer remains challenging to treat, and there is a clear need for innovation in treatment options. Intervening in the early stages of triple-negative breast cancer is critical to improving outcomes.

Early time to recurrence predicts worse survival in patients with localized or regionally advanced cutaneous melanoma.

To investigate the prognostic significance of time to recurrence (TTR) for overall survival (OS) and survival after recurrence (SAR) in patients with localized or regionally advanced cutaneous melanoma. A total of 731 cutaneous melanoma patients with an initial diagnosis of 8th American Joint Committee on Cancer (AJCC) clinical stage I-III were included in this study. The prognostic factors associated with OS and SAR were estimated through Kaplan-Meier and Cox regression analysis. Of the total cohort, 329 patients (45%) died, and 418 patients (57%) experienced recurrence. The median follow-up and TTR were 55.6 months and 9.6 months, respectively. A total of 141 patients (19%) experienced recurrence in <6 months, and 277 patients (38%) experienced recurrence in ≥6 months. Patients with stage III and positive lymph node dissection (LND) were more common in the early TTR group than in the late TTR group. Both the OS and SAR rates at 5 years and 10 years in the early TTR group were significantly poorer than those in the late TTR group (P < .001 and P = .008, respectively). Furthermore, early TTR, along with truncal tumor, higher TNM stage and therapeutic variables (extended resection, LND and adjuvant therapy), were significant independent predictors of worse OS and SAR in multivariate analysis (all P < .05). Early TTR predicts worse survival and could be considered an independent prognostic factor for patients with localized or regionally advanced cutaneous melanoma. TTR should be evaluated in all patients with recurrence to guide post-recurrence risk stratification and follow-up schedules.

Oncologic Outcomes of Salvage Chemotherapy in Patients with Recurrent or Metastatic Lesions after Radical Nephroureterectomy: A Multi-Institutional Retrospective Study.

BACKGROUND: Radical nephroureterectomy (RNU) is the standard treatment for patients with upper tract urothelial carcinoma (UTUC). However, approximately 25% of patients experience recurrence or metastasis after RNU. This study evaluated the clinical outcome and efficacy of salvage chemotherapy (SC) after recurrence or metastasis. PATIENTS AND METHODS: Of the 441 nonmetastatic UTUC patients who underwent RNU, 147 patients with recurrent or metastatic lesions were analyzed; patients with bladder cancer recurrence were excluded. Time from disease recurrence or metastasis to cancer-specific survival (CSS) was estimated by the Kaplan-Meier method. Multivariate analyses were performed with the Cox proportional hazards regression model, controlling for the effects of clinicopathological factors. RESULTS: The median time from RNU to disease recurrence or metastasis was 13.2 months. In the recurrent or metastatic sites, 31 cases (21%) were liver. In multivariate analyses, pT stage (≥pT3), time to recurrence (<12 months), and liver metastasis were independently predictive factors. In the risk stratification model for CSS after recurrence, patients were categorized into 2 groups based on pT stage, time to recurrence, and liver metastasis. The low-risk group (0-1 risk factors) included 87 patients, and the high-risk group (2-3 risk factors) included 60 patients. In the high-risk group, 27 patients received SC. The probability of CSS after recurrence or metastasis was higher in patients in the SC group compared to the non-SC group (9.5 vs. 3.7 months; p < 0.001). CONCLUSION: Two or more risk factors defined the high-risk group for patients with recurrence or metastasis after RNU. SC was associated with improved survival in patients with high-risk UTUC.

The Norwegian dietary guidelines and colorectal cancer survival (CRC-NORDIET) study: a food-based multicentre randomized controlled trial.

