Recurrent Setting Research Articles

Alterations in tumor immune microenvironment and progressive immune exhaustion with advancing penile squamous cell carcinoma using multiplex immunofluorescence and image analysis.

9 Background: Penile squamous cell carcinoma (PSCC) is a rare and aggressive malignancy with limited treatment options in the advanced or recurrent settings. Immunotherapy can yield clinical responses in PSCC, but less than 20% of patients benefit. Herein, using multiplex immunofluorescence (MIF), we analyzed the composition of the tumor immune microenvironment as it varies with human papillomavirus (HPV) status and across advancing disease stages with an aim to further our understanding of how immune composition may impact clinical outcome, potential role in disease progression and response to immune therapies. Methods: Formalin-fixed and paraffin-embedded tissue samples from men with PSCC treated at Moffitt cancer center (Tampa, FL) were immunostained for CD3, CD4, CD8, CD68, PD-1, PD-L1, CD163 and CD 206 using OPAL TM 7 kit (AKOYA Biosciences) for MIF. Densities of various cell phenotypes (expressed as cells/mm2) were quantified using an automated quantitative image analysis system (InForm). Immune cell phenotype densities were stratified by HPV status and by tumor stage. We will apply the nearest neighbor cell analysis to identify the spatial orientation of immune cells in the tumor microenvironment. Results: 57 PSCC patients (median age, 60 years [IQR (interquartile range) 31-92]; 60% HPV negative) had MIF analysis. More than half (31/57) had lymph nodes involved (6 N1, 25 N2-3). The immune composition did not differ significantly with HPV status. When investigated by individual clinical stage, we observed an increase in median density of total (CD3+), helper (CD3+CD4+), cytotoxic (CD3+CD8+) and CD3+PD-L1+ T cells from N0 to N1 stage (pN0: CD3+ 44.23, CD3+CD4+ 14.77, CD3+CD8+ 16.15 cells/mm2; pN1: CD3+ 188.36, CD3+CD4+ 71.69, CD3+CD8+ 40.22 cells/mm2) followed by a decrease in N2-N3 stage (CD3+CD4+ 18.45 and CD3+CD8+ 28.22 cells/mm2).The median density of total macrophages increased with stage (pN0: 306.38; pN1: 502.47; pN2-3: 648.27 cells/mm2). While the activated M1 macrophages increased from N0 to N1 and decreased in the more advanced N2-3 stage, M2 macrophages steadily increased across stages and became the dominant type in N2-3. Conclusions: This study describes the interplay of T cells and macrophages across disease stages using MIF. We observed an initial T cell and myeloid immune response in the early locoregional stage, followed by the emergence of immune exhaustion, marked by a decline in the density of cytotoxic T cells, rising PD-L1 expression, and the progressive replacement of anti-tumor M1 macrophages with pro-tumorigenic M2 macrophages across stages. Our findings can inform treatments utilizing immune manipulation. Geospatial analysis exploring the proximity relationships of different immune cell types to each other and to the tumor is ongoing and will be presented at the meeting.

Lucanthone, a Potential PPT1 Inhibitor, Perturbs Stemness, Reduces Tumor Microtube Formation, and Slows the Growth of Temozolomide-Resistant Gliomas In Vivo.

Glioblastoma (GBM) is the most frequently diagnosed primary central nervous system tumor in adults. Despite the standard of care therapy, which includes surgical resection, temozolomide chemotherapy, radiation and the newly added tumor-treating fields, median survival remains only ∼20 months. Unfortunately, GBM has a ∼100% recurrence rate, but after recurrence there are no Food and Drug Administration-approved therapies to limit tumor growth and enhance patient survival, as these tumors are resistant to temozolomide (TMZ). Recently, our laboratory reported that lucanthone slows GBM by inhibiting autophagic flux through lysosome targeting and decreases the number of Olig2+ glioma stem-like cells (GSC) in vitro and in vivo. We now additionally report that lucanthone efficiently abates stemness in patient-derived GSC and reduces tumor microtube formation in GSC, an emerging hallmark of treatment resistance in GBM. In glioma tumors derived from cells with acquired resistance to TMZ, lucanthone retains the ability to perturb tumor growth, inhibits autophagy by targeting lysosomes, and reduces Olig2 positivity. We also find that lucanthone may act as an inhibitor of palmitoyl protein thioesterase 1. Our results suggest that lucanthone may function as a potential treatment option for GBM tumors that are not amenable to TMZ treatment. SIGNIFICANCE STATEMENT: We report that the antischistosome agent lucanthone impedes tumor growth in a preclinical model of temozolomide-resistant glioblastoma and reduces the numbers of stem-like glioma cells. In addition, it acts as an autophagy inhibitor, and its mechanism of action may be via inhibition of palmitoyl protein thioesterase 1. As there are no defined therapies approved for recurrent, TMZ-resistant tumor, lucanthone could emerge as a treatment for glioblastoma tumors that may not be amenable to TMZ both in the newly diagnosed and recurrent settings.

