Active surveillance for low-risk prostate cancer with high tumor burden at biopsy: lessons learned from a contemporary radical prostatectomy cohort.

INTRODUCTION: To investigate whether initial tumor burden at biopsy could predict adverse features after radical prostatectomy (RP) in International Society of Urological Pathology (ISUP) 1 prostate cancer (PCa) patients. METHODS: This retrospective study was conducted in six referral centers. The cohort included patients with ISUP 1 PCa at systematic and MRI-targeted biopsy. We defined a high tumor burden at biopsy if ≥ 20% of cores were positive. The endpoint of the study was adverse features at RP, defined as ≥ pT3a stage and/or N1 and/or ISUP ≥ 3. Sensitivity analyses were performed to assess associations between different thresholds on biopsy (percentage of positive cores [PPC] ≥ 25%, ≥ 33%, ≥ 50%, bilateral positivity and positive cores > 3) and adverse features. As the number of targeted biopsies sampled may influence the number of positive cores, we used a virtual biopsy model in which all targeted biopsy results were interpreted as a single targeted biopsy. RESULTS: A total of 312 contemporary patients were included. At final pathology, 99 patients (32%) had adverse features. In multivariate logistic regression analysis, there was no statistical association between PPC > 20% and adverse features (OR = 1.22; 95%CI:0.69-2.22, p = 0.5). In sensitivity analysis, tumor burden at biopsy was not associated with the risk of adverse features, regardless of the definition used (all p > 0.05). When we considered a unique virtual targeted biopsy, tumor burden remained not associated with adverse features (all p > 0.05). CONCLUSIONS: ISUP 1 PCa tumor burden at biopsy did not predict adverse features in this study, suggesting that it should not be used alone as an exclusion criterion when assessing eligibility for active surveillance.

Tumor response rates based on initial TNM stage and tumor size in locally advanced rectal cancer: a useful tool for shared decision-making.

BACKGROUND: It is accepted that tumor stage and size can influence response to neoadjuvant therapy in locally advanced rectal cancer (LARC). Studies on organ preservation to date have included a wide variety of size and TNM stage tumors. The aim of this study was to report tumor response based on each relevant TNM stage and tumor size. METHODS: Patients treated with LARC from 2014 to 2021 with cT2-3NxM0 tumors who received neoadjuvant chemoradiotherapy with or without induction chemotherapy were included. Tumors were staged and tumor size calculated on pelvic MRI at the time of diagnosis (cTNM). Tumor size was based on the largest dimension taken on the longest axis of each tumor. Clinical response was defined on the basis of post-treatment pelvic MRI and pathological response following surgery, when performed. Statistical analysis was performed using IBM SPSS Statistics™, version 20. Data from 432 patients were analyzed as follows: cT2N0 (n = 51), cT2N+ (n = 36), cT3N0 (n = 76), cT3N+ (n = 270). RESULTS: The rate of complete or near-complete response (cCR or nCR) varied from 77% in cT2N0 ≤ 3 cm to 20% in cT3N+ > 4 cm. Organ preservation without recurrence at 2 years was achieved in 86% of patients with cT2N0, 50% in cT2N+, 39% in cT3N0, and 12% in cT3N+. CONCLUSION: There is significant variation in tumor response according to tumor stage and size. Tumor response appears inversely proportional to increasing TNM stage and tumor size. This data can support both refinement of selective patient recruitment to organ preservation programs and shared decision-making.

Diagnostic accuracy and safety of renal tumour biopsy in patients with small renal masses and its impact on treatment decisions.

OBJECTIVE: To assess the safety and diagnostic accuracy of renal tumour biopsy (RTB) in patients with small renal masses (SRM) and to assess if RTB prevents overtreatment in patients with benign SRM. MATERIAL AND METHODS: In a retrospective, single-centre study from Västmanland, Sweden, 195 adult patients (69 women and 126 men) with SRM ≤ 4 cm who had undergone RTB during 2010-2023 were included. The median age was 70 years (range 23-89). The sensitivity, specificity and predictive values of RTB were calculated using the final diagnosis as the reference standard. Treatment outcomes were recorded for a median 42-month follow-up. Complications following the biopsies were assessed according to the Clavien-Dindo system. RESULTS: The overall sensitivity of RTB was 95% (95% confidence interval [CI] 90% - 98%) and specificity was 100% (95% CI 95% - 100%). The positive predictive value was 100% and negative predictive value was 92%. The rate of agreement between RTB and the final diagnosis measured using kappa statistics was 0.92. Of the 195 patients, 62 underwent surgery and 48 were treated with ablation. The concordance rate between the RTB histology and final histology after surgery was 89%. Treatment was withheld in 67 of 195 patients with a benign or inconclusive RTB. No patients developed renal cell carcinoma or metastasis during follow-up. Complications occurred in two patients that were classified with Clavien-Dindo grades I and IV. CONCLUSIONS: Percutaneous renal tumour biopsy appears to be a safe diagnostic method that provides accurate histopathological information about small renal masses and reduces overtreatment of benign SRM.

