Larger Tumor Volume Research Articles

Long-Term Outcomes of Stereotactic Radiosurgery for Pineocytomas: An International Multicenter Study.

Pineocytomas are grade 1 tumors arising from the pineal parenchyma. Gross total resection can potentially cure these benign lesions but can be associated with morbidity. This study was designed to provide multi-institutional data to evaluate the results of stereotactic radiosurgery (SRS) for pineocytomas. Centers participating in the International Radiosurgery Research Foundation were asked to review their database and provide data for patients who had SRS for histology confirmed grade 1 pineocytomas, for whom clinical and imaging follow-up of at least 6 months was available. In total, 38 patients underwent SRS as part of the management of a pineocytoma. The median age at SRS was 39 years (range 8-76). SRS was performed as primary approach in 68%, adjuvant after partial resection 19%, and at recurrence in 13% of patients. The median margin dose was 15 Gy (range 11-25 Gy). The median treatment volume was 3.35 cc (range 0.1-17.9 cc). Local tumor control was achieved in 92% of patients, with a mean actuarial progression-free survival of 21.6 years (median not reached). At last follow-up, 82% were still controlled, 8% had local recurrence, and 10% had cerebrospinal fluid dissemination. Tumor control was significantly better when SRS was used as primary care compared with the adjuvant or recurrent setting (P = .016). Five patients (13%) died during follow-up, all from tumor progression. The actuarial mean survival duration was 24.3 years, with a 5-year survival rate of 91%, and an estimated rate of 76% at 29 years. Larger tumor volume at SRS was found to be correlated to increased risk of death (P = .045). Transient symptomatic adverse radiation effects were observed in 4 patients (11%). SRS appears safe and effective for the management of pineocytomas. Long-term tumor control is achieved in most cases. SRS can be offered to selected patients as an alternative to surgical resection.

Analysis of Benign Retroperitoneal Schwannomas: A Single-center Experience.

Retroperitoneal schwannomas are rare. The purpose of this study was to present our experience with the diagnosis and treatment of 67 such tumors. We retrospectively analyzed 67 patients with retroperitoneal schwannoma admitted to the Peking University International Hospital from 2015 to 2021. Thirty-seven of the 67 patients had no obvious clinical symptoms. Complete excision was obtained in 62 and subtotal excision in 5 cases. In7 cases, tumor resection was combined with organ resection. The intraoperative blood loss was 300 ml (20-9,000 ml), the maximum size of the tumor was 9 cm (2.5-26 cm), and postoperative complication occurred in six cases (9.0%). Compared with abdominal retroperitoneal tumors, pelvic retroperitoneal tumors had larger tumor volume, more bleeding, higher proportion of block resection, and longer postoperative hospitalization time (p < 0.05). The residual mass progressed slowly in five patients with subtotal resection, and no obvious malignant transformation occurred. Complete resection of a retroperitoneal schwannoma can achieve a good long-term prognosis. Residual tumor after surgery progresses slowly and rarely become malignant. We recommend early resection after the discovery of a pelvic retroperitoneal schwannoma.

Growth velocity of fetal sacrococcygeal teratoma as predictor of perinatal morbidity and mortality: multicenter study.

To identify prenatal predictors of poor perinatal outcome in fetuses with isolated sacrococcygeal teratoma (SCT). This was a retrospective study of fetuses with isolated (non-syndromic) SCT managed at one of five pediatric surgery and/or fetal medicine centers between January 2007 and December 2017. The primary outcome was the occurrence of poor perinatal outcome, defined as prenatal death (including termination), or neonatal death or severe compromise (hemorrhagic shock). Data regarding prenatal diagnosis (sonographic features both at referral and at the last ultrasound examination before pregnancy outcome, assessment of SCT growth velocity), perinatal complications and outcome, and neonatal course were analyzed to determine prenatal SCT characteristics associated with adverse perinatal outcome. Fifty-five fetuses were included, diagnosed with isolated SCT at a median gestational age of 22 (interquartile range, 18-23) weeks. There was a poor perinatal outcome in 31% (n = 17) of these cases, including intrauterine fetal demise (4%, n = 2), pregnancy termination (13%, n = 7) and neonatal severe compromise (15%, n = 8), leading to neonatal death in five cases. The overall survival rate after prenatal diagnosis of isolated SCT was 75% (n = 41 of 55). Earlier gestational age at diagnosis (P = 0.02), large tumor volume at referral (P < 0.001), presence of one or more hemodynamic complications (P = 0.02), fast tumor growth velocity (P < 0.001) and high tumor grade (highest tumor grade ≥ 3) (P = 0.049) were associated with poor perinatal outcome on univariate analysis. On stepwise logistic regression analysis, tumor growth velocity was the only remaining independent factor associated with poor perinatal outcome (odds ratio (OR) (per 1-mm/week increase), 1.48 (95%CI, 1.22-1.97), P = 0.001). The best predictive cut-off of tumor growth velocity for poor perinatal outcome was 7 mm/week (OR, 25.7 (95%CI, 5.6-191.3), P < 0.001), yielding a sensitivity of 88% and a specificity of 77%. Approximately 30% of fetuses with a diagnosis of isolated SCT have poor perinatal outcome. Tumor growth velocity ≥ 7 mm/week appears to be an appropriate discriminative cut-off for poor perinatal outcome. These results could help to inform prenatal management and counseling of parents with an affected pregnancy. © 2024 The Author(s). Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Development and application of explainable artificial intelligence using machine learning classification for long-term facial nerve function after vestibular schwannoma surgery.