Next generation sequencing of high-grade adult-type diffuse glioma in the Netherlands: interlaboratory variation in the primary diagnostic and recurrent setting.

Next generation sequencing (NGS) is an important tool used in clinical practice to obtain the required molecular information for accurate diagnostics of high-grade adult-type diffuse glioma (HGG). Since individual centers use either in-house produced or standardized panels, interlaboratory variation could play a role in the practice of HGG diagnosis and treatment. This study aimed to investigate the current practice in NGS application for both primary and recurrent HGG. This nationwide Dutch survey used the expertise of (neuro)pathologists and clinical scientists in molecular pathology (CSMPs) by sending online questionnaires on clinical and technical aspects. Primary outcome was an overview of panel composition in the different centers for diagnostic practice of HGG. Secondary outcomes included practice for recurrent HGG and future perspectives. Out of twelve neuro-oncology centers, the survey was filled out by eleven (neuro)pathologists and seven CSMPs. The composition of the diagnostic NGS panels differed in each center with numbers of genes ranging from 12 to 523. Differences are more pronounced when tests are performed to find therapeutic targets in the case of recurrent disease: about half of the centers test for gene fusions (60%) and tumor mutational burden (40%). Current notable interlaboratory variations as illustrated in this study should be reduced in order to refine diagnostics and improve precision oncology. In-house developed tests, standardized panels and routine application of broad gene panels all have their own advantages and disadvantages. Future research would be of interest to study the clinical impact of variation in diagnostic approaches.

Medical cannabis and its effect on oncological outcomes in patients with ovarian cancer treated with PARP inhibitors.

Poly (ADP-ribose) polymerase inhibitors (PARPi) play a pivotal role in ovarian cancer management. With medical cannabis emerging as a novel component of supportive care, this study investigated the impact of medical cannabis use on oncological outcomes in patients with ovarian cancer undergoing PARPi therapy. The study included patients from a single institution database treated for ovarian cancer between January 2014 and January 2020 who received PARPi maintenance therapy in a first-line or recurrent disease setting after a confirmed response to platinum-based treatment. The study categorized patients as cannabis users and cannabis-naïve. Univariate and multivariate Cox regression analysis and the Kaplan-Meier method were used to assess the effects of medical cannabis use on the duration of PARPi therapy, progression-free survival, and overall survival. Among the eligible patients (n=93), most were cannabis-naïve (69%, n=64) while the rest used medical cannabis (31%, n=29). Medical cannabis use rates were comparable for patients receiving PARPi therapy post-primary treatment or for recurrence (42%, n=9, vs 27%, n=20; p=0.1). Both groups exhibited similar median duration for PARPi therapy (12.1 vs 9.5 months; p=0.89) and progression-free survival (20 vs 21 months; p=0.83). Kaplan-Meier analysis detected no differences in progression-free survival associated with cannabis use. Although cannabis users had an extended overall survival compared with the cannabis-naïve group (129.3 vs 99 months; p=0.03), cannabis use was insignificant for overall survival on multivariate analysis (p=0.10). Multivariate analysis showed stage IV at diagnosis (p=0.02) to be the sole factor associated with progression-free survival (p=0.02). Medical cannabis usage in patients receiving PARPi treatment showed no association with duration of PARPi therapy, progression-free survival, or overall survival.