[Effects of high-fat and low-carbohydrate diet combined with radiotherapy on tumor microenvironment of Lewis lung cancer bearing mice].

Objective: To investigate the effect of high-fat and low-carbohydrate diet combined with radiotherapy on the tumor microenvironment of mice with lung xenografts. Methods: C57BL/6J mice were selected to establish the Lewis lung cancer model, and they were divided into the normal diet group, the high-fat and low-carbohydrate diet group, the normal diet + radiotherapy group, and the high-fat and low-carbohydrate diet + radiotherapy group, with 18 mice in each group. The mice in the normal diet group and the normal diet + radiotherapy group were fed with the normal diet with 12.11% fat for energy supply, and the mice in the high-fat and low-carbohydrate diet group and the high-fat and low-carbohydrate diet + radiotherapy group were fed with high-fat and low-carbohydratediet with 45.00% fat for energy. On the 12th to 14th days, the tumor sites of the mice in the normal diet + radiotherapy group and the high-fat and low-carbohydrate diet + radiotherapy group were treated with radiotherapy, and the irradiation dose was 24 Gy/3f. The body weight, tumor volume, blood glucose and blood ketone level, liver and kidney function, and survival status of the mice were observed and monitored. Immunohistochemical staining was used to detect the tumor-associated microangiogenesis molecule (CD34) and lymphatic endothelial hyaluronan receptor 1 (LYVE-1), Sirius staining was used to detect collagen fibers, and multiplex immunofluorescence was used to detect CD8 and programmed death-1 (PD-1). Expression of immune cell phenotypes (CD3, CD4, CD8, and Treg) was detected by flow cytometry. Results: On the 27th day after inoculation, the body weigh of the common diet group was(24.78±2.22)g, which was significantly higher than that of the common diet + radiotherapy group [(22.15±0.48)g, P=0.030] and high-fat low-carbohydrate diet + radiotherapy group [(22.02±0.77)g, P=0.031)]. On the 15th day after inoculation, the tumor volume of the high-fat and low-carbohydrate diet + radiotherapy group was (220.88±130.05) mm3, which was significantly smaller than that of the normal diet group [(504.37±328.48) mm3, P=0.042)] and the high-fat, low-carbohydrate diet group [(534.26±230.42) mm3, P=0.016], but there was no statistically significant difference compared with the normal diet + radiotherapy group [(274.64±160.97) mm3]. In the 4th week, the blood glucose values of the mice in the high-fat and low-carbohydrate diet group were lower than those in the normal diet group, with the value being (8.00±0.36) mmol/L and (9.57±0.40) mmol/L, respectively, and the difference was statistically significant (P＜0.05). The blood ketone values of the mice in the high-fat and low-carbohydrate diet group were higher than those in the normal diet group, with the value being (1.00±0.20) mmol/L and (0.63±0.06) mmol/L, respectively, in the second week. In the third week, the blood ketone values of the two groups of mice were (0.90±0.17) mmol/L and (0.70±0.10) mmol/L, respectively, and the difference was statistically significant (P＜0.05). On the 30th day after inoculation, there were no significant differences in aspartate aminotransferase, alanine aminotransferase, creatinine, and urea between the normal diet group and the high-fat, low-carbohydrate diet group (all P＞0.05). The hearts, livers, spleens, lungs, and kidneys of the mice in each group had no obvious toxic changes and tumor metastasis. In the high-fat and low-carbohydrate diet + radiotherapy group, the expression of CD8 was up-regulated in the tumor tissues of mice, and the expressions of PD-1, CD34, LYVE-1, and collagen fibers were down-regulated. The proportion of CD8+ T cells in the paratumoral lymph nodes of the high-fat and low-carbohydrate diet + radiotherapy group was (25.13±0.97)%, higher than that of the normal diet group [(20.60±2.23)%, P＜0.050] and the normal diet + radiotherapy group [(19.26±3.07)%, P＜0.05], but there was no statistically significant difference with the high-fat and low-carbohydrate diet group [(22.03±1.75)%, P＞0.05]. The proportion, of CD4+ T cells in the lymph nodes adjacent to the tumor in the normal diet + radiotherapy group (31.33±5.16)% and the high-fat and low-carbohydrate diet + radiotherapy group (30.63±1.70)% were higher than that in the normal diet group [(20.27±2.15)%, P＜0.05] and the high-fat and low-carbohydrate diet group (23.70±2.62, P＜0.05). Treg cells accounted for the highest (16.58±5.10)% of T cells in the para-tumor lymph nodes of the normal diet + radiotherapy group, but compared with the normal diet group, the high-fat and low-carbohydrate diet group, and the high-fat and low-carbohydrate diet + radiotherapy group, there was no statistically significant difference (all P＞0.05). Conclusion: High-fat and low-carbohydrate diet plus radiotherapy can enhance the recruitment and function of immune effector cells in the tumor microenvironment, inhibit tumor microangiogenesis, and thus inhibit tumor growth.

