Recurrent Setting Research Articles

Viral infections in pediatric brain tumor patients treated with targeted therapies.

Brain tumors are the most common solid malignancies and the leading cause of cancer-related mortality in children. While numerous studies report on viral infections in children with hematologic malignancies and solid organ transplantation, epidemiologic data on the incidence and outcome of viral infections in pediatric patients with brain tumors treated with targeted therapies are still lacking. We retrospectively reviewed all children with brain tumors receiving targeted therapies in a primary or recurrent setting at the Medical University of Vienna from 2006 to 2021. Demographic variables, quantitative and qualitative parameters of possible infections, and treatment outcomes were recorded. In our cohort (n=117), 36% of the patients developed at least one PCR-proven viral infection. Respiratory and gastrointestinal tract infections were most common, with 31% and 25%, respectively. Central nervous system (CNS) infections occurred in approximately 10%, with an almost equal distribution of varicella-zoster virus, John Cunningham virus (JCV), and enterovirus. Two patients tested PCR-positive for SARS-CoV-2 infection, with one virus-related death caused by a SARS-CoV-2-related acute respiratory distress syndrome. Patients receiving bevacizumab or mTOR inhibitors seem to have a greater susceptibility to viral infections. Pediatric patients with brain tumors receiving targeted therapies have a higher risk of viral infections when compared to children receiving conventional chemotherapy or the general population, and life-threatening infections can occur. Fast detection and upfront treatment are paramount to prevent life-threatening infections in immunocompromised children suffering from brain tumors receiving targeted therapies.

Prospectively Observed Histopathologic Predictors of Progression after Stereotactic Radiosurgery for Recurrent Atypical Meningioma

<h3>Purpose/Objective(s)</h3> Atypical meningiomas (AM) have high rates of progression and recurrence after initial treatment. Optimal management of recurrent AM remains an unresolved issue. In turn, we sought to correlate histopathologic findings of AM at initial resection with survival outcomes after stereotactic radiosurgery (SRS) for treatment of recurrent disease. <h3>Materials/Methods</h3> Prospectively enrolled radiation-naïve patients who were treated with SRS for recurrent AM between 2014 and 2020 were retrospectively reviewed in our institutional review board (IRB) approved database. Kaplan-Meier analysis with log rank testing was used to compare local control and survival in patients with varying histopathological features and Cox regression was used to examine possible prognostic factors for progression after SRS. <h3>Results</h3> Two hundred and seventy-seven patients with meningioma were treated with SRS from 2014 to 2020. Of these, 49 were identified who underwent resection for an atypical meningioma at our institution and then received salvage SRS for first recurrence. Forty-five (92%) patients received salvage radiation after recurrence following a subtotal resection (STR) and four patients (8%) received salvage radiation for recurrent disease after an initial gross total resection (GTR). Patients receiving salvage SRS underwent treatment for recurrent disease at a mean time of 23 months after surgery. Tumor size was not associated with progression after SRS treatment. On univariable analysis, presence of necrosis, presence of brain invasion, and presence of bone invasion predicted for progression. At 2 years, patients treated with SRS had a local control rate of 93%. In the subset of patients found to have necrosis, bone invasion, or brain invasion on surgical pathology, local control at 2 years was 81%. <h3>Conclusion</h3> Histopathologic variables can predict for treatment outcomes of recurrent atypical meningioma treated with radiotherapy and should be considered when deciding on an individual patient's treatment plan in the setting of recurrence. Brain and bone invasion as well as presence of necrosis predict for decreased local control after SRS. Future investigation is warranted to optimize outcomes in this group.

Characterization of Immune Infiltrates Associated with Radiation Necrosis in the Setting of Brain Metastases Following Stereotactic Radiosurgery and Immunotherapy