Serial cytoreductive surgery and survival outcomes in recurrent adult-type ovarian granulosa cell tumors

BackgroundFew studies have evaluated the role of cytoreductive surgery in patients with recurrent adult granulosa cell tumors of the ovary. Despite a multitude of treatment modalities in the recurrent setting, the optimal management strategy is not known. Cytoreductive surgery offers an attractive option for disease confined to the abdomen/pelvis. However, few studies have evaluated the role of surgery compared to systemic therapy alone following the first recurrence and subsequent disease progressions. ObjectiveTo determine the impact of secondary, tertiary, and quaternary cytoreductive surgery on survival outcomes in recurrent adult granulosa cell tumors of the ovary. Study DesignThis is a multicenter, retrospective cohort study evaluating patients with recurrent adult granulosa cell tumor of the ovary enrolled in the MD Anderson Rare Gynecologic Malignancy Registry from 1970 to 2022. Study inclusion criteria consisted of histology-proven recurrent disease, at least one documented recurrence, and treatment/treatment planning at MD Anderson Cancer Center or Lyndon B. Johnson General Hospital. The primary exposure was cytoreductive surgery and the outcomes of interest were progression-free survival and overall survival. Survival analyses were restricted to eligible patients with resectable disease without medical barriers to surgery at each progression episode. Demographic and Clinicopathologic characteristics were summarized using descriptive statistics. Progression-free survival (after first, second, and third progression) and overall survival were estimated with methods of Kaplan and Meier and were modeled via cox proportional hazards regression. Multivariable analyses were performed for progression-free survival after first progression and overall survival. ResultsAmong the 369 patients with adult granulosa cell tumors of the ovary in the registry, there were 149 patients who met the study inclusion criteria. Secondary cytoreductive surgery was associated with a significant improvement in progression-free survival on univariable (HR 0.37, 95% CI 0.17 – 0.81, p = 0.01) and multivariable analyses (HR 0.42, 95% CI 0.19 – 0.92, p = 0.03). Those who underwent secondary cytoreductive surgery had a significantly improved median overall survival compared to those who did not undergo cytoreductive surgery (181.92 months vs 61.56 months, respectively; p = 0.002). Overall survival benefit remained statistically significant on multivariable analysis (HR 0.28, 95% CI 0.11 – 0.67, p = 0.004). Tertiary cytoreductive surgery was similarly associated with a significant improvement in progression-free survival (HR 0.43, 95% CI 0.26 – 0.70, p = 0.001). Despite a similar trend, quaternary cytoreductive surgery was not associated with a significant improvement in progression-free survival (HR 0.74, 95% CI 0.42 – 1.26, p = 0.27). ConclusionsAmong those with resectable disease and no medical contraindications to surgery, cytoreductive surgery may offer a beneficial impact on progression-free survival and overall survival in patients with recurrent adult granulosa cell tumor of the ovary.

Generalized rotation sets and rotational entropy for circle maps

In this paper, we consider the generalized rotation set and rotational entropy for circle maps. Let f:S1→S1 be continuous and F be a lifting of f. In [1] a notion of F-rotation set of a point x∈S1 was given when f is homotopic to the identity. We firstly extend this notion, designated ‘generalized rotation set’ ρ(F), to the general continuous map of the circle, not necessarily homotopic to identity. We show that ρ(F) is compact and connected, i.e., a closed interval, and moreover, each of its endpoints is a generalized rotation number of a recurrent point of f. We also consider the generalized rotation set for f on its invariant sets. Secondly, we introduce a notion of generalized rotational entropy hr(f) for f, which follows the definition that Botelho proposed in [3] for the annulus, and then we show that it exactly vanishes.

Updated Response Assessment in Neuro-Oncology (RANO) for Gliomas.

The response assessment in Neuro-Oncology (RANO) criteria and its versions were developed by expert opinion consensus to standardize response evaluation in glioma clinical trials. New patient-based data informed the development of updated response assessment criteria, RANO 2.0. In a recent study of patients with glioblastoma, the post-radiation brain MRI was a superior baseline MRI compared to the pretreatment MRI, and confirmation scans were only beneficial within the first 12weeks of completion of radiation in newly diagnosed disease. Nonenhancing disease evaluation did not improve the correlation between progression-free survival and overall survival in newly diagnosed and recurrent settings. RANO 2.0 recommends a single common response criteria for high- and low-grade gliomas, regardless of the treatment modality being evaluated. It also provides guidance on the evaluation of nonenhancing tumors and tumors with both enhancing and nonenhancing components.

Major clinical research advances in gynecologic cancer in 2023: a tumultuous year for endometrial cancer.