Critical appraisal of the adequacy of surgical indications for non-functioning pancreatic neuroendocrine tumours.

BACKGROUND: The lack of preoperative prognostic factors to accurately predict tumour aggressiveness in non-functioning pancreatic neuroendocrine tumours may result in inappropriate management decisions. This study aimed to critically evaluate the adequacy of surgical treatment in patients with resectable non-functioning pancreatic neuroendocrine tumours and investigate preoperative features of surgical appropriateness. METHODS: A retrospective study was conducted on patients who underwent curative surgery for non-functioning pancreatic neuroendocrine tumours at San Raffaele Hospital (2002-2022). The appropriateness of surgical treatment was categorized as appropriate, potential overtreatment and potential undertreatment based on histologic features of aggressiveness and disease relapse within 1 year from surgery (early relapse). RESULTS: A total of 384 patients were included. Among them, 230 (60%) received appropriate surgical treatment, whereas the remaining 154 (40%) underwent potentially inadequate treatment: 129 (34%) experienced potential overtreatment and 25 (6%) received potential undertreatment. The appropriateness of surgical treatment was significantly associated with radiological tumour size (P < 0.001), tumour site (P = 0.012), surgical technique (P < 0.001) and year of surgical resection (P < 0.001). Surgery performed before 2015 (OR 2.580, 95% c.i. 1.570 to 4.242; P < 0.001), radiological tumour diameter < 25.5 mm (OR 6.566, 95% c.i. 4.010 to 10.751; P < 0.001) and pancreatic body/tail localization (OR 1.908, 95% c.i. 1.119 to 3.253; P = 0.018) were identified as independent predictors of potential overtreatment. Radiological tumour size was the only independent determinant of potential undertreatment (OR 0.291, 95% c.i. 0.107 to 0.791; P = 0.016). Patients subjected to potential undertreatment exhibited significantly poorer disease-free survival (P < 0.001), overall survival (P < 0.001) and disease-specific survival (P < 0.001). CONCLUSIONS: Potential overtreatment occurs in nearly one-third of patients undergoing surgery for non-functioning pancreatic neuroendocrine tumours. Tumour diameter emerges as the sole variable capable of predicting the risk of both potential surgical overtreatment and undertreatment.

Predicting Tumor Volume Doubling Time and Progression-Free Survival in Untreated Patients from Patient-Derived-Xenograft (PDX) Models: A Translational Model-Based Approach.

Tumor volume doubling time (TVDT) has been shown to be a potential surrogate marker of biological tumor activity. However, its availability in clinics is strongly limited due to ethical and practical reasons, as its assessment requires at least two subsequent tumor volume measurements in untreated patients. Here, a translational modeling framework to predict TVDT distributions in untreated cancer patient populations from tumor growth data in patient-derived xenograft (PDX) mice is proposed. Eleven solid cancer types were considered. For each of them, a set of tumor growth studies in PDX mice was selected and analyzed through a mathematical model to characterize the distribution of the exponential tumor growth rate in mice. Then, assuming an exponential growth of the tumor mass in humans, the growth rates were scaled from PDX mice to humans through an allometric scaling approach and used to predict TVDTs in untreated patients. A very good agreement was found between model predicted and clinically observed TVDTs, with 91% of the predicted TVDT medians fell within 1.5-fold of observations. Further, exploiting the intrinsic relationship between tumor growth dynamics and progression free survival (PFS), the exponential growth rates in humans were used to generate the expected PFS curves in absence of anticancer treatment. Predicted curves were extremely close to published PFS data from studies involving patient cohorts treated with supportive care or low effective therapies. The proposed approach shows promise as a potential tool to increase knowledge about TVDT in humans without the need of directly measuring tumor dimensions in untreated patients, and to predict PFS curves in untreated patients, that could fill the absence of placebo-controlled arms against which to compare treaded arms during clinical trials. However, further validation and refinement are needed to fully assess its effectiveness in this regard.