Vestibular schwannomas (VSs) represent the most common cerebellopontine angle tumors, posing a challenge in preserving facial nerve (FN) function during surgery. We employed the Extreme Gradient Boosting machine learning classifier to predict long-term FN outcomes (classified as House-Brackmann grades 1-2 for good outcomes and 3-6 for bad outcomes) after VS surgery. In a retrospective analysis of 256 patients, comprehensive pre-, intra-, and post-operative factors were examined. We applied the machine learning (ML) classifier Extreme Gradient Boosting (XGBoost) for the following binary classification: long-term good and bad FN outcome after VS surgery To enhance the interpretability of our model, we utilized an explainable artificial intelligence approach. Short-term FN function (tau = 0.6) correlated with long-term FN function. The model exhibited an average accuracy of 0.83, a ROC AUC score of 0.91, and Matthew's correlation coefficient score of 0.62. The most influential feature, identified through SHapley Additive exPlanations (SHAP), was short-term FN function. Conversely, large tumor volume and absence of preoperative auditory brainstem responses were associated with unfavorable outcomes. We introduce an effective ML model for classifying long-term FN outcomes following VS surgery. Short-term FN function was identified as the key predictor of long-term function. This model's excellent ability to differentiate bad and good outcomes makes it useful for evaluating patients and providing recommendations regarding FN dysfunction management.

Scoring System Assessing Risks of Growth in Sporadic Vestibular Schwannoma.

Surveillance studies offer sparse knowledge of predictors of future growth in sporadic vestibular schwannomas (VS).Our aim was identification of these risk factors. We propose a scoring system to estimate the risk of growth in sporadic vestibular schwannoma. This retrospective study is based on the demographic and radiological data of 615 adult patients under the surveillance for single VS in our center. Univariate analysis, multivariate regression, and Kaplan-Meier analysis were used when appropriate. The regression coefficient-based "VS score" was calculated based on Cox proportional-hazards regression. During surveillance, 285 tumors (46%) remained stable, 314 tumors (51%) grew, and 16 tumors (3%) shrank. The significant risks factors for future growth identified both in univariate and multivariate analyses were younger age at onset, cystic morphology, larger tumor volume, and cisternal location (as per Hannover grade). The proportion of growing tumors was 40%, 75%, and 96% among the homogeneous VS, primary cystic, and VS transformed to cystic, respectively. Moreover, tumor growth during the 1st year was significant predictor of continuous growth. Our "VS score" includes variables such as age, sex, morphology, and Hannover grade. The score extends between -3 and 6 points. Kaplan-Meier, confusion matrix, and receiver operating characteristic analysis proved high accuracy of our scoring model. Our retrospective study revealed that younger age, cystic morphology, cisternal extent, larger volume, and growth during 1st year were strong predictors of future growth. Moreover, we propose a scoring system that accurately estimates the risks of future tumor growth.

Cribriform intraductal carcinoma of the prostate may be more aggressive than cribriform conventional/acinar prostatic adenocarcinoma

It remains to be determined if the prognostic value of cribriform morphology (Crib) associated with intraductal carcinoma of the prostate (IDC) is equivalent to that in conventional/acinar prostatic adenocarcinoma (CPA). We herein assessed radical prostatectomy findings and long-term oncologic outcomes in 732 men with Grade Group 2-4 CPA without any Gleason pattern 5. Our cases were divided into 4 cohorts according to the absence or presence of Crib within CPA and/or IDC: Cohort-1) no Crib (n=347; 47.4%); Cohort-2) Crib only in CPA (n=203; 27.7%); Cohort-3) Crib only in IDC (n=17; 2.3%); and Cohort-4) Crib in both CPA and IDC (n=165; 22.5%). Compared with that in CPA only (Cohort-2), Crib in both CPA and IDC (Cohort-4) was significantly associated with adverse histopathological features, including higher tumor grade/stage and larger tumor volume. Univariate analysis revealed significantly higher risks of postoperative recurrence in patients with Crib in IDC only [Cohort-3; hazard ratio (HR) 2.450, P=0.022] or both CPA and IDC (Cohort-4; HR=2.835, P<0.001) than in those with Crib in CPA only (Cohort-2), while the prognosis was analogous between Cohort-3 vs. Cohort-4 (P=0.913). In multivariable analysis [Crib in CPA only (Cohort-2) as a reference], Crib in IDC only (Cohort-3; HR=3.821, P=0.002) or both CPA and IDC (Cohort-4; HR=1.905, P=0.004) showed significantly worse recurrence-free survival. Compared with Crib in CPA only, its presence in both CPA and IDC was thus found to be independently associated with a poorer prognosis, suggesting a potentially greater clinical impact of Crib in IDC than in CPA.