In the 2023 series, we summarized the major clinical research advances in gynecologic oncology based on communications at the conference of Asian Society of Gynecologic Oncology Review Course. The review consisted of 1) Endometrial cancer: immune checkpoint inhibitor, antibody drug conjugates (ADCs), selective inhibitor of nuclear export, CDK4/6 inhibitors WEE1 inhibitor, poly (ADP-ribose) polymerase (PARP) inhibitors. 2) Cervical cancer: surgery in low-risk early-stage cervical cancer, therapy for locally advanced stage and advanced, metastatic, or recurrent setting; and 3) Ovarian cancer: immunotherapy, triplet therapies using immune checkpoint inhibitors along with antiangiogenic agents and PARP inhibitors, and ADCs. In 2023, the field of endometrial cancer treatment witnessed a landmark year, marked by several practice-changing outcomes with immune checkpoint inhibitors and the reliable efficacy of PARP inhibitors and ADCs.

A phase 1 dose escalation of pritumumab in patients with refractory or recurrent gliomas or brain metastases.

This phase 1 (NCT04396717) open-label, multicenter study, evaluated Pritumumab, a IgG1 monoclonal antibody, in patients with gliomas and brain metastases. The primary objective was to evaluate the safety and/or tolerability and to identify a recommended phase 2 dose (RP2D) of Pritumumab. Adult patients with recurrent gliomas or brain metastases were enrolled in the dose cohort that was open at the time of their consent. Study treatment consisted of pritumumab administered intravenously weekly on days 1, 8, 15, and 22 in 28-day cycles. Safety, pharmacokinetics (PK), pharmacodynamics (PD), and clinical activity were evaluated. Fifteen patients received Pritumumab in the recurrent setting. Pritumumab was well tolerated, with no serious adverse events related to Pritumumab reported. The most common drug-related toxicities were constipation and fatigue. There were no dose-limiting toxicities observed, and a maximum tolerable dose was not reached. Thus, the maximum feasible dose and recommended phase 2 dose of Pritumumab was established at 16.2 mg/kg weekly. Out of eleven patients evaluated for efficacy, one patient (9.1%) demonstrated partial response based on response assessment in neuro-oncology criteria, and disease stabilization was seen in 3 patients (27.3%). Pritumumab was well tolerated with no DLTs observed up to 16.2 mg/kg weekly. Further studies are warranted to determine clinical benefit in patients.

Survival Outcomes and Prognostic Factors in Oral Squamous Cell Carcinoma with Locoregional Recurrence: A Retrospective Analysis

Introduction: Recurrence is known to occur in approximately 25% to 45% of patients treated for oral cancer. It is the most common cause of treatment failure in oral squamous cell carcinoma (OSCC), which adversely affects survival. Although recurrences in the oral cavity may be detected early, survival rates remain low. Aim: To identify the survival outcomes and prognostic factors in OSCC with locoregional recurrence. Materials and Methods: This retrospective study was conducted at the Malabar Cancer Centre between November 2020 to March 2021, analysing patients who were treated with curative intent between January 1997 and December 2017. It included 118 patients with OSCC who experienced recurrence-local, regional, or both-after curative treatment. Demographic variables, clinical variables, and follow-up details were analysed. Characteristics of the primary tumour, including nodal metastasis, stage, Extranodal Extension (ENE), Perineural Invasion (PNI), the extent of treatment, adjuvant therapy, and days to recurrence, were recorded. For the recurrent tumour, site, time to recurrence, and type of treatment received were noted additionally. Overall Survival (OS) was defined from the date of initial diagnosis, while the date of recurrence was determined by pathological confirmation. Statistical analysis was performed using SPSS software, version 20. All significant variables (p<0.05) were then tested in a multivariate analysis using Cox regression methods. Disease-specific survival (DSS) and OS were analysed using the Kaplan-Meier method. Results: A total of 146 patients with OSCC (15.01%) experienced a recurrence-local, regional, or both-upon analysis of 973 OSCC patients who underwent primary curative intent surgery. One hundred eighteen patients were included in the final analysis. Salvage surgery was performed on 65 (55.08%) patients. Thirtyeight patients (32.3%) who presented with early-stage disease initially developed a recurrence, whereas recurrences were more common among patients with advanced-stage disease, accounting for 80 (67.7%) cases. The median age of patients with recurrence was 60 years, with a median follow-up period of 46 months. The median OS time for patients with recurrence was 34 months ranging from 26.343 to 42.457 months. Univariate analysis revealed that nodal stage, salvage surgery, and time to recurrence were significant factors affecting OS. On multivariate analysis, salvage surgery and time to recurrence remained significant factors impacting survival. Conclusion: Salvage surgery and time to recurrence were identified as significant prognostic factors affecting survival outcomes in patients with OSCC experiencing locoregional recurrence. Salvage surgery significantly improves survival in oral cancer, where recurrence is usually detected more easily unlike other subsites. Patients with late recurrences demonstrated better survival outcomes. Tumours that recur early indicated poor oncological outcomes, suggesting an aggressive nature. Tumor biology is essential in guiding treatment options in recurrent settings.