High tumor burden score indicated the unfavorable prognosis in patients with hepatocellular carcinoma: A meta-analysis.

BACKGROUND: Tumor burden score (TBS) based on maximum tumor diameter and number has been shown to correlate with prognosis in patients with hepatocellular carcinoma (HCC). Nevertheless, the results are conflicting. Hence, we conducted a meta-analysis to analyze the association between TBS and survival outcomes of HCC patients. METHODS: A comprehensively search of the databases including PubMed, Embase and Web of Science was performed to retrieve studies satisfying the inclusion criteria until August 31, 2023. The hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated. All the data analyses were carried out by STATA 12.0. RESULTS: 10 retrospective studies containing 25073 patients were incorporated in the study. The results demonstrated that high TBS was markedly association with poor overall survival (OS) (HR: 1.79, 95% CI: 1.45-2.23) and relapse-free survival / progression-free survival(RFS/PFS) (HR: 1.71; 95% CI: 1.42-2.07). Subgroup analysis showed that the prognostic value of TBS in HCC was not affected by any subgroup. CONCLUSIONS: TBS may be an efficient prognostic index in HCC patients.

Practical parameter identifiability and handling of censored data with Bayesian inference in mathematical tumour models.

Mechanistic mathematical models (MMs) are a powerful tool to help us understand and predict the dynamics of tumour growth under various conditions. In this work, we use 5 MMs with an increasing number of parameters to explore how certain (often overlooked) decisions in estimating parameters from data of experimental tumour growth affect the outcome of the analysis. In particular, we propose a framework for including tumour volume measurements that fall outside the upper and lower limits of detection, which are normally discarded. We demonstrate how excluding censored data results in an overestimation of the initial tumour volume and the MM-predicted tumour volumes prior to the first measurements, and an underestimation of the carrying capacity and the MM-predicted tumour volumes beyond the latest measurable time points. We show in which way the choice of prior for the MM parameters can impact the posterior distributions, and illustrate that reporting the most likely parameters and their 95% credible interval can lead to confusing or misleading interpretations. We hope this work will encourage others to carefully consider choices made in parameter estimation and to adopt the approaches we put forward herein.

Impact of geometric correction on echo-planar imaging-based apparent diffusion coefficient maps for abdominal radiotherapy.

Objective. The apparent diffusion coefficient (ADC) extracted from diffusion-weighted magnetic resonance imaging (DWI) is a potential biomarker in radiotherapy (RT). DWI is often implemented with an echo-planar imaging (EPI) read-out due to speed, but unfortunately low geometric accuracy follows. This study aimed to investigate the influence of geometric distortions on the ADCs extracted from the gross tumor volume (GTV) and on the shape of the GTV in abdominal EPI-DWI.Approach. Twenty-one patients had EPI-DWI scans on a 1.5 T MRI sim before treatment and on a 1.5 T MRI-Linac at one of the first treatment fractions. Off-resonance correction with and without eddy current correction were applied to ADC maps. The clinical GTVs were deformed based on the same (but inverted) corrections to assess the local-regional geometric influence of distortions. Mean surface distance (MSD), Hausdorff distance (HD), and Dice similarity coefficient (DSC) were calculated to compare the original and distorted GTVs, and ADC values were calculated based on a mono-exponential model. Phantom measurements were performed to validate the applied correction method.Main results. The median (range) ADC change within the GTV after full distortion correction was 1.3% (0.02%-6.9%) for MRI-Sim and 1.5% (0.1%-6.4%) for MRI-Linac. The additional effect of the eddy current correction was small in both systems. The median (range) MSD, HD, and DSC comparing the original and off-resonance distorted GTVs for all patients were 0.43 mm (0.11-0.94 mm), 4.00 mm (1.00-7.81 mm) and 0.93 (0.82-0.99), respectively.Significance. Overall effect of distortion correction was small in terms of derived ADC values, indicating that distortion correction is unimportant for prediction of outcomes based on ADC. However, large local geometric changes occurred after off-resonance distortion correction for some patients, suggesting that if the spatial information from ADC maps is to be used for dose painting strategies, corrections should be applied.

The effect of preoperative embolization rate on surgical outcomes for carotid paraganglioma resection.