<h3>Purpose/Objective(s)</h3> Radiation necrosis (RN) represents an inflammatory sequel and hyalinization secondary to radiotherapy (RT). The impact of immunotherapy on immune cellular microenvironment in patients with brain metastasis (BM) is unknown. The objective of this study was to characterize the inflammatory microenvironment in the setting of RN compared to recurrent tumor and determine whether immunotherapy treatment affects cellular infiltrates. <h3>Materials/Methods</h3> Adult patients with BM from solid tumors who received both systemic immunotherapy (IO) and radiotherapy (RT) who then underwent resection for progressively enlarging abnormality following IO+RT were retrospectively analyzed. A group of BM patients who developed RN confirmed by surgery and who did not receive IO was reviewed as control. Surgical specimens were stained for immune and inflammatory components and reviewed by a neuro-pathologist who remained blinded during the analysis. The presence or absence of lymphocytes, cuffing, plasma cells, macrophages, and fibrinoid were used as surrogates of immune infiltrate and were characterized in a semiquantitative manner. <h3>Results</h3> A total of 18 patients were categorized into 1 of 3 groups: (1) Necrosis, IO+RT (2) Tumor, IO+RT (3) Necrosis, RT. The median age was 61.5 years (range 37-82 years). 77% of primary cancers were melanoma. Review of surgical specimens demonstrated a higher but not statistically significant extent of immune infiltrates in the groups with RN when compared to the group with tumor recurrence. Higher lymphocytes, cuffing, and macrophages were found in "Necrosis, IO+RT" patients compared to "Tumor, IO+RT" patients (83.3% and 16.7%, respectively). Further analysis demonstrated 100% of "Necrosis, IO+RT" patients have quantifiable cell counts while 83.3% of "Tumor, IO+RT" patients do not have quantifiable cell counts. <h3>Conclusion</h3> The immune microenvironment of BM following radiotherapy and immunotherapy shows higher levels of cell infiltrates in the RN setting versus recurrent tumor setting. Lower level of presence of immune cells in tumor recurrence following IO+RT may suggest an environment lacking primed immune cells with implication to potential decreased efficacy in immunotherapy.

Atezolizumab and Stereotactic Body Radiation Therapy in Metastatic, Recurrent or Persistent Cervical Cancer: Interim Results from a Non-Randomized, Open-Label Phase II Multi-Institutional Study

<h3>Purpose/Objective(s)</h3> Inhibition of the anti-PD-1/PD-L1 axis has been approved in the metastatic, recurrent, or persistent settings for cervical cancer. Stereotactic body radiation therapy (SBRT) has a well-defined role in the management of oligometastatic disease. There may be potential synergy between stereotactic radiation and anti-PD-1/PD-L1 checkpoint inhibition in advanced cervical cancer. We hypothesize treatment with atezolizumab and SBRT will be well tolerated and may improve tumor control rates compared to atezolizumab alone in the management of metastatic, recurrent, or persistent cervical cancer. <h3>Materials/Methods</h3> The study is designed as a prospective, single arm, nonrandomized, open-label, phase II multi-institutional trial of SBRT with 24 Gy in 3 fractions to patients with ≥ 2 metastatic sites followed 1 week later by atezolizumab (1200 mg IV every 3 weeks) for patients with recurrent, persistent, or metastatic cervical cancer. The primary objective of the study is to evaluate the objective response rate by immune-related response evaluation criteria in solid tumors (irRECIST) criteria following SBRT and atezolizumab at the unirradiated target lesion. Secondary endpoints include progression free survival (PFS), overall survival (OS), and adverse events. Results of the pre-planned interim analysis are reported. Clinical trial information: NCT03614949. <h3>Results</h3> Between January 2019 and September 2021, a total of 13 patients were enrolled. The majority of patients had adenocarcinoma (n=9; 69%) with a median age of 50 (range: 36-69). Median number of lines of prior therapy was 2 (range: 1-5). Median follow-up is 18 months (range: 2.7-35.8 months). The median PFS was 4.5 months (95% CI: 3.87- Not reached) with a 6-month PFS of 46%. The median OS was 11 months (95% CI 7.77 – Not reached) with a 6-month OS of 84%. The overall response (irRECIST) was a partial response in 3 (23%) and stable disease in 4 (31%) patients. An objective response was observed in 2 patients meeting criteria to move to the stage II portion of the trial. Study therapy was well tolerated with no patients discontinuing therapy due to side effects. The most common grade ≥2 toxicities at least possibly attributed to study therapy included lymphopenia (n=4; 31%), fatigue (n=3; 23%), and hypothyroidism (n=2; 15%). <h3>Conclusion</h3> Atezolizumab and SBRT was well tolerated in the first stage of the phase II trial. Objective responses were noted in two patients meeting the pre-planned criteria to warrant opening of the second stage of the study.