Microtubule-Targeting Agents: Disruption of the Cellular Cytoskeleton as a Backbone of Ovarian Cancer Therapy.

Microtubules are dynamic polymers composed of α- and β-tubulin heterodimers. Microtubules are universally conserved among eukaryotes and participate in nearly every cellular process, including intracellular trafficking, replication, polarity, cytoskeletal shape, and motility. Due to their fundamental role in mitosis, they represent a classic target of anti-cancer therapy. Microtubule-stabilizing agents currently constitute a component of the most effective regimens for ovarian cancer therapy in both primary and recurrent settings. Unfortunately, the development of resistance continues to present a therapeutic challenge. An understanding of the underlying mechanisms of resistance to microtubule-active agents may facilitate the development of novel and improved approaches to this disease.

Exploring the Role of Circulating Tumor Cells in Contralateral Neck Metastasis

Background: The management of neck nodes in oral cavity cancers discernibly depends on the approach adopted for the primary tumor. There are abundant literature and consensus guidelines established for ipsilateral neck metastasis in small lateralized oral cavity cancers. However, the literature on the mechanism of contralateral neck metastasis and their management in recurrent settings is sparse. The current analysis aims at elucidating the role of circulating tumor cells (CTCs) in contralateral neck metastasis and the incidence of the same. Materials and Methods: We performed a retrospective cohort study to include all the patients with recurrent ipsilateral oral cavity squamous cell carcinoma who underwent treatment between January 2016 and October 2021. Various parameters were analyzed, and the data were curated to arrive at a conclusion. Results: The analysis of several parameters, including demographics of the patient, tumor site, individual tumor, lymph node, metastasis (TNM) category, depth of invasion (DOI), extra-nodal extension (ENE) status, CTCs, adjuvant treatment received after first surgery followed by TNM category, DOI, worst pattern of invasion, ENE, type of neck dissection, histological grading of tumor, perineural invasion, lymphovascular invasion, nodal yield, and number of nodes positive in the contralateral neck were studied in detail. Conclusion: The study showed a significant correlation between contralateral neck metastasis and CTCs.

Evaluation of ex vivo drug combination optimization platform in recurrent high grade astrocytic glioma: An interventional, non-randomized, open-label trial protocol.

High grade astrocytic glioma (HGG) is a lethal solid malignancy with high recurrence rates and limited survival. While several cytotoxic agents have demonstrated efficacy against HGG, drug sensitivity testing platforms to aid in therapy selection are lacking. Patient-derived organoids (PDOs) have been shown to faithfully preserve the biological characteristics of several cancer types including HGG, and coupled with the experimental-analytical hybrid platform Quadratic Phenotypic Optimization Platform (QPOP) which evaluates therapeutic sensitivity at a patient-specific level, may aid as a tool for personalized medical decisions to improve treatment outcomes for HGG patients. This is an interventional, non-randomized, open-label study, which aims to enroll 10 patients who will receive QPOP-guided chemotherapy at the time of first HGG recurrence following progression on standard first-line therapy. At the initial presentation of HGG, tumor will be harvested for primary PDO generation during the first biopsy/surgery. At the point of tumor recurrence, patients will be enrolled onto the main study to receive systemic therapy as second-line treatment. Subjects who undergo surgery at the time of recurrence will have a second harvest of tissue for PDO generation. Established PDOs will be subject to QPOP analyses to determine their therapeutic sensitivities to specific panels of drugs. A QPOP-guided treatment selection algorithm will then be used to select the most appropriate drug combination. The primary endpoint of the study is six-month progression-free survival. The secondary endpoints include twelve-month overall survival, RANO criteria and toxicities. In our radiological biomarker sub-study, we plan to evaluate novel radiopharmaceutical-based neuroimaging in determining blood-brain barrier permeability and to assess in vivo drug effects on tumor vasculature over time. This trial was registered on 8th September 2022 with ClinicalTrials.gov Identifier: NCT05532397.