OBJECTIVE: Preoperative embolization of paragangliomas decreases tumor volume and reduces intraoperative blood loss. This study aimed to evaluate the effect of the rate of devascularization achieved by preoperative embolization of carotid body tumors on surgical outcomes. METHODS: Patients with carotid body tumors who underwent preoperative transarterial embolization between 2013 and 2024 were included in this retrospective study. The Shamblin classification of all patients was carried out using radiological imaging. Devascularization rates obtained after the embolization of carotid body tumors were determined from angiographic images. Patients were divided into two groups: near-complete embolization (devascularization rate >90%) and incomplete embolization (devascularization rate <90%). Hemoglobin loss was calculated with blood tests before and immediately after surgery. Tumor volume loss was calculated by preoperative radiological tumor volume and postoperative surgical specimen volume. Hemoglobin loss, tumor volume loss, and postoperative complication rates of the two groups were compared. RESULTS: A total of 31 patients with carotid body tumors who underwent surgery were included in the study. Near-complete embolization was achieved in 21 patients (67.74%), while incomplete embolization was achieved in 10 patients (32.25%). Shamblin classification was statistically similar (p>0.05) between the two groups. The vascular complication rate in the near-complete embolization group was significantly lower than in the incomplete embolization group (p=0.027). However, no significant difference was observed in neurological complication rates, hemoglobin loss, and tumor volume loss parameters between the two groups (p>0.05). CONCLUSION: The preoperative devascularization rate should be at least 90% to minimize the risk of vascular complications.

Magnolol's Therapeutic Efficacy and Immunomodulatory Effects in Oral Squamous Cell Carcinoma.

BACKGROUND/AIM: Oral squamous cell carcinoma (OSCC) presents a significant health challenge, requiring effective treatments. Magnolol, a compound with potential anticancer properties, warrants investigation in OSCC treatment. Here, we aimed to assess the efficacy of magnolol in inhibiting progression of OSCC and to explore the underlying mechanisms of its action. MATERIALS AND METHODS: We evaluated the effect of magnolol on tumor progression using the MOC1-bearing orthotopic model. We examined its impact on pathology and toxicity through hematoxylin and eosin (H&E) staining, immunohistochemistry (IHC), and biochemical analysis. We also investigated the immunoregulatory effects of magnolol in the MOC1-bearing model using flow cytometry. RESULTS: At high doses, magnolol significantly reduced tumor volume (p<0.0001 for comparisons between treated with magnolol and untreated groups) and weight loss by 70% in vivo. It also induced caspase-dependent apoptosis, evidenced by 2.42-, 2-, and 2.2-fold increases in the expression of caspase-3, -8, and -9, respectively, in mouse tumors treated with high 60 mg/kg of magnolol compared to untreated (p<0.0001 for all comparisons). Magnolol demonstrated no toxicity, maintaining body weight and normal biochemical parameters, including liver and kidney function. Pathological evaluations showed no adverse effects on organs in all treatment groups. Moreover, high doses of magnolol enhanced natural killer cells (by 3%), dendritic cells (20-25%), and cytotoxic T cells (20-40%) while reducing myeloid-derived suppressor cells and regulatory T cells by 1.5 times. CONCLUSION: Magnolol demonstrates potential as a therapeutic agent for OSCC, offering antitumor efficacy and immunomodulatory benefits.

Utilizing multiclassifier radiomics analysis of ultrasound to predict high axillary lymph node tumour burden in node-positive breast cancer patients: a multicentre study.

BACKGROUND: The tumor burden within the axillary lymph nodes (ALNs) constitutes a pivotal factor in breast cancer, serving as the primary determinant for treatment decisions and exhibiting a close correlation with prognosis. OBJECTIVE: This study aimed to investigate the potential of ultrasound-based radiomics and clinical characteristics in non-invasively distinguishing between low tumor burden (1-2 positive nodes) and high tumor burden (more than 2 positive nodes) in patients with node-positive breast cancer. METHODS: A total of 215 patients with node-positive breast cancer, who underwent preoperative ultrasound examinations, were enrolled in this study. Among these patients, 144 cases were allocated to the training set, 37 cases to the validation set, and 34 cases to the testing set. Postoperative histopathology was used to determine the status of ALN tumor burden. The region of interest for breast cancer was delineated on the ultrasound image. Nine models were developed to predict high ALN tumor burden, employing a combination of three feature screening methods and three machine learning classifiers. Ultimately, the optimal model was selected and tested on both the validation and testing sets. In addition, clinical characteristics were screened to develop a clinical model. Furthermore, Shapley additive explanations (SHAP) values were utilized to provide explanations for the machine learning model. RESULTS: During the validation and testing sets, the models demonstrated area under the curve (AUC) values ranging from 0.577 to 0.733 and 0.583 to 0.719, and accuracies ranging from 64.9% to 75.7% and 64.7% to 70.6%, respectively. Ultimately, the Boruta_XGB model, comprising five radiomics features, was selected as the final model. The AUC values of this model for distinguishing low from high tumor burden were 0.828, 0.715, and 0.719 in the training, validation, and testing sets, respectively, demonstrating its superiority over the clinical model. CONCLUSIONS: The developed radiomics models exhibited a significant level of predictive performance. The Boruta_XGB radiomics model outperformed other radiomics models in this study.