Determinants of long-term survival in patients with IDH-mutant gliomas.

Survival times of patients with IDH-mutant gliomas are variable and can extend to decades. Many studies provide progression-free rather than overall survival times and prognostic factors remain ill-defined. Here we explored characteristics of short- and long-term survivors within a cohort of patients with extended follow-up. This single-center, case-control study included 86 patients diagnosed between 1998 and 2023 who either died within 6 years after diagnosis or survived at least 15 years. Patient characteristics and prognostic factors were stratified by short- (< 6 years) versus long-term (≥ 15 years) survival. Forty-seven patients (55%) diagnosed with astrocytoma and 39 patients (45%) with oligodendroglioma were included retrospectively. Median follow-up of the survivors was 16.6 years (range 15-28.9). Thirty-four deaths (40%) had been reported at database closure. Long-term survival was associated with CNS WHO grade 2 (p < 0.01), smaller tumor volumes (p = 0.01), lack of contrast enhancement (p < 0.01), wait-and-scan strategies (p < 0.01) and female sex (p = 0.04). In multivariate analyses for oligodendroglioma, larger T2 tumor volumes were associated with shorter survival (HR 1.02; 95% CI 1.01-1.05; p = 0.04). In patients with astrocytoma, lack of contrast enhancement (HR 0.38; 95% CI 0.15-0.94; p = 0.04) and wait-and-scan strategies (HR 5.75; 95% CI 1.66-26.61; p = 0.01) were associated with longer survival. Large T2 tumor volume and contrast enhancement may be important risk factors for shorter survival, while age might be of lesser importance. Wait-and-scan strategies may yield excellent long-term survival in some patients with astrocytoma.

Relationship between TIGIT expression on T cells and the prognosis of patients with hepatocellular carcinoma

BackgroundTranscatheter arterial chemoembolization (TACE) combined with targeted therapy and immunotherapy can significantly improve the prognosis of patients with hepatocellular carcinoma (HCC). T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) is a novel immunosuppressive molecule. This study aimed to analyze the clinical correlation between TIGIT expression on T cells and patients with HCC.MethodsClinical data from 140 patients with HCC were retrospectively collected, and TIGIT expression on T cells was examined in each patient. Patients were subsequently divided into high- and low-expression groups, and their prognosis was analyzed.ResultsPatients with a high TIGIT expression on their T cells at baseline had a larger tumor volume, later staging, higher proportion of regulatory T cells, higher blood concentrations of interleukin (IL)-6 and IL-10, and lower interferon-γ concentrations. Following TACE, CD155 concentration decreased; however, TACE did not affect TIGIT expression on T cells. Additionally, among patients receiving TACE combined with apatinib and camrelizumab treatment, patients with a high TIGIT expression on T cells had significantly shorter progression-free survival (PFS) and overall survival times than those of patients in the low-expression group. Patients receiving TACE combined with apatinib and camrelizumab treatment with higher TIGIT expression have shorter PFS time than those receiving TACE combined with apatinib treatment.ConclusionsPatients with HCC that have a high TIGIT expression on their T cells exhibited poorer baseline characteristics, immunosuppressive status, and prognosis after receiving TACE combined with apatinib and camrelizumab and maybe more suited to receive TACE combined with apatinib treatment instead.

Radiographic and neurological outcomes of Gamma Knife radiosurgery for lower cranial nerve schwannomas: a single-institution experience.