Dispersive problem and control sets of linear control systems on Lie groups

This paper is dedicated to the study of dispersiveness and controllability of linear control systems on Lie groups. Dispersiveness means absence of recursiveness, that is contrary to the existence of control set. A linear control system on a Lie group associates with a derivation operator. For a linear system with stable derivation, it is shown that the system is dispersive if and only if the trajectories through the neutral element have no limit at infinity. As a consequence, a nonempty limit set at the neutral element is a necessary condition for the linear system to admit a control set or to be controllable. In the nondispersive case, the control sets are described by the Lie subgroup of all recurrent points of the automorphism flow of the system. If the derivation operator is asymptotically stable, the central limit set at the neutral element is the unique control set of the system.

Comparison of nonparametric estimators of the expected number of recurrent events.

We compare the performance of nonparametric estimators for the mean number of recurrent events and provide a systematic overview for different recurrent event settings. The mean number of recurrent events is an easily interpreted marginal feature often used for treatment comparisons in clinical trials. Incomplete observations, dependencies between successive events, terminating events acting as competing risk, or gaps between at risk periods complicate the estimation. We use survival multistate models to represent different complex recurrent event situations, profiting from recent advances in nonparametric estimation for non-Markov multistate models, and explain several estimators by using multistate intensity processes, including the common Nelson-Aalen-type estimators with and without competing mortality. In addition to building on estimation of state occupation probabilities in non-Markov models, we consider a simple extension of the Nelson-Aalen estimator by allowing for dependence on the number of prior recurrent events. We pay particular attention to the assumptions required for the censoring mechanism, one issue being that some settings require the censoring process to be entirely unrelated while others allow for state-dependent or event-driven censoring. We conducted extensive simulation studies to compare the estimators in various complex situations with recurrent events. Our practical example deals with recurrent chronic obstructive pulmonary disease exacerbations in a clinical study, which will also be used to illustrate two-sample-inference using resampling.

A Case Report on Prolonged Response with Trastuzumab Emtansine (T-DM1) in Recurrent Advance Breast Cancer Setting

Breast cancer holds the dubious distinction of being the most prevalent malignant tumor among women worldwide the 5 year survival rate for patients with advanced or metastatic forms of the disease is estimated at a mere 23%, with approximately 20% of cases exhibiting an amplification of the human epidermal growth factor receptor 2 (HER2). HER2 overexpression was linked to a dismal prognosis prior to the advent of targeted HER2 therapies. The introduction of ado-trastuzumab emtansine (T-DM1) has emerged as one of the standard treatment options for HER2-positive breast cancer patients who experience a recurrence or progression of the disease. This case concerns a patient with recurrent metastatic breast cancer who achieved an unusually extended period of time without the disease progressing while on T-DM1 treatment. After experiencing disease progression on multiple treatment lines involving trastuzumab, the patient achieved a nearly complete clinical remission (cCR) with T-DM1 therapy. The availability of cost-effective biosimilars has expanded access to advanced biologic therapies, which were previously limited to a small segment of the population due to the cost barrier.