Peritumoral radiomics increases the efficiency of classification of pure ground-glass lung nodules: a multicenter study.

PURPOSE: We aimed to evaluate the efficiency of computed tomography (CT) radiomic features extracted from gross tumor volume (GTV) and peritumoral volumes (PTV) of 5, 10, and 15 mm to identify the tumor grades corresponding to the new histological grading system proposed in 2020 by the Pathology Committee of the International Association for the Study of Lung Cancer (IASLC). METHODS: A total of 151 lung adenocarcinomas manifesting as pure ground-glass lung nodules (pGGNs) were included in this randomized multicenter retrospective study. Four radiomic models were constructed from GTV and GTV + 5/10/15-mm PTV, respectively, and compared. The diagnostic performance of the different models was evaluated using receiver operating characteristic curve analysis RESULTS: The pGGNs were classified into grade 1 (117), 2 (34), and 3 (0), according to the IASLC grading system. In all four radiomic models, pGGNs of grade 2 had significantly higher radiomic scores than those of grade 1 (P < 0.05). The AUC of the GTV and GTV + 5/10/15-mm PTV were 0.869, 0.910, 0.951, and 0.872 in the training cohort and 0.700, 0.715, 0.745, and 0.724 in the validation cohort, respectively. CONCLUSIONS: The radiomic features we extracted from the GTV and PTV of pGGNs could effectively be used to differentiate grade-1 and grade-2 tumors. In particular, the radiomic features from the PTV increased the efficiency of the diagnostic model, with GTV + 10 mm PTV exhibiting the highest efficacy.

Automated lattice radiation therapy treatment planning personalised to tumour size and shape.

PURPOSE: Lattice radiation therapy (LRT) alternates regions of high and low doses inside the tumour. Whilst this technique reported positive results in tumour size reduction, optimal lattice parameters are still unknown. We introduce an automated LRT planning method personalised to tumour shape and designed to allow investigation of lattice geometry. METHODS: Patients with retroperitoneal sarcoma were considered for inclusion. Automation was performed with the Eclipse Scripting Application Interface (v16, Varian Medical Systems, Palo Alto). By iterating over vertex size (V) and centre-to-centre distance (D), vertices were segmented within the gross tumour volume (GTV) in an alternating square pattern. Iterations stopped when the number of inserted vertices was contained between a prespecified lower and upper bound. Forty sets of lattices were considered, produced by varying V and D in five lower/upper bound pairs. Best-scoring sets were determined with a score favouring the maximization of GTV dose uniformity and heterogeneity whilst minimizing the maximum dose to organs at risk. RESULTS: Fifty patients with tumour volumes between 150 cm3 and 10,000 cm3 were included. Best-scoring sets were characterised by a low number of vertices (<15). Based on the best-scoring set, the predicted parameters to use for new patients were V = 0.19 (GTV volume)1/3 and D = 2V, in centimetres. The number of vertices (N) to insert in the GTV can be estimated with N ≤ (24 × 3% GTV volume)/(4πV3). CONCLUSIONS: The automated LRT treatment planning personalised to tumour size allows investigation of lattice geometry over a large range of GTV volumes.

Dynamics and bifurcations in a model of chronic myeloid leukemia with optimal immune response windows.

Chronic Myeloid Leukemia is a blood cancer for which standard therapy with Tyrosine-Kinase Inhibitors is successful in the majority of patients. After discontinuation of treatment half of the well-responding patients either present undetectable levels of tumor cells for a long time or exhibit sustained fluctuations of tumor load oscillating at very low levels. Motivated by the consequent question of whether the observed kinetics reflect periodic oscillations emerging from tumor-immune interactions, in this work, we analyze a system of ordinary differential equations describing the immune response to CML where both the functional response against leukemia and the immune recruitment exhibit optimal activation windows. Besides investigating the stability of the equilibrium points, we provide rigorous proofs that the model exhibits at least two types of bifurcations: a transcritical bifurcation around the tumor-free equilibrium point and a Hopf bifurcation around a biologically plausible equilibrium point, providing an affirmative answer to our initial question. Focusing our attention on the Hopf bifurcation, we examine the emergence of limit cycles and analyze their stability through the calculation of Lyapunov coefficients. Then we illustrate our theoretical results with numerical simulations based on clinically relevant parameters. Besides the mathematical interest, our results suggest that the fluctuating levels of low tumor load observed in CML patients may be a consequence of periodic orbits arising from predator-prey-like interactions.