BACKGROUND: Colorectal cancer survivors are not only at risk for recurrent disease but also at increased risk of comorbidities such as other cancers, cardiovascular disease, diabetes, hypertension and functional decline. In this trial, we aim at investigating whether a diet in accordance with the Norwegian food-based dietary guidelines and focusing at dampening inflammation and oxidative stress will improve long-term disease outcomes and survival in colorectal cancer patients. METHODS/DESIGN: This paper presents the study protocol of the Norwegian Dietary Guidelines and Colorectal Cancer Survival study. Men and women aged 50-80 years diagnosed with primary invasive colorectal cancer (Stage I-III) are invited to this randomized controlled, parallel two-arm trial 2-9 months after curative surgery. The intervention group (n = 250) receives an intensive dietary intervention lasting for 12 months and a subsequent maintenance intervention for 14 years. The control group (n = 250) receives no dietary intervention other than standard clinical care. Both groups are offered equal general advice of physical activity. Patients are followed-up at 6 months and 1, 3, 5, 7, 10 and 15 years after baseline. The study center is located at the Department of Nutrition, University of Oslo, and patients are recruited from two hospitals within the South-Eastern Norway Regional Health Authority. Primary outcomes are disease-free survival and overall survival. Secondary outcomes are time to recurrence, cardiovascular disease-free survival, compliance to the dietary recommendations and the effects of the intervention on new comorbidities, intermediate biomarkers, nutrition status, physical activity, physical function and quality of life. DISCUSSION: The current study is designed to gain a better understanding of the role of a healthy diet aimed at dampening inflammation and oxidative stress on long-term disease outcomes and survival in colorectal cancer patients. Since previous research on the role of diet for colorectal cancer survivors is limited, the study may be of great importance for this cancer population. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01570010 .

The GOLMePsA study protocol: an investigator-initiated, double-blind, parallel-group, randomised, controlled trial of GOLimumab and methotrexate versus methotrexate in early diagnosed psoriatic arthritis using clinical and whole body MRI outcomes.

BACKGROUND: Psoriatic arthritis (PsA) is a chronic inflammatory arthritis which impacts significantly on the quality of life and work capacity of affected individuals. Recent evidence has shown that early control of inflammation in PsA leads to improved long-term outcomes. It is postulated that prompt intervention after diagnosis using a remission-induction treatment strategy will lead to improved outcomes and optimal disease control of PsA. The aim of the present study was to compare the clinical efficacy of a treatment strategy in newly diagnosed, treatment naïve PsA subjects, using the combination of golimumab (GOL), methotrexate (MTX) and steroids versus standard care (MTX monotherapy plus steroids). METHODS/DESIGN: GOLMePsA is an investigator initiated, phase IIIb, single-centre, randomised, double-blind, placebo-controlled, two-armed, parallel-group, imaging-supplemented study. Eighty-eight PsA patients, diagnosed within 24 months prior to screening and treatment naïve, will be randomised at baseline to receive: (arm 1) the combination of intramuscular/intra-articular prednisolone, MTX and GOL or (arm 2) the combination of intramuscular/intra-articular prednisolone, MTX and placebo for 24 weeks (interventional period). Primary outcome measure is clinical improvement (at least 1 unit difference) in the Psoriatic ArthritiS Disease Activity Score (PASDAS) composite index. Reflecting a "step down" therapeutic approach, all participants successfully completing the interventional period will be followed up for a further 28 weeks. During this observational period, stable maintenance MTX monotherapy will continue for both arms, unless in case of intolerance or PsA relapse. In the latter case, additional treatment will be provided. Overall, the GOLMePsA study length is planned to be 52 weeks. DISCUSSION: The hypothesis underlining this study is that very early treatment with first-line GOL reduces disease activity in PsA, in comparison to conventional therapy. TRIAL REGISTRATION: EudraCT 2013-004122-28 . 24/09/2013.

Drug discovery using clinical outcome-based Connectivity Mapping: application to ovarian cancer.

BACKGROUND: Epithelial ovarian cancer (EOC) is the fifth leading cause of cancer death among women in the United States (5 % of cancer deaths). The standard treatment for patients with advanced EOC is initial debulking surgery followed by carboplatin-paclitaxel combination chemotherapy. Unfortunately, with chemotherapy most patients relapse and die resulting in a five-year overall survival around 45 %. Thus, finding novel therapeutics for treating EOC is essential. Connectivity Mapping (CMAP) has been used widely in cancer drug discovery and generally has relied on cancer cell line gene expression and drug phenotype data. Therefore, we took a CMAP approach based on tumor information and clinical endpoints from high grade serous EOC patients. METHODS: We determined tumor gene expression signatures (e.g., sets of genes) associated with time to recurrence (with and without adjustment for additional clinical covariates) among patients within TCGA (n = 407) and, separately, from the Mayo Clinic (n = 326). Each gene signature was inputted into CMAP software (Broad Institute) to determine a set of drugs for which our signature "matches" the "reference" signature, and drugs that overlapped between the CMAP analyses and the two studies were carried forward for validation studies involving drug screens on a set of 10 EOC cell lines. RESULTS: Of the 11 drugs carried forward, five (mitoxantrone, podophyllotoxin, wortmannin, doxorubicin, and 17-AAG) were known a priori to be cytotoxics and were indeed shown to effect EOC cell viability. CONCLUSIONS: Future research is needed to investigate the use of these CMAP and similar analyses for determining combination therapies that might work synergistically to kill cancer cells and to apply this in silico bioinformatics approach using clinical outcomes to other cancer drug screening studies.