Gamma Knife radiosurgery (GKRS) is widely used for treating small- to medium-sized or postoperative residual, recurrent lower cranial nerve schwannomas (LCNSs). This study aimed to evaluate the radiographic and neurological outcomes of GKRS for LCNS. A total of 60 patients with 47 jugular foramen schwannomas (JFSs) and 13 hypoglossal nerve schwannomas (HNSs) who underwent GKRS were included. Dysphagia (40.4%) and hoarseness (23.4%) were the most common preexisting symptoms associated with JFS, whereas tongue deviation (53.8%) was prevalent in HNS. The median tumor volumes were 3.2 cm3 and 2.2 cm3 for JFSs and HNSs, respectively. The median marginal dose administered to the tumor was 13 Gy (range 12-15 Gy). The median follow-up duration was 52.8 months. Local tumor control was achieved in 91.5% of JFSs and 92.3% of HNSs. The preexisting neurological symptoms improved in 48.9% of patients with JFS and remained stable in 29.8%. However, 10 patients (21.3%) experienced exacerbation of symptoms associated with cranial nerves VII, VIII, IX, X, and XI. Among these, 3 patients (6.4%) exhibited persistent symptomatic deterioration. Patients with HNSs demonstrated a stable trajectory without symptom aggravation. Larger tumor volume and cystic portion were significantly associated with tumor progression (p = 0.017 and 0.003, respectively), and post-GKRS transient swelling was associated with neurological deterioration (p = 0.044). GKRS is an alternative treatment option for LCNS that reduces surgical morbidity and enhances tumor control. However, GKRS can potentially lead to neurological deterioration, necessitating extreme caution throughout the procedure, specifically for JFSs.

Germline AIP variants in sporadic young acromegaly and pituitary gigantism: clinical and genetic insights from a Han Chinese cohort.

Variants in the Aryl hydrocarbon receptor-interacting protein (AIP) gene have been identified in sporadic acromegaly and pituitary gigantism, especially in young patients, with a predisposition to aggressive clinical phenotype and poor treatment efficacy. The clinical characteristics of patients with sporadic acromegaly and pituitary gigantism as well as AIP variants in Han Chinese have been rarely reported. We aimed to identify AIP gene variants and analyze the clinical characteristics of patients with sporadic acromegaly and pituitary gigantism in Han Chinese. The study included 181 sporadic acromegaly (N = 163) and pituitary gigantism (N = 18) patients with an onset age of no more than 45 years old, who were diagnosed, treated, and followed up in Huashan Hospital. All 6 exons and their flanking regions of the AIP gene were analyzed with Sanger sequencing or NGS. The clinical characteristics were compared between groups with and without AIP variants. Germline AIP variants were found in 15/181 (8.29%) cases. In patients with an onset age ≤30 years old, AIP variants were identified in 12/133 (9.02%). Overall, 13 variants were detected. The pathogenic (P) variants p.R304X and p.R81X were identified in four cases, with two instances of each variant. Six exon variants (p.C254R, p.K103fs, p.Q228fs, p.Y38X, p.Q213*, and p.1115 fs) have not been reported before, which were likely pathogenic (LP). Patients with P/LP variants had younger onset ages, a higher prevalence of pituitary gigantism, larger tumor volumes, and a higher percentage of Ki-67-positive cells in tumors. In addition, the group with P/LP variants showed a less significant reduction of GH levels in an acute octreotide suppression test (OST) [17.7% (0, 65.0%) vs. 80.5% (63.9%, 90.2%), P = 0.001], and a trend of less GH decrease after the 3-month treatment with long-acting somatostatin analogs (SSAs). Germline AIP variants existed in sporadic Chinese Han acromegaly and pituitary gigantism patients and were more likely to be detected in young patients. AIP variants were associated with more aggressive tumor phenotypes and less response to SSA treatment.

Self-reporting photodynamic nanobody conjugate for precise and sustainable large-volume tumor treatment

Nanobodies (Nbs), the smallest antigen-binding fragments with high stability and affinity derived from the variable domain of naturally occurring heavy-chain-only antibodies in camelids, have been shown as an efficient way to improve the specificity to tumors for photodynamic therapy (PDT). Nonetheless, the rapid clearance of Nbs in vivo restricts the accumulation and retention of the photosensitizer at the tumor site causing insufficient therapeutic outcome, especially in large-volume tumors. Herein, we develop photodynamic conjugates, MNB-Pyra Nbs, through site-specific conjugation between 7D12 Nbs and type I photosensitizer MNB-Pyra (morpholine-modified nile blue structure connected to pyrazolinone) in a 1:2 ratio. The photosensitizers with long-term retention can be released at the tumor site by reactive oxygen species cleavage after illumination, accompanied with fluorescence recovery for self-reporting the occurrence of PDT. Ultimately, a single dose of MNB-Pyra Nbs demonstrate highly effective tumor suppression with high biosafety in the large-volume tumor models after three rounds of PDT. This nanobody conjugate provides a paradigm for the design of precise long-time retention photosensitizers and is expected to promote the development of PDT.

Predictors of Hydrocephalus Risk After Stereotactic Radiosurgery for Vestibular Schwannomas: Utility of the Evans Index.