Stereotactic Body Radiation Therapy is Safe and Feasible for the Treatment of Locally Recurrent Pancreatic Adenocarcinoma after Curative Resection

<h3>Purpose/Objective(s)</h3> Locoregional relapse rates following surgical resection of pancreatic cancer can be as high as 45-50%. The majority of these patients are not candidates for re-resection due to co-morbidities and/or technically unresectable disease, highlighting the role of non-invasive options such as radiation therapy. The purpose of this study was to report on a cohort of radiation-naïve patients who developed isolated local recurrence following surgical resection and were subsequently treated with stereotactic body radiation therapy (SBRT). <h3>Materials/Methods</h3> Patients who were treated with SBRT for locally recurrent pancreatic cancer after initial curative resection were retrospectively reviewed. Clinical outcomes were calculated from completion of SBRT and included overall survival (OS), local progression-free survival (LPFS), distant metastasis-free survival (DMFS), and progression-free survival (PFS). Univariate and multivariate analyses were performed to identify variables associated with clinical outcomes. Kaplan-Meier analysis was performed for survival outcomes. Toxicity was assessed using the Common Terminology Criteria for Adverse Events version 4.0. <h3>Results</h3> From September 2012 to November 2018, a total of 19 patients were treated with SBRT for locally recurrent pancreatic cancer after initial surgical resection. No patients had prior radiation. The most common SBRT dose/fractionation was 33 Gy in 5 fractions (12/19, 63.1 %), followed by 25 Gy in 5 fractions (4/19, 21.0%), 28 Gy in 5 fractions (1/19, 5.3%), 27 Gy in 4 fractions (1/19, 5.3%), and 26.4 Gy in 4 fractions (1/19, 5.3%). Peri-SBRT chemotherapy was administered to 10 patients, in the pre-SBRT (3/19, 15.7%) and/or post-SBRT (8/19, 42.1%) setting. Median OS was 17.1 months, with 6-month and 1-year OS rates of 94.4% and 69.6%, respectively. A total of 9 patients (47.4%) developed local failure after SBRT. Pattern of first failure after SBRT was distant in 7 patients (46.7%), local in 5 patients (33.3%), and synchronous distant and local in 3 patients (20.0%). One patient developed local failure after developing distant disease first. Of the 9 local failures, 3 (33.3%) were out-of-field, involving the porta hepatis (n=1), pancreaticojejunostomy (n=1), and pancreatic remnant (n=1). Median LPFS was 22.2 months, with 6-month and 1-year LPFS rates of 86.9% and 63.2%, respectively. A biologically effective dose (BED₁₀) < 54.8 Gy was associated with inferior LPFS (1-year LPFS, 25.0% vs 80.2%, p<0.009). Median DMFS and PFS were 15.6 months. There was 1 case (5.3 %) of grade 3 gastric perforation. There were no cases of grade 4-5 toxicity events. <h3>Conclusion</h3> Stereotactic body radiation therapy for local recurrence after initial curative resection is safe and feasible. A BED₁₀ < 54.8 Gy was significantly associated with inferior local control, and one-third of local failures were out-of-field. Further studies investigating dose escalation and optimal treatment volumes in the locally recurrent setting are warranted.

Recapitulating the Pharmacological Interactions of Cetuximab with Sunitinib and Cisplatin in Head and Neck Carcinoma Cells in vitro

Introduction: Cisplatin is extensively used in the treatment of head and neck carcinomas. Cetuximab combination therapy is employed in recurrent and metastatic settings. Sunitinib showed positive results in the treatment of head and neck carcinomas, both as monotherapy or in combination with cetuximab. Nonetheless, the mechanism governing these pharmacological interactions is largely unresolved. This study investigates the impact of cetuximab on the cytotoxicity of cisplatin and sunitinib using cells representative of head and neck carcinoma and the oral epithelium. Methods: The uptake and efflux activities of cells were determined using the prototypical fluorescent substrates 4-[4-[dimethylamino]styryl)-1-methyl pyridinium iodide, Hoechst 33342, and calcein-AM in the presence or absence of specific inhibitors in cells pretreated with cetuximab. The expression of key uptake and efflux drug transporters was analyzed using qPCR and immunofluorescence. Cisplatin and sunitinib cytotoxicities after cetuximab pretreatment were evaluated using the PrestoBlue viability assay. Results: Both tumor and nontumor cells showed significant active drug transport activity. Cetuximab substantially deregulated the expression of key transporters involved in drug resistance in head and neck cancer cells. Transporter expression in the nontumor cell was unaffected. Upon cetuximab pretreatment, the half maximal effective toxic concentration of cisplatin was reduced by 0.75-fold and sunitinib by 0.82-fold in cancer cells. Nontumor cells were not sensitive to cisplatin or sunitinib under the conditions tested. Conclusion: Cetuximab regulates the expression and activity of key membrane drug transporters in head and neck cancer cells, involved in drug resistance. The deregulation of the transport mechanism behind cisplatin and sunitinib uptake reverses drug resistance and enhances the cytotoxicity of both drugs.