Low expression of B-cell-associated protein 31 in human primary hepatocellular carcinoma correlates with poor prognosis.

AIMS: The aim of the present study was to investigate the prognostic value of B-cell associated protein 31 (BAP31) in human primary hepatocellular carcinoma (HCC). METHODS AND RESULTS: BAP31 levels were evaluated by immunohistochemistry on tissue microarrays. The integral optical density, representing the expression level of BAP31 in each tissue sample, was calculated with image-pro plus. Immunohistochemical analysis of BAP31 levels in 74 paired HCC tissues and peritumoral non-cancerous tissues showed that BAP31 expression was significantly higher in HCC tumour tissues (P = 0.025). The prognostic value of BAP31 in HCC was evaluated in 234 cases in a training cohort and in 63 cases in a validation cohort. The expression level of BAP31 was significantly correlated with overall survival (OS) in both the training cohort and the validation cohort. The lower the level of BAP31 expression in HCC tissue, the poorer the prognosis. Univariate and multivariate analyses showed that the expression level of BAP31 in HCC was an independent prognostic factor for OS in both the training cohort and the validation cohort. CONCLUSIONS: BAP31 expression is an independent prognostic factor for OS of patients with postoperative HCC, and low expression levels of BAP31 in HCC may indicate poor outcomes of HCC patient after surgical resection.

Risk factors for seizure recurrence in children after first unprovoked seizure.

BACKGROUND: The question of whether to treat a patient after a first unprovoked seizure is controversial. This prospective study assessed the time to recurrence and risk factors for seizure recurrence after a first unprovoked seizure in children. METHODS: Participants were recruited between 1 July 1997, and 30 June 2009. Eligible candidates were children between 1 month and 15 years old who presented with their first unprovoked afebrile seizure. After enrollment, recurrence of seizures was investigated. All participants were followed for at least 2 years. Log-rank test was used for bivariate analysis to check associations, and hazard ratios were used to analyze variables and clinical outcome (recurrence) during follow-up. RESULTS: Of 73 subjects, 42 (57.5%) experienced recurrence. The overall product-limit estimate of recurrence was 61.9% at 6 months, 85.7% at 1 year, and 95.2% at 2 years after seizure onset, respectively. Incidence of recurrence with partial and generalized seizures was 69.0% and 31.0%, respectively. Children with partial seizures had recurrence significantly more often than those with generalized seizures (P < 0.001). Recurrent seizures occurred after normal findings on electroencephalogram (EEG) in 21.4%, after generalized spike-and-wave complexes in 16.7%, and after focal epileptic discharge in 61.9%. Children with focal epileptic discharge had recurrence significantly more often than children with normal EEG findings (P < 0.001). CONCLUSION: The time to seizure recurrence after first unprovoked seizure may be within 1 year, and particularly within 6 months; and partial seizure and abnormal EEG with focal epileptic discharge may be risk factors for seizure recurrence.

MUC15 inhibits dimerization of EGFR and PI3K-AKT signaling and is associated with aggressive hepatocellular carcinomas in patients.