Hydrocephalus after Gamma Knife® stereotactic radiosurgery (SRS) for vestibular schwannomas is a rare but manageable occurrence. Most series report post-SRS communicating hydrocephalus in about 1% of patients, thought to be related to a release of proteinaceous substances into the cerebrospinal fluid. While larger tumor size and older patient age have been associated with post-SRS hydrocephalus, the influence of baseline ventricular anatomy on hydrocephalus risk remains poorly defined. A single-institution retrospective cohort study examining patients who developed symptomatic communicating hydrocephalus after undergoing Gamma Knife® SRS for unilateral vestibular schwannomas from 2011 to 2021 was performed. Patients with prior hydrocephalus and cerebrospinal fluid diversion or prior surgical resection were excluded. Baseline tumor volume, third ventricle width, and Evans Index (EI)-maximum width of the frontal horns of the lateral ventricles/maximum internal diameter of the skull-were measured on axial postcontrast T1-weighted magnetic resonance imaging. A total of 378 patients met the inclusion criteria; 14 patients (3.7%) developed symptomatic communicating hydrocephalus and 10 patients (2.6%) underwent shunt placement and 4 patients (1.1%) were observed with milder symptoms. The median age of patients who developed hydrocephalus was 69 years (IQR, 67-72) and for patients younger than age 65 years, the risk was 1%. For tumor volumes <1 cm3, the risk of requiring shunting was 1.2%. The odds of developing symptomatic hydrocephalus were 5.0 and 7.7 times higher in association with a baseline EI > 0.28 (P = .024) and tumor volume >3 cm3 (P = .007), respectively, in multivariate analysis. Fourth ventricle distortion on pre-SRS imaging was significantly associated with hydrocephalus incidence (P < .001). Patients with vestibular schwannoma with higher baseline EI, larger tumor volumes, and fourth ventricle deformation are at increased odds of developing post-SRS hydrocephalus. These patients should be counseled regarding risk of hydrocephalus and carefully monitored after SRS.

Hypopituitarism after gamma knife radiosurgery for pituitary adenomas: long-term results from a single-center experience

ObjectiveThe aim of this study was to investigate the incidence and risk factors of new-onset hypopituitarism after gamma knife radiosurgery (GKRS) for pituitary adenomas in a single center.MethodsIn this retrospective study, 241 pituitary adenoma patients who underwent GKRS from 1993 to 2016 were enrolled. These patients had complete endocrine, imaging, and clinical data before and after GKRS. The median follow-up time was 56.0 (range, 12.7–297.6) months.ResultsFifty patients (20.7%) developed new-onset hypopituitarism after GKRS, including hypogonadism (n = 22), hypothyroidism (n = 29), hypocortisolism (n = 20), and growth hormone deficiency (n = 4). The median time to new-onset hypopituitarism was 44.1 (range, 13.5–141.4) months. The rates of new-onset hypopituitarism were 7%, 16%, 20%, 39%, and 45% at 1, 3, 5, 10, and 15 years, respectively. For those patients treated with a single GKRS, sex (p = 0.012), suprasellar extension (p = 0.048), tumor volume (≥ 5 cm3) (p < 0.001), tumor progression (p = 0.001), pre-existing hypopituitarism (p = 0.011), and previous surgery (p = 0.009) were significantly associated with new-onset hypopituitarism in univariate analysis. In the multivariate analysis, tumor volume (≥ 5 cm3) and tumor progression were associated with new-onset hypopituitarism (hazard ratio [HR] = 3.401, 95% confidence interval [CI] = 1.708–6.773, p < 0.001 and HR = 3.594, 95% CI = 1.032–12.516, p = 0.045, respectively). For patients who received 2 or more times GKRS, no risk factors associated with new-onset hypopituitarism were found.ConclusionNew-onset hypopituitarism was not uncommon after GKRS for pituitary adenomas. In this study, large tumor volume (≥ 5 cm3) and tumor progression were associated with new-onset hypopituitarism after a single GKRS.

Identifying prognostic predictors for postoperative pituitary neuroendocrine tumour recurrence: an integrated clinical, radiological, and immunohistochemistry assessment

