Recurrent Primary Tumors Research Articles

Head and Neck Cancer in Fanconi Anemia: Report of 11 Cases and a Systematic Review

Background/Objectives: Head and neck cancer is one of the most common malignancies in patients with Fanconi anemia (FA), with a greater than 500-fold incidence of head and neck squamous cell carcinoma. Treatment of HNSCC in these patients is particularly challenging because of poor tolerance to radiation therapy and to some chemotherapeutic agents such as cisplatin. For these reasons, new research is needed to determine the best treatment course for these patients. With this goal in mind, we assessed the characteristics of head and neck squamous cell carcinoma (SCC) in Fanconi anemia (FA). Subjects and Methods: Data for 11 patients (mean age 31 years) with head and neck SCC and FA attended to between 2005 and 2021 were analyzed. Results: The primary tumor site was the oral cavity in eight patients, and five had advanced stages. All patients underwent primary tumor resection. Four patients received adjuvant radiotherapy (mean 57.2 Gy), but three developed toxicity. The mean follow-up was 48.4 months. Six patients experienced 19 episodes of primary tumor recurrence and five developed secondary head and neck tumors. The 3-year disease-free survival was 47%, and the 5-year cause-specific survival was 48%. These findings are similar to the data for 72 patients collected from the literature. Conclusions: The prognosis of head and neck cancer in patients with Fanconi anemia is poor, with an overall survival lower than 50% at 5 years.

Stimulus Responsive Nanocarrier for Enhanced Antitumor Responses Against Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a serious global health concern, accounting for about 90% of all liver cancer instances. Surgical treatment is a fundamental aspect of HCC management; however, the challenge of postoperative recurrence significantly impacts mortality rates. We have developed a pH and reactive oxygen species (ROS) dual stimulus-responsive drug delivery system (PN@GPB-PEG NPs) loaded with chemotherapeutic paclitaxel (PTX) and indoleamine 2.3-dioxygenase (IDO) inhibitor NLG919, for HCC chemoimmunotherapy. The physiochemical properties, such as particle size, zeta potential, morphology, and encapsulation efficiency, were characterized. Furthermore, we investigated in vitro cytotoxicity, cellular uptake and immunogenic cell death in tumor cells treated with our nanoparticles. In vivo biodistribution, antitumor effects and immune responses were assessed in an HCC mice model. PN@GPB-PEG NPs display pH-responsive properties with improved targeting abilities toward tumors and improved uptake by HCC cells. Upon exposure to oxygen peroxide (H2O2), the sophisticated design allows for rapid release of therapeutic agents. In this process, PTX induces immunogenic cell death (ICD), which activates the immune system to generate an antitumor response. Simultaneously, NLG919 works to inhibit IDO, mitigating the immunosuppressive environment. This combination strategy leverages the advantages of both chemotherapy and immunotherapy, resulting in a powerful synergistic antitumor effect. In a mouse model of HCC, our