BACKGROUND & AIMS: Aberrant expression of MUC15 correlates with development of colorectal adenocarcinoma, and MUC15 has been reported to prevent trophoblast invasion of human placenta. However, little is known about the role of MUC15 in pathogenesis of hepatocellular carcinoma (HCC). METHODS: We analyzed HCC samples and matched nontumor liver tissues (controls) collected from 313 patients who underwent hepatectomy in Shanghai, China, from January 2006 through September 2009. Levels of messenger RNAs and proteins were determined by immunohistochemical, quantitative reverse transcription polymerase chain reaction, and immunoblot analyses. Statistical analyses were used to associate levels of MUC15 with tumor features and patient outcomes. RESULTS: Levels of MUC15 messenger RNA and protein were reduced in a greater percentage of HCC samples than control tissues. Tumors with reduced levels of MUC15 were more likely to have aggressive characteristics (eg, high levels of α-fetoprotein, vascular invasion, lack of encapsulation, and poor differentiation) than those with low levels. Patients whose tumors had reduced levels of MUC15 had shorter overall survival times (24 months vs 46 months for patients with tumors with high levels of MUC15) and time to disease recurrence. Stable expression of MUC15 in HCC cell lines (SMMC-7721 and HCC-LM3) reduced their proliferation and invasive features in vitro, and ability to form metastatic tumors in mice. MUC15 reduced transcription of the matrix metalloproteinases 2 and 7 increased expression of tissue inhibitor of metalloproteinase-2, which required phosphoinositide 3-kinase-v-akt murine thymoma viral oncogene homolog signaling. Physical interaction between MUC15 and epidermal growth factor receptor led to its relocation and degradation within early endosomes and was required for inactivation of phosphoinositide 3-kinase-v-akt murine thymoma viral oncogene homolog signaling. CONCLUSIONS: Reduced levels of MUC15 in HCCs are associated with shorter survival times of patients and reduced time to disease recurrence. Expression of MUC15 in HCC cells reduces their aggressive behavior in vitro and in mice by inducing dimerization of epidermal growth factor receptor and decreasing phosphoinositide 3-kinase signaling via v-akt murine thymoma viral oncogene homolog.

Recurrence in intracranial atherosclerotic disease: a stenosis-based analysis.

BACKGROUND: Intracranial atherosclerotic disease is a common cause of stroke; its incidence and prevalence vary widely by ethnicity. The aim of our study was to analyze the recurrence rate of cerebrovascular events in patients with symptomatic and asymptomatic intracranial stenosis (IS). METHODS: We conducted a historical cohort study including all patients admitted in our hospital for stroke or transient ischemic attack (TIA) during 2011 and 2012 with information on intracranial circulation (ultrasonography and/or computed tomography angiography). We identified patients with symptomatic and asymptomatic IS and studied the recurrence of cerebrovascular events (TIA or ischemic stroke within the territory of the stenosis) for a minimum follow-up period of 6 months after the diagnosis of IS. For the recurrence rate estimation, patients with other potentially embolic diseases (in cervical arteries or heart) were excluded. We calculated the rate of recurrence of cerebrovascular events and performed Kaplan-Meier survival curves for symptomatic and asymptomatic IS. RESULTS: We investigated 1302 patients, mean age was 72.41 years (standard deviation 12.75). We identified 218 IS in 158 patients, 77 were symptomatic and 141 were asymptomatic. The recurrence rate of cerebrovascular events was 12.32 per 100 patient-years, with a mean time to recurrence of 1.73 months for symptomatic intracranial stenosis (SIS) and .88 per 100 patient-years for asymptomatic IS (P < .001). CONCLUSIONS: These results indicate a high risk of early recurrence of stroke in the territory of a SIS, highlighting the importance of its early diagnosis and aggressive treatment.

Effectiveness of Adjuvant Chemotherapy in Variant Histology Upper Tract Urothelial Carcinoma Following Radical Nephroureterectomy: Stabilized Inverse Probability Treatment Weighting Analysis of Single Center Experience.

PURPOSE: The study aimed to investigate the impact of adjuvant chemotherapy on time to recurrence (TTR) and overall survival (OS) in patients with histologic variants of upper tract urothelial carcinoma (VUTUC) following radical nephroureterectomy (RNU). MATERIALS AND METHODS: A retrospective review of 131 VUTUC patients' medical records, from a pool of 368 non-metastatic localized or locally advanced UTUC cases, treated at a single tertiary referral center between January 2011 and January 2021. The intervention was adjuvant chemotherapy administration post-RNU. TTR and OS were evaluated using Kaplan-Meier and Cox proportional hazard regression, covariates adjusted for age, postoperative GFR, history of neoadjuvant chemotherapy, T and N stage with stabilized inverse probability of treatment weighting (sIPTW). RESULTS: The application of adjuvant chemotherapy showed a significant extension in TTR (P = .01), but no substantial impact on OS (P = .19) after sIPTW adjustment for covariates. Multivariate analysis revealed adjuvant chemotherapy, tumor size, and lymphovascular invasion as significant prognostic factors for TTR. In contrast, only tumor size and perineural invasion were significant for OS. Adjuvant chemotherapy reduced the progression risk in certain VUTUC subtypes (squamous or glandular/micropapillary), but not in sarcomatoid variants. CONCLUSIONS: Adjuvant chemotherapy appears to improve TTR, albeit without a significant effect on OS, in nonmetastatic localized and locally advanced VUTUC patients post-RNU. While beneficial to some VUTUC subtypes, it did not yield significant advantages for sarcomatoid variants. Despite adjustments for known confounders, the study's findings may be subject to potential selection bias and unmeasured confounding factors.