10213-GMC-16 A DECADE REVIEW: BEVACIZUMAB'S IMPACT ON GLIOBLASTOMA TREATMENT

Abstract OBJECTIVE This study aims to assess the efficacy of Bevacizumab (Bev) therapy, ten years after its initiation in treating glioblastoma patients at our department. METHODS Eighty-four patients treated with Bev from July 2013 to December 2022 were classified into three groups: the initial treatment group given the Stupp regimen with Bev (first-dose group), the group given the Stupp regimen plus Bev followed by tumor resection (neoadjuvant group), and those receiving the Stupp regimen post tumor resection (recurrence group). PET scans were conducted pre- and post- Bev therapy, and variations in Tumor-to-Normal ratio (TNR), Tumor-to-Blood ratio (TBR), and Metabolic Tumor Volume (MTV) were investigated. RESULTS The median Progression-Free Survival (PFS) and Overall Survival (OS) rates in the first, neoadjuvant, and recurrence groups were respectively (7.86, 14.27, 4.33) and (12.53, 21.57, 13.23) months. Notably, changes in MET and FMISO MTV in the first-treatment group, MET MTV and FMISO TBR changes in the recurrence group, and MET MTV change in the neoadjuvant group significantly influenced prognosis. In the recurrence group, patients who underwent total resection during initial treatment experienced a prolonged period of 25.9 months from initial treatment to the administration of Bev due to recurrence. Furthermore, cases where the FMISO TBR at recurrence was higher than at the initial treatment observed an extended median OS of 18.63 months upon administering Bev treatment at recurrence. CONCLUSION Bev neoadjuvant therapy demonstrated a significant correlation with enhanced PFS and OS outcomes, notably in patients subjected to total resection. In the context of recurrent disease, while the initiation of Bev administration was delayed, a distinct elevation in treatment effectiveness was observed in patients exhibiting an augmented FMISO TBR at the point of recurrence. The observed decreases in MET MTV and FMISO TBR emerge as robust predictors of the efficacy of Bev treatment.

AI-Based Risk Score from Tumour-Infiltrating Lymphocyte Predicts Locoregional-Free Survival in Nasopharyngeal Carcinoma.

Locoregional recurrence of nasopharyngeal carcinoma (NPC) occurs in 10% to 50% of cases following primary treatment. However, the current main prognostic markers for NPC, both stage and plasma Epstein-Barr virus DNA, are not sensitive to locoregional recurrence. We gathered 385 whole-slide images (WSIs) from haematoxylin and eosin (H&E)-stained NPC sections (n = 367 cases), which were collected from Sun Yat-sen University Cancer Centre. We developed a deep learning algorithm to detect tumour nuclei and lymphocyte nuclei in WSIs, followed by density-based clustering to quantify the tumour-infiltrating lymphocytes (TILs) into 12 scores. The Random Survival Forest model was then trained on the TILs to generate risk score. Based on Kaplan-Meier analysis, the proposed methods were able to stratify low- and high-risk NPC cases in a validation set of locoregional recurrence with a statically significant result (p < 0.001). This finding was also found in distant metastasis-free survival (p < 0.001), progression-free survival (p < 0.001), and regional recurrence-free survival (p < 0.05). Furthermore, in both univariate analysis (HR: 1.58, CI: 1.13-2.19, p < 0.05) and multivariate analysis (HR:1.59, CI: 1.11-2.28, p < 0.05), we also found that our methods demonstrated a strong prognostic value for locoregional recurrence. The proposed novel digital markers could potentially be utilised to assist treatment decisions in cases of NPC.

Is There a Place for Brachytherapy in Vulvar Cancer? A Narrative Review

Vulvar cancer is a relatively rare neoplasm. The essential treatment is surgery for the primary tumour. However, postoperative recurrence rates are high, even in early-stage disease when tumour-free surgical margins are achieved or in the absence of associated risk factors (lymph node metastases, deep stromal invasion or invasion of the lymphatic vascular space). Radiotherapy plays an important role in the treatment of vulvar cancer. Adjuvant treatment after surgery as well as primary treatment of locally advanced vulvar cancer (LAVC) is composed of two key radiotherapy treatment scenarios, external beam radiation therapy (EBRT) either combined or not combined with brachytherapy (BT). In a recurrence setting, where surgery is not an option, BT alone or in combination with EBRT can be used. Compared to EBRT, BT has the radiobiological potential to improve dose to the target volume, minimise the dose to organs at risk, and facilitate hypofractionated-accelerated treatment. This narrative review presents recent data on the role of BT in the treatment of primary and/or recurrent vulvar cancer, including radiobiological, clinical, and therapeutic aspects.

Relatively pointwise recurrence on local dendrites

Let X be a local dendrite and let f : X → X be a continuous map. Denote by P ( f ) and R ( f ) the sets of periodic and recurrent points of f, respectively. We say that f is relatively pointwise recurrent if R ( f ) ¯ = X . We show that, if X is almost meshed (i.e the union of the interior of all free arcs is dense in X), then f is relatively pointwise recurrent if and only if either f is topologically conjugate to an irrational rotation on the circle or it has a dense set of periodic points.