Objective Pituitary neuroendocrine tumours (PitNETs) are the second most common type of intracranial tumour. Several studies have explored the prognostic factors for PitNETs. However, prognostic factors for postoperative PitNET recurrence remain not fully understood. This study aimed to explore potential prognostic factors for PitNET recurrence, such as surrounding tissue invasion and the extent of surgical resection in patients with postoperative PitNETs. Methods We included 106 patients who underwent PitNET surgery between 2013 and 2018, dividing them into two groups: those with recurrence and those without recurrence. Tumours were classified based on demographics, neuroradiological, and immunohistological characteristics. Univariate and multivariate analyses were used to determine factors predicting recurrence. Kaplan–Meier plots and log-rank tests were used to analyse each independent factor based on the cumulative 5-year recurrence rate. Results During the 5-year follow-up period, 29.2% of the patients (n = 31) had disease recurrence. Univariate analysis showed that predictors of recurrence included cavernous and sphenoid sinus invasions, optic chiasm compression, larger tumour volume, giant adenoma >4 cm, and gross total resection (GTR). Multivariate analysis showed that lactotroph tumour type, sphenoid sinus invasion, and GTR were independent predictors. Kaplan–Meier analysis revealed significant differences in the 5-year recurrence rate among the three independent predictors, with significantly lower recurrence rate in patients with lactotroph tumours and GTR, and a significantly higher recurrence risk in patients with sphenoid sinus invasion. Conclusions Lactotroph tumour type, sphenoid sinus invasion, and GTR are independent predictors of postoperative PitNET recurrence. This study provides insights into the factors affecting postoperative PitNET recurrence.

Implications of unconventional histological subtypes on magnetic resonance imaging and oncological outcomes in patients who have undergone radical prostatectomy

The prognostic significance of unconventional histology (UH) subtypes including intraductal carcinoma of the prostate (IDC-P), ductal adenocarcinoma, and cribriform pattern has been investigated for prostate cancer (PCa). However, little is known about magnetic resonance imaging (MRI) features and the oncological impact of tumor localization in localized PCa with UH. Clinical data of 211 patients with acinar adenocarcinoma (conventional histology [CH]) and 82 patients with UH who underwent robotic-assisted radical prostatectomy (RARP) were reviewed. Patients with UH are more likely to be older and have higher Gleason grade group, higher Prostate Imaging-Reporting and Data System (PI-RADS) v2.1 score, and larger tumor volume (TV) than those with CH. Multivariate analysis identified the presence of UH as an independent prognostic factor for progression-free survival (PFS) (hazard ration (HR) 2.41, 95% confidence interval (CI) 0.22–0.79, P = 0.0073). No significant difference in PFS was seen regarding tumor localization (transition zone [TZ] or peripheral zone [PZ]) in patients with UH (P = 0.8949), whereas PZ cancer showed shorter PFS in patients with CH (P = 0.0174). PCa with UH was associated with higher progression than PCa with CH among resection margin (RM)-negative cases (P < 0.0001). Further, increased PI-RADS v2.1 score did not correlate with larger TV in UH (P = 0.991), whereas a significant difference in TV was observed in CH (P < 0.0001). The prognostic significance of UH tumor was independent of tumor localization, and shorter PFS was observed even in RM-negative cases, indicating an aggressive subtype with micro-metastatic potential. Furthermore, UH tumors are more likely to harbor a large TV despite PI-RADS v2.1 score ≤ 3. These findings will help optimal perioperative management for PCa with UH.

Clusters of resilience and vulnerability: executive functioning, coping and mental distress in patients with diffuse low-grade glioma

PurposeDiffuse low-grade gliomas (dLGG) often have a frontal location, which may negatively affect patients’ executive functions (EF). Being diagnosed with dLGG and having to undergo intensive treatment can be emotionally stressful. The ability to cope with this stress in an adaptive, active and flexible way may be hampered by impaired EF. Consequently, patients may suffer from increased mental distress. The aim of the present study was to explore profiles of EF, coping and mental distress and identify characteristics of each profile.Methods151 patients with dLGG were included. Latent profile analysis (LPA) was used to explore profiles. Additional demographical, tumor and radiological characteristics were included.ResultsFour clusters were found: 1) overall good functioning (25% of patients); 2) poor executive functioning, good psychosocial functioning (32%); 3) good executive functioning, poor psychosocial functioning (18%) and; 4) overall poor functioning (25%). Characteristics of the different clusters were lower educational level and more (micro)vascular brain damage (cluster 2), a younger age (cluster 3), and a larger tumor volume (cluster 4). EF was not a distinctive factor for coping, nor was it for mental distress. Maladaptive coping, however, did distinguish clusters with higher mental distress (cluster 3 and 4) from clusters with lower levels of mental distress (cluster 1 and 2).ConclusionFour distinctive clusters with different levels of functioning and characteristics were identified. EF impairments did not hinder the use of active coping strategies. Moreover, maladaptive coping, but not EF impairment, was related to increased mental distress in patients with dLGG.

Harnessing adrenergic blockade in stress-promoted TNBC in vitro and solid tumor in vivo: disrupting HIF-1α and GSK-3β/β-catenin driven resistance to doxorubicin.