Distinct roles of treatment schemes and BRCA2 on the restoration of homologous recombination DNA repair and PARP inhibitor resistance in ovarian cancer.

Poly (ADP-ribose) polymerase inhibitors (PARPis) represent a major advance in ovarian cancer, now as a treatment and as a maintenance therapy in the upfront and recurrent settings. However, patients often develop resistance to PARPis, underlining the importance of dissecting resistance mechanisms. Here, we report different dosing/timing schemes of PARPi treatment in BRCA2-mutant PEO1 cells, resulting in the simultaneous development of distinct resistance mechanisms. PARPi-resistant variants PEO1/OlaJR, established by higher initial doses and short-term PARPi treatment, develops PARPi resistance by rapidly restoring functional BRCA2 and promoting drug efflux activity. In contrast, PEO1/OlaR, developed by lower initial doses with long-term PARPi exposure, shows no regained BRCA2 function but a mesenchymal-like phenotype with greater invasion ability, and exhibits activated ATR/CHK1 and suppressed EZH2/MUS81 signaling cascades to regain HR repair and fork stabilization, respectively. Our study suggests that PARPi resistance mechanisms can be governed by treatment strategies and have a molecular basis on BRCA2 functionality. Further, we define different mechanisms that may serve as useful biomarkers to assess subsequent treatment strategies in PARPi-resistant ovarian cancer.

Single-fraction prostate-specific membrane antigen positron emission tomography- and multiparametric magnetic resonance imaging-guided stereotactic body radiotherapy for prostate cancer local recurrences.

To analyse the efficacy and safety of focal prostate-specific membrane antigen positron emission tomography (PSMA-PET)- and multiparametric magnetic resonance imaging (mpMRI)-guided single-fraction stereotactic body radiotherapy (SBRT) for the treatment of prostate cancer (PCa) local recurrences. Patients with PSMA-PET-positive PCa local recurrences treated with single-fraction SBRT between 2016 and 2020 were included. Identification for subsequent recurrences or metastatic spread based on increasing prostate-specific antigen (PSA) levels were evaluated using PSMA-PET imaging. A total of 64 patients were identified. Patients received various treatments before SBRT (31 patients with radical prostatectomy [RP], 18 external beam radiotherapy [EBRT] with RP, five EBRT, and the remaining 10 other combinations). The median follow-up was 21.6 months. The median PSA level before SBRT was 1.47 ng/mL. All patients received a single-fraction treatment with a median prescription dose and isodose line of 21 Gy and 65%, respectively. At the time of SBRT, six patients (9%) received an androgen deprivation therapy (ADT). PSA levels decreased after SBRT (P = 0.03) and three local recurrences were detected during the follow-up. The progression-free survival after 1-, 2-, and 3-years was 85.3%, 65.9%, and 51.2%, respectively. Six patients (9%) started ADT after SBRT due to disease progression. The rates of newly started ADT after 1-, 2-, and 3-years were 1.8%, 7.3%, and 22.7%, respectively. Grade 1 or 2 toxicities occurred in six patients (9%); no high-grade toxicity was observed. While the available data for SBRT in the PCa local recurrence setting describe outcomes for fractionated irradiations, the findings of this first analysis of single-fraction, PSMA-PET- and mpMRI-guided focal SBRT are encouraging. Such treatment appears to be a safe, efficient, and time-saving therapy even in intensively pretreated patients. Recurrence-directed treatments can delay the use of ADT and could avoid prostate bed irradiation in selected patients.

Transcriptomic Analysis of Cirrhosis-Like Hepatocellular Carcinoma Reveals Distinct Molecular Characteristics and Pathologic Staging Implications.

Cirrhosis-like hepatocellular carcinoma (CL-HCC) is a rare hepatocellular malignancy characterized by multiple tumor nodules that clinically, radiologically, macroscopically, and microscopically mimic cirrhosis. We aimed to elucidate the molecular biology of CL-HCC and determine tumor nodule clonality. We performed RNA sequencing on formalin-fixed, paraffin-embedded tissue from confirmed CL-HCC cases (n = 6), along with corresponding nonneoplastic hepatic tissue (n = 4) when available. Transcriptomes from our previous work on steatohepatitic hepatocellular carcinoma and The Cancer Genome Atlas (TCGA) were used for comparison purposes. Histologically, CL-HCC displayed innumerable nodules and extensive vascular invasion. Intratumoral nodule comparison indicated that the multiple nodules were all clonally related, not independent primaries. The unique histomorphologic appearance corresponded with a distinct transcriptome compared with other HCCs, including fibrolamellar HCC (n = 6), steatohepatitic HCC (n = 8), and conventional HCC in TCGA (n = 424). Tumor-normal gene expression analysis revealed consistent overexpression of several genes involved in degradation of tissue matrix. No recurrent translocations or point mutations were identified. CL-HCC showed a gene expression profile indicative of zone 2 hepatocytes. CL-HCC's distinctive clinicopathologic features correspond to a unique gene expression profile, increased expression of invasive markers, features of zone 2 hepatocytes, and features suggestive of intratumoral nodule monoclonality.