Prognostic Value of Tumor Deposits in Patients with Colorectal Cancer.

Tumor nodules or tumor deposits (TDs) are a histopathological prognostic factor that are associated with a negative evolutionary course in patients with colorectal cancer (CRC). There are still controversial aspects of TDs, including how they should be integrated into the TNM classification system. The objective of this study was to analyze the predictive value of TDs for cancer-related survival (CRS) and time-to-recurrence survival (TTR) and to evaluate the prognostic value of TDs in patients whose tumors also presented lymph node metastasis (LNM). In this retrospective observational study, all patients treated for CRC between January 2010 and December 2020 at the same hospital were included. CRS and TTR were classified by tumor stage. The results were compared between patients whose tumors had TDs and patients whose tumors did not. A total of 1426 patients met the criteria for inclusion in the analysis. TDs were detected in 178 patients (12.5%): 60 had tumors without LNM, and 118 had LNM. Patients with TD tumors had a lower CRS at 60 months after diagnosis (42% vs. 82%; p < 0.001) and a shorter TTR (34% vs. 79%; p < 0.001). Cox multiple regression analysis revealed that the presence of TD was associated with an increased risk of death from CRC (HR: 1.820; 95% CI: 1.327-2.496) and an increased risk of recurrence (HR: 2.315; 95% CI: 1.743-3.073). In each N stage category, the CRS was significantly lower in the subgroup with TD+: in patients with N1a tumors, the CRS was 44% when TD+ vs. 70% when TD- (p = 0.019); in the N1b group it was 36% vs. 66% (p < 0.001); in the N2a group it was 34% vs. 58% (p = 0.012); and in N2b tumors it was 23% vs. 53% (p = 0.031). The present study shows that the information on the presence of TDs is complementary to that provided by LNM and allows the identification of subgroups of patients in each N stage determined by two metrics, CRS and TTR. TDs should be included in the definition of TNM system categories in patients who simultaneously present with LNM.

High-Grade Glioma Recurrence Is Delayed in Hispanic Patients despite Severe Social Vulnerability: A Retrospective Cohort Study.

High-grade gliomas (HGGs; WHO grade III or IV) are the most common and lethal brain malignancy. Patients of Hispanic ethnicity are diagnosed with HGGs earlier than non-Hispanic patients, but they exhibit improved HGG survival following diagnosis. Either environmental or biological factors could explain this survival benefit. We aimed to determine if post-diagnosis advantages would still be present in Hispanic patients with high social vulnerability, an environmental condition predisposing patients to poor oncologic outcomes. HGG outcomes were retrospectively assessed in a cohort of 22 Hispanic patients and 33 non-Hispanic patients treated for HGGs from 2015 to 2020 at a single institution that serves a highly vulnerable region. Compared to non-Hispanic patients, Hispanic patients demonstrated higher social vulnerability index scores (96.8 + 0.7 vs. 76.3 + 4.6; *** p = 0.0002) and a 14-month longer interval between diagnosis and recurrence (19.7 + 5.9 (n = 13) vs. 5.5 + 0.6 months (n = 19); ** p = 0.001). In only those patients with more aggressive IDH-1 wildtype tumors (glioblastoma), Hispanic ethnicity still related to a longer time before recurrence (15.8 + 5.9 months (n = 9); 5.5 + 0.6 months (n = 18); * p = 0.034), and in a multivariate analysis, Hispanic ethnicity predicted time-to-recurrence (* p = 0.027) independent of patient age, functional status, MGMT gene methylation, or treatments received. Therefore, environmental factors, specifically social vulnerability, did not obscure the post-diagnosis benefits associated with Hispanic ethnicity. In future experiments, basic studies should be prioritized which investigate the cellular or genetic mechanisms underlying this ethnicity effect on HGG progression in the hopes of improving care for these devastating malignancies.