Sympathetic activation triggered by chronic stress afflicting cancer survivors is an emerging modulator of tumorigenesis. Adrenergic blockade was previously associated with improving response to doxorubicin (DOX) in triple-negative breast cancer (TNBC), yet the precise underlying mechanisms remain obscure. The resilience of cancer stem cells (CSCs) during chemotherapy fosters resistance and relapse. Hypoxia-inducible factor-1α (HIF-1α) and β-catenin are intertwined transcriptional factors that enrich CSCs and evidence suggests that their expression could be modulated by systemic adrenergic signals. Herein, we aimed to explore the impact of adrenoreceptor blockade using carvedilol (CAR) on DOX and its potential to modulate CSCs overcoming chemoresistance. To achieve this aim, in vitro studies were conducted using adrenaline-preincubated MDA-MB-231 cells and in vivo studies using a chronic restraint stress-promoted solid tumor mouse model. Results revealed that adrenaline increased TNBC proliferation and induced a phenotypic switch reminiscent of CSCs, as evidenced by enhanced mammosphere formation. These results paralleled an increase in aldehyde dehydrogenase-1 (ALDH-1) and Nanog expression levels as well as HIF-1α and β-catenin upsurge. In vivo, larger tumor volumes were observed in mice under chronic stress compared to their unstressed counterparts. Adrenergic blockade using CAR, however, enhanced the impact DOX had on halting TNBC cell proliferation and tumor growth via enhanced apoptosis. CAR also curbed HIF-1α and β-catenin tumor levels subsequently suppressing ALDH-1 and SOX2. Our study unveils a central role for HIF-1α linking stress-induced sympathetic activation fueling CSC enrichment via the β-catenin pathway. It also highlights novel insights into CAR's capacity in reversing DOX chemoresistance in TNBC.

High glucose inhibits autophagy and promotes the proliferation and metastasis of colorectal cancer through the PI3K/AKT/mTOR pathway.

Colorectal cancer (CRC) ranks among the most prevalent malignancies worldwide, characterized by its complex etiology and slow research progress. Diabetes, as an independent risk factor for CRC, has been widely certified. Consequently, this study centers on elucidating the intricacies of CRC cells initiation and progression within a high-glucose environment. A battery of assays was employed to assess the proliferation and metastasis of CRC cells cultured under varying glucose concentrations. Optimal glucose levels conducive to cells' proliferation and migration were identified. Western blot analyses were conducted to evaluate alterations in apoptosis, autophagy, and EMT-related proteins in CRC cells under high-glucose conditions. The expression of PI3K/AKT/mTOR pathway-associated proteins was assessed using western blot. The effect of high glucose on xenograft growth was investigated invivo by MC38 cells, and changes in inflammatory factors (IL-4, IL-13, TNF-α, IL-5, and IL-12) were measured via serum ELISA. Our experiments demonstrated that elevated glucose concentrations promoted both the proliferation and migration of CRC cells; the most favorable glucose dose is 20 mM. Western blot analyses revealed a decrease in apoptotic proteins, such as Bim, Bax, and caspase-3 with increasing glucose levels. Concurrently, the expression of EMT-related proteins, including N-cadherin, vimentin, ZEB1, and MMP9, increased. High-glucose cultured cells exhibited elevated levels of PI3K/AKT/mTOR pathway proteins. In the xenograft model, tumor cells stimulated by high glucose exhibited accelerated growth, larger tumor volumes, and heightened KI67 expression of immunohistochemistry. ELISA experiments revealed higher expression of IL-4 and IL-13 and lower expression of TNF-α and IL-5 in the serum of high-glucose-stimulated mice. The most favorable dose and time for tumor cells proliferation and migration is 20 mM, 48 h. High glucose fosters CRC cell proliferation and migration while suppressing autophagy through the activation of the PI3K/AKT/mTOR pathway.

Personalized cell-free tumor DNA analysis for patients with HNSCC: Liquid biopsy for minimal residual disease detection in head and neck squamous cell carcinoma (LIONESS).