Combination of US hyperthermia and radiotherapy on a preclinical glioblastoma model.

In this work the effect of combining ultrasound (US) hyperthermia (HT) with radiotherapy (RT) was investigated. The treatment was applied to a GBM xenograft nude mouse model obtained by injecting 2 × 10 6 U87 luc+ cells. The combined treatment group received 6 Gy and HT at 43 ∘ for 8 min. The ultrasound field was generated by a closed-loop computationally controlled system, consisting of a High Intensity Focused Ultrasound (HIFU) transducer with centre frequency 3.57 MHz, a power amplifier, a function generator and a MATLAB controller. A mechanical cone adaptor has been designed to use the HIFU beam at a pre-defined post-focal distance. Two thermocouples were placed between the mechanical cone and the mice skin to measure and control the temperature during the HT treatment. Radiotherapy was carried out by using a dedicated small animal image guided radiotherapy system. Measurements of tumor volume performed with a caliper showed good tumor control for the RT-HT group with respect to the RT or control groups for up to 21 days after treatment. The mean value of the normalized (before therapy) tumor volume was almost equal to 0.5 for two weeks after treatment with an increase to 1.5 at sacrifice. The control and HT groups showed a higher value of about 1.5 during the first two weeks and 3.5 at the end of the follow-up period. We concluded that the use of HT as a radiosensitizer can improve the outcome for glioblastoma treatments.

Mathematical Modeling of Tumor Growth in Preclinical Mouse Models with Applications in Biomarker Discovery and Drug Mechanism Studies.

Oncology drug efficacy is evaluated in mouse models by continuously monitoring tumor volumes, which can be mathematically described by growth kinetic models. Although past studies have investigated various growth models, their reliance on small datasets raises concerns about whether their findings are truly representative of tumor growth in diverse mouse models under different vehicle or drug treatments. In this study, we systematically evaluated six parametric models (exponential, exponential quadratic, monomolecular, logistic, Gompertz, and von Bertalanffy) and the semiparametric generalized additive model (GAM) on fitting tumor volume data from more than 30,000 mice in 930 experiments conducted in patient-derived xenografts, cell line-derived xenografts, and syngeneic models. We found that the exponential quadratic model is the best parametric model and can adequately model 87% studies, higher than other models including von Bertalanffy (82%) and Gompertz (80%) models; the latter is often considered the standard growth model. At the mouse group level, 7.5% of growth data could not be fit by any parametric model and were fitted by GAM. We show that endpoint gain integrated in time, a GAM-derived efficacy metric, is equivalent to exponential growth rate, a metric we previously proposed and conveniently calculated by simple algebra. Using five studies on paclitaxel, anti-PD1 antibody, cetuximab, irinotecan, and sorafenib, we showed that exponential and exponential quadratic models achieve similar performance in uncovering drug mechanism and biomarkers. We also compared exponential growth rate-based association analysis and exponential modeling approach in biomarker discovery and found that they complement each other. Modeling methods herein are implemented in an open-source R package freely available at https://github.com/hjzhou988/TuGroMix. SIGNIFICANCE: We present a general strategy for mathematically modeling tumor growth in mouse models using data from 30,000 mice and show that modeling and nonmodeling approaches are complementary in biomarker discovery and drug mechanism studies.

Agreement between frozen section and histopathology to detect malignancy in adnexal masses according to size and morphology by ultrasound.

Objective: Management of suspect adnexal masses involves surgery to define the best treatment. Diagnostic choices include a two-stage procedure for histopathology examination (HPE) or intraoperative histological analysis - intraoperative frozen section (IFS) and formalin-fixed and paraffin-soaked tissues (FFPE). Preoperative assessment with ultrasound may also be useful to predict malignancy. We aimed at determining the accuracy of IFS to evaluate adnexal masses stratified by size and morphology having HPE as the diagnostic gold standard. Methods: A retrospective chart review of 302 patients undergoing IFS of adnexal masses at Hospital de Clínicas de Porto Alegre, between January2005 and September2011 was performed. Data were collected regarding sonographic size (≤10cm or >10cm), characteristics of the lesion, and diagnosis established in IFS and HPE. Eight groups were studied: unilocular lesions; septated/cystic lesions; heterogeneous (solid/cystic) lesions; and solid lesions, divided in two main groups according to the size of lesion, ≤10cm or >10cm. Kappa agreement between IFS and HPE was calculated for each group. Results: Overall agreement between IFS and HPE was 96.1% for benign tumors, 96.1% for malignant tumors, and 73.3% for borderline tumors. Considering the combination of tumor size and morphology, 100% agreement between IFS and HPE was recorded for unilocular and septated tumors ≤10cm and for solid tumors. Conclusion: Stratification of adnexal masses according to size and morphology is a good method for preoperative assessment. We should wait for final HPE for staging decision, regardless of IFS results, in heterogeneous adnexal tumors of any size, solid tumors ≤10cm, and all non-solid tumors >10cm.

Potential and Pitfalls of Postoperative Volumetric Assessment of Extent of Resection in High-Grade Glioma in Resource-Constrained Settings.

BACKGROUND: While literature suggests the need for routine postoperative volumetric estimation of the EOR and residual tumour volume (RTV) in all cases of gliomas, the utility and feasibility of this protocol in resource-constrained centers remain underinvestigated. OBJECTIVES: Our objective was to study the feasibility of volumetric EOR in routine neurosurgical practice and determine correlation with surgeons' intraoperative estimation of EOR. The secondary objective was to determine the survival impact of EOR and RTV on survival. METHODS AND MATERIALS: A prospective study of pathologically proven high-grade gliomas (WHO grades 3 and 4) in adults was conducted at a tertiary care center. Pre- and postoperative magnetic resonance imaging (MRI) was obtained for volumetric analysis using OsiriX software and manual segmentation. Overall survival and predictors were studied using Kaplan-Meier and Cox regression analysis. RESULTS: Postoperative volumetry was feasible in 31% patients (n = 25) of study eligible patients (n = 84). The median EOR, CE-PTV, and CE-RTV were 79.1%, 69.8 cm3, and 8.7 cm3, respectively. There was a poor correlation of surgeons' intraoperative impression and volumetric data (P = 0.359). Interestingly, the EOR was not significantly associated with the survival time (P = 0.920), while tumor grade, molecular profile, Ki 67 score, and postoperative functional status showed statistically significant impact. CONCLUSION: Logistic difficulties impede routine implementation of this protocol in developing countries. MRI volumetry is clearly more accurate than surgeons' intraoperative estimation of EOR. Notwithstanding the role of EOR in survival, our study reveals a perhaps bigger impact of tumor biology and postoperative functional status in this equation.

Mathematical modeling of meningioma volume change after radiation treatment.

OBJECTIVE: Meningiomas are the most common primary central nervous tumor and are often treated with radiation therapy. This study examines the long-term volumetric changes of intracranial meningiomas in response to radiation therapy. The objective is to analyze and model the volumetric changes following treatment. METHODS: Data from a retrospective single-institution database (2005-2015) were used, with inclusion criteria being patients with a diagnosis of meningiomas, along with additional inclusion criteria consisting of treatment with radiation, having at least three magnetic resonance imaging (MRI) scans with one or more before and after radiation treatment, and the patients following up for at least eighteen months. Exclusion criteria consisted of patients less than 18 years old, patients receiving surgery and/or adjuvant chemotherapy following radiation, and patients without any available details regarding radiation treatment parameters. Tumor volumes were measured via T1-weighted post-contrast MRI and calculated using the ABC/2 ellipsoidal approximation, a method allowing for the measurement of non-linear growth volume reduction. RESULTS: Of 48 meningioma patients considered, 10 % experienced post-radiation growth, while 75 % witnessed a ≥50 % decrease in volume over a follow-up period of 0.3-14.9 years. Median decay rate was 0.81, and within 1.17 years, 90 % achieved the predicted volume reduction. Predicted vs. actual volumes showed a mean difference of 0.009 ± 0.347 cc. Initial tumor volumes strongly correlated (Pearson's R=0.98, R-squared=0.96) with final asymptotic volumes, which had a median of 1.50 cc, with interquartile range (IQR) = [0.39, 3.67]. CONCLUSION: 90 % of patients achieved tumor-volume reduction at 1.17 years post-treatment, reaching a non-zero asymptote strongly correlated with initial tumor volume, and 75 % experienced at least a 50 % volume decrease. Individual volume changes for responsive meningiomas can be modeled and predicted using exponential decay curves.