SC12 - The impact of histological variants on the performance characteristics of 68Ga-PSMA PET/CT in the primary and recurrent setting

SC12 - The impact of histological variants on the performance characteristics of 68Ga-PSMA PET/CT in the primary and recurrent setting

Impact of salvage surgery for recurrent sinonasal cancers with skull base and intracranial involvement.

Patients with recurrent sinonasal cancers (RSNCs) often present with extensive involvement of the skull base and exhibit high rates of subsequent recurrence and death after therapy. The impact of salvage surgery and margin status on progression-free survival (PFS) and overall survival (OS) has yet to be demonstrated. The goal of this study was to determine whether skull base resection with negative margins has an impact on outcomes in the recurrent setting. A retrospective chart review of 47 patients who underwent surgery for RSNC with skull base invasion between November 1993 and June 2020 was conducted. The following variables were extracted from the clinical records: patient demographic characteristics (age and sex), tumor pathology, dural and orbital invasion, and prior radiation exposure and induction chemotherapy. Metastatic disease status, surgical approach, margin status, and history of postoperative chemotherapy and/or postoperative radiation therapy were noted. The primary and secondary outcomes were PFS and OS, respectively. The cohort included 30 males (63.8%) and 17 females (36.2%), with a mean ± SD age of 54.8 ± 14.4 years. Thirty-five (74.5%) patients showed disease progression, and 29 (61.7%) patients died during the study period. The mean ± SD patient follow-up period was 61.8 ± 64.4 months. Dural invasion was associated with increased risk of death (HR 2.62, 95% CI 1.13-6.08). High-risk histopathology (HR 3.14, 95% CI 1.10-8.95) and induction chemotherapy (HR 2.32, 95% CI 1.07-5.06) were associated with increased odds of disease progression. When compared to patients with positive margins or gross-total resection with unknown margin status, those with negative margins had decreased odds of disease progression (HR 0.30, 95% CI 0.14-0.63) and death (HR 0.38, 95% CI 0.17-0.85). RSNCs show high rates of subsequent disease progression and mortality. This study demonstrated that negative margins may be associated with improved PFS and OS in carefully selected patients who have undergone salvage surgery for RSNC.

221 (PB101) - Phase I/II study of a novel MDM-2 inhibitor (APG-115) in TP53 wild type salivary gland cancers

Background: Malignant salivary gland cancers (SGC) are rare tumors of the head and neck with no approved therapeutics in the recurrent and/or metastatic setting. The most common histology is adenoid cystic carcinoma (ACC) and the median progression free survival (mPFS) in patients with untreated disease is 2.8 months (mo). MDM2 gene amplifications are common in these tumors and preclinical evidence supports the activity of MDM2 inhibitors both as monotherapy and in combination with chemotherapy.

The Therapeutic Potential of Imidazole or Quinone-Based Compounds as Radiosensitisers in Combination with Radiotherapy for the Treatment of Head and Neck Squamous Cell Carcinoma.

Simple SummaryPatients with curable head and neck cancers are usually treated with a combination of chemotherapy and radiotherapy, but they experience significant, severe side effects, which greatly affect their quality of life. Some of these patients still experience disease relapse after an intensive course of treatment due to tumours that are resistant to radiotherapy and chemotherapy because of hypoxia (lack of oxygen). In addition, some patients are not suitable for and/or are not able to have combined chemotherapy with radiotherapy due to their age or other physical conditions. Certain small-molecule drugs, which are used to treat various infections including malaria, have been shown to reduce hypoxia and thus make radiotherapy more effective. Therefore, their combination with radiotherapy could have less toxicities compared with the combination of chemotherapy with radiotherapy. Here, we discuss the promising results from preclinical work and clinical trials of these agents, and their potential use in the clinic, to reduce hypoxia and to sensitise radiotherapy. These agents could potentially be used for patients who are not suitable for combined chemotherapy and radiotherapy; they may also be used to reduce the dose of radiotherapy if able to enhance radiotherapy effect at lower dose in order to reduce toxicities while maintaining the treatment efficacy in a more personalised manner. The addition of platinum chemotherapy to primary radiotherapy (chemoradiation) improves survival outcomes for patients with head and neck squamous cell carcinoma (HNSCC), but it carries a high incidence of acute and long-term treatment-related complications, resulting in a poor quality of life. In addition, patients with significant co-morbidities, or older patients, cannot tolerate or do not benefit from concurrent chemoradiation. These patients are often treated with radiotherapy alone resulting in poor locoregional control and worse survival outcomes. Thus, there is an urgent need to assess other less toxic treatment modalities, which could become an alternative to chemoradiation in HNSCC. Currently, there are several promising anti-cancer drugs available, but there has been very limited success so far in replacing concurrent chemoradiation due to their low efficacy or increased toxicities. However, there is new hope that a treatment strategy that incorporates agents that act as radiosensitisers to improve the efficacy of conventional radiotherapy could be an alternative to more toxic chemotherapeutic agents. Recently, imidazole-based or quinone-based anti-malarial compounds have drawn considerable attention as potential radiosensitisers in several cancers. Here, we will discuss the possibility of using these compounds as radiosensitisers, which could be assessed as safe and effective alternatives to chemotherapy, particularly for patients with HNSCC that are not suitable for concurrent chemotherapy due to their age or co-morbidities or in metastatic settings. In addition, these agents could also be tested to assess their efficacy in combination with immunotherapy in recurrent and metastatic settings or in combination with radiotherapy and immunotherapy in curative settings.

Special cases and equivalent forms of Katznelson’s problem on recurrence

We make the following three observations regarding a question popularized by Katznelson: is every subset of \({\mathbb {Z}}\) which is a set of Bohr recurrence also a set of topological recurrence? (i) If G is a countable abelian group and \(E\subseteq G\) is an \(I_0\) set, then every subset of \(E-E\) which is a set of Bohr recurrence is also a set of topological recurrence. In particular every subset of \(\{2^n-2^m : n,m\in {\mathbb {N}}\}\) which is a set of Bohr recurrence is a set of topological recurrence. (ii) Let \({\mathbb {Z}}^{\omega }\) be the direct sum of countably many copies of \({\mathbb {Z}}\) with standard basis E. If every subset of \((E-E)-(E-E)\) which is a set of Bohr recurrence is also a set of topological recurrence, then every subset of every countable abelian group which is a set of Bohr recurrence is also a set of topological recurrence. (iii) Fix a prime p and let \({\mathbb {F}}_p^\omega \) be the direct sum of countably many copies of \({\mathbb {Z}}/p{\mathbb {Z}}\) with basis \(({\mathbf {e}}_i)_{i\in {\mathbb {N}}}\). If for every p-uniform hypergraph with vertex set \({\mathbb {N}}\) and edge set \({\mathcal {F}}\) having infinite chromatic number, the Cayley graph on \(\mathbb F_p^\omega \) determined by \(\{\sum _{i\in F}{\mathbf {e}}_i:F\in {\mathcal {F}}\}\) has infinite chromatic number, then every subset of \(\mathbb F_p^\omega \) which is a set of Bohr recurrence is a set of topological recurrence.

Capecitabine-A "Permanent Mission" in Head and Neck Cancers "War Council"?

Capecitabine, an oral pro-drug that is metabolized to 5-FU, has been used in clinical practice for more than 20 years, being part of the therapeutic standard for digestive and breast cancers. The use of capecitabine has been evaluated in many trials including cases diagnosed in recurrent or metastatic settings. Induction regimens or a combination with radiation therapy were evaluated in head and neck cancers, but 5-FU still remained the fluoropyrimidine used as a part of the current therapeutic standard. Quantifications of levels or ratios for enzymes are involved in the capecitabine metabolism to 5-FU but are also involved in its conversion and elimination that may lead to discontinuation, dose reduction or escalation of treatment in order to obtain the best therapeutic ratio. These strategies based on biomarkers may be relevant in the context of the implementation of precision oncology. In particular for head and neck cancers, the identification of biomarkers to select possible cases of severe toxicity requiring discontinuation of treatment, including “multi-omics” approaches, evaluate not only serological biomarkers, but also miRNAs, imaging and radiomics which will ensure capecitabine a role in both induction and concomitant or even adjuvant and palliative settings. An approach including routine testing of dihydropyrimidine dehydrogenase (DPD) or even the thymidine phosphorylase (TP)/DPD ratio and the inclusion of miRNAs, imaging and radiomics parameters in multi-omics models will help implement “precision chemotherapy” in HNC, a concept supported by the importance of avoiding interruptions or treatment delays in this type of cancer. The chemosensitivity and prognostic features of HPV-OPC cancers open new horizons for the use of capecitabine in heavily pretreated metastatic cases. Vorinostat and lapatinib are agents that can be associated with capecitabine in future clinical trials to increase the therapeutic ratio.

Is every pseudo-orbit of some homeomorphism near an exact orbit of a nearby homeomorphism?

We propose a relaxed notion of shadowing. In particular, for a homeomorphism f on a metric space, we ask whether every approximate orbit is near some actual orbit of some nearby system. We distinguish the cases where the nearby homeomorphism is close or arbitrarily close to f. We prove the relations between these notions and ordinary shadowing and present various examples. We finally discuss an application, a \(C^0\)-closing lemma for chain recurrent points of a homeomorphism on a topological manifold, not necessarily compact. This result leads to a characterization of explosion phenomena for various recurrent sets on such manifolds.

Progression-free survival and overall survival after BRCA1/2-associated epithelial ovarian cancer: A matched cohort study.

Germline BRCA1/2-associated epithelial ovarian cancer has been associated with better progression-free survival and overall survival than sporadic epithelial ovarian cancer, but conclusive data are lacking. We matched 389 BRCA1-associated and 123 BRCA2-associated epithelial ovarian cancer patients 1:1 to sporadic epithelial ovarian cancer patients on year of birth, year of diagnosis, and FIGO stage (< = IIA/> = IIB). Germline DNA test was performed before or after epithelial ovarian cancer diagnosis. All patients received chemotherapy. We used Cox proportional hazards models to estimate the associations between mutation status (BRCA1 or BRCA2 versus sporadic) and progression-free survival and overall survival. To investigate whether DNA testing after epithelial ovarian cancer diagnosis resulted in survival bias, we performed additional analyses limited to BRCA1/2-associated epithelial ovarian cancer patients with a DNA test result before cancer diagnosis (n = 73 BRCA1; n = 9 BRCA2) and their matched sporadic controls. The median follow-up was 4.4 years (range 0.1-30.1). During the first three years after epithelial ovarian cancer diagnosis, progression-free survival was better for BRCA1 (HR 0.88, 95% CI 0.74-1.04) and BRCA2 (HR 0.58, 95% CI 0.41-0.81) patients than for sporadic patients. Overall survival was better during the first six years after epithelial ovarian cancer for BRCA1 (HR 0.7, 95% CI 0.58-0.84) and BRCA2 (HR 0.41, 95% CI 0.29-0.59) patients. After surviving these years, survival benefits disappeared or were in favor of the sporadic patients. For epithelial ovarian cancer patients who received chemotherapy, we confirmed survival benefit for BRCA1 and BRCA2 germline pathogenic variant carriers. This may indicate higher sensitivity to chemotherapy, both in first line treatment and in the recurrent setting. The observed benefit appears to be limited to a relatively short period after epithelial ovarian cancer diagnosis.

The changing role for extended resections in an era of advanced radiotherapy techniques and novel therapies in gynaecological malignancy

Pelvic exenteration, first described in 1948 and subsequently refined, may be offered as a last hope of cure to patients with recurrent or locally advanced pelvic tumours, where radiotherapy is not an option. It is a complex, morbid, ultra-radical procedure involving en-bloc resection of the female reproductive organs, lower urinary tract, and a portion of the rectosigmoid.This article discusses the evolution of and current indications for pelvic exenteration in gynaecologic oncology as well as the reasons for its decline: primary and secondary prevention of cervical cancer (the recurrence of which is the most common indication for exenteration); improvements in treatment of cervical, endometrial, vaginal and vulvar cancer in the primary and recurrent setting; and the advent of novel therapies.

Abstract B004: ATR-CHK1-WEE1 pathway is a critical dependency in the context of DNA damage and replicative stress in osteosarcoma

Abstract Osteosarcoma (OS) is characterized by widespread somatic copy number alterations (SCNAs) and structural variations (SVs) with few recurrent point mutations. We previously demonstrated proof-of-principle for a genome-informed strategy for treatment of OS based on rank-ordering SCNAs within specific oncogenes identified by WGS and RNAseq. Although we identified several potentially effective therapeutic strategies using this approach, it is likely that effective therapy for OS will require use of combination therapies. To identify new combination therapy approaches for OS, we used a panel of PDX-derived cell lines (PDXC) and performed a combination drug screen. We assessed 5 drug backbones against 15 targeted agents in 8 PDXC and 2 established OS cell lines. When we combined Gemcitabine with agents that target the ATR-CHK1-WEE1 pathway, we observed strong synergy across all PDXC tested. These results were validated in a secondary screen using a combination matrix across 10 PDXC. Use of targeted agents inhibiting ATR, CHK1 or WEE1 in combination with Gemcitabine led to decreased proliferation and a marked increase in apoptosis in vitro. In subcutaneous tumor models, we observed that decreased tumor growth with either ATRi or Gemcitabine alone, whereas tumors shrank when treated with the combination. However, when we treated OS774 in vivo, there was no effect on tumor growth for either single agent alone or when in combination. This effect was dependent on the presence of ATR as a PDXC with no ATR detectable by western blotting showed not effect in vivo. In an orthotopic model in which PDXC are implanted along the tibia, this combination therapy effectively decreased tumor growth. In a lung metastasis model, ATRi and Gemcitabine resulted a durable reduction in metastatic lesions over time. In summary, we have identified a susceptibility to the ATR-CHK1-WEE1 pathway when combined with gemcitabine. These studies suggest that further investigation ATR-CHK1-WEE1 and gemcitabine are warranted to address the unmet need for new therapeutic approaches for relapsed and recurrent OS patients. Citation Format: Leanne C. Sayles, Henry Martell, Amanda Koehne, Kean-Hooi Ang, Chris Wilson, Michelle Arkin, E. Alejandro Sweet-Cordero. ATR-CHK1-WEE1 pathway is a critical dependency in the context of DNA damage and replicative stress in osteosarcoma [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr B004.

P17.09.A Regorafenib and Re-irradiation: analysis of clinical outcomes and toxicities in patients with recurrent glioblastomas

Abstract Background Glioblastoma is the most common and aggressive primary brain tumor in adults.The aggressiveness and poor prognosis related to this disease join to the limited available treatment options. The current standard of care involves surgical resection followed by concomitant radiotherapy and chemotherapy. At recurrence, no standard treatment exists and there are no guidelines to facilitate decisions in the recurrent setting. Available options include re-operation, re-irradiation, systemic therapy, alone or in combination. In recent years, immunotherapy strategies have revolutionized the treatment of many cancers, increasing the hope for GBM therapy. Regorafenib (Stivarga) is an inhibitor of several kinases involved in the mechanisms that regulate neoangiogenesis processes, through the inhibition vascular endothelial growth factor (VEGF) receptors and the modifications of the tumor microenvironment; specifically, Regorafenib binds and stabilizes PSAT1 (phosphoserine aminotransferase 1). The dual regulatory mechanism underlying PSAT1-induced autophagy arrest accounts for the superior anti-GBM effect of Regorafenib compared with Temozolomide. Material and Methods 15 patients with documented disease progression after surgery followed by RT and TMZ were assigned to receive regorafenib (REG) 160 mg once daily for the first 3 weeks of each 4-week cycle. All patients received prior radiation therapy (RT) to a median dose of 60 Gy (range 40.05 -60). Median time to retreatment after prior RT was 16 months (range 14-33). Tumor volumes ranged from 81.7 cm3 to 422.4 cm3 (CTV) and from 112.7 cm3 to 422.4 cm3 (PTV).3 patients (20%) received concomitant reirradiation with a radiation dose of 37.5 Gy in 15 fractions of 2.5 Gy. Results the median follow-up was 9.5 months (range 5-22). The overall survival and the progression-free survival rates were 53,8 %, and 46,6 % respectively at 2 years. In 53% the symptoms were stable. Only one patient developed late toxicity: acute pancreatitis (Grade I) regressed on interruption of Regorafenib. No other neurological deficits occurred during follow-up. At last follow up 60% of patients were alive. Conclusion we report our experience with Regorafenib, administered in patients with rapid progression after the end of postoperative radio chemotherapy treatment. Regorafenib might be a new potential treatment option for recurrent glioblastoma: it was well tolerated also in cases of combined treatment with reirradiation and appeared effective. Other studies will be necessary to evaluate and confirm the role of Regorafenib in glioblastoma patients and the potential effectiveness of the combined therapeutic strategy: Regorafenib-reirradiation.