3010 Background: Early relapse and development of metastatic disease are some of the primary reasons for the poor prognosis of patients with head and neck squamous cell carcinoma (HNSCC). We conducted LIONESS, a single-center prospective cohort study to assess ctDNA in plasma and saliva from 76 patients with HNSCC receiving primary surgery with curative intent. Our objectives were to determine whether postoperative ctDNA detection can act as a biomarker for surgical tumor clearance and detection of molecular residual disease (MRD) and to evaluate the potential of tumor-informed ctDNA analysis for early molecular-level detection of relapse or prior to clinically confirmed recurrence. Methods: Plasma and saliva samples from 76 HNSCC patients (37% stage I/II, 63% stage III/IV; 93% p16-negative) were collected pre- and postoperatively and during clinical follow-up. Whole exome sequencing was performed on FFPE tumor tissue. Tumor-specific variants for personalized assay design (RaDaR, NeoGenomics Laboratories) were selected and used in the analysis of serial samples for evidence of MRD. ctDNA levels were correlated to tumor volumes from staging CT, as well as pathological and other clinical parameters. Results: 617 longitudinal plasma and 128 saliva samples were collected pre- and postoperatively and during clinical follow-up (median follow-up time of 805 days). In plasma, ctDNA was detected at a median estimated variant allele frequency (eVAF) of 0.036% (0.000327% - 18.43%). 34% of positive samples had ctDNA levels detected at an eVAF of ≤0.01%. Increased plasma ctDNA levels were detected postoperatively in 96% of cases with confirmed clinical recurrences (21/22) with a median lead time of 160 days (6 – 763 days). Of the remaining 54 patients with no clinically confirmed relapse, ctDNA was detected immediately postop in 7 of them. In 5 patients, adjuvant therapy resulted in persistent ctDNA clearance, while 2 patients are deceased. ctDNA was also detected in baseline saliva samples from patients with HNSCC of various anatomical locations with a 74% overlap with the corresponding plasma ctDNA profiles. There was a strong linear correlation between larger tumor volumes and higher eVAF and a trend towards higher eVAF in cases with regional and distant recurrences in comparison to local relapse. Pathological tumor stage and lymph node involvement were both strongly correlated with preoperative ctDNA shedding. Conclusions: The use of ctDNA detection in surgically treated patients with HNSCC has significant potential to guide treatment decisions, improve disease outcome and potentially spare patients unnecessary, partially invasive interventions during clinical follow-up. Our work demonstrates the feasibility of tumor-informed ctDNA assays for detection of MRD postoperatively and for monitoring for early detection of relapse.

A first-in-human phase 1 trial of T cell membrane-anchored tumor targeted IL12 (ATTIL12) -T cell therapy in advanced/metastatic soft tissue and bone sarcoma.

TPS11586 Background: Interleukin-12 (IL12) is a cytokine that induces antitumor immune response and immune memory by activation of NK cells, induction of IFNg, and maturation of DC cells in the tumor microenvironment (TME). However, prior clinical experience with IL12 has been limited by toxicities including cytokine release syndrome (CRS) and hepatotoxicity. We developed a novel tumor-targeted IL12 gene (ttIL12) that encodes the p35 and p40 VNTANST fusion subunits that targets cell surface vimentin (CSV). Vimentin is expressed intracellularly in many normal and neoplastic mesenchymal cells but our group discovered that intracellular vimentin is often flipped to the cell surface (referred to as CSV) across multiple tumor types.2 Preclinical studies demonstrated efficacy and induction of long-term memory of ttIL12 against metastatic osteosarcoma with reduced toxicity in immune competent models.3 However, ttIL12 had limited efficacy in treating large volume tumors and did not completely eliminate toxic peripheral cytokines. To address this, our team generated a membrane anchored ttIL12 to arm T cells known as attIL12-T cell therapy. We hypothesize attIL12 will minimize toxic cytokines in peripheral tissues but promote induction of INFg/TNFa in the TME to decrease the toxicity and boost efficacy. Methods: This is a phase 1 trial of attIL12-T cells in patients (pts) with locally advanced or metastatic soft tissue or bone sarcomas to assess safety, maximal tolerated dose (MTD) and recommended phase 2 dose (RP2D). Pts in part A (dose finding) will be enrolled using a Bayesian optimal interval (BOIN) design in up to 6 dose levels. Part B (dose expansion) will evaluate preliminary efficacy in 10 additional pts with osteosarcoma treated at the RP2D. Treatment:Pts will undergo leukapheresis to collect peripheral blood mononuclear cells (PBMCs) for generation of attIl12-T cells. Bridging therapy is permitted but not required. Pts will receive cyclophosphamide (Cy) IV prior to planned T cell administration. attIL12 T cells will be administered at the specified dose level IV in a single infusion (dose level 1 and 2) or 2 serial doses (dose level 3-6) on day 0 and day 14. Pts will be monitored for toxicity and response evaluation. Pts will also undergo pre-treatment/on-treatment tumor biopsies for translational and correlative analysis. Eligibility:Pts must be ≥ 12 years of age, have a confirmed diagnosis of locally advanced or metastatic sarcoma, evaluable disease, received at least 1 prior line of standard systemic therapy, ECOG PS 0-1, and adequate organ function to tolerate immune-effector cell therapy. Pts with known sensitivity to Cy, active/prior autoimmune disease, uncontrolled CNS disease, or other uncontrolled comorbidities that pose potential safety risk will be excluded. Enrollment to cohort 1 began in Dec 2023. Clinical trial information: NCT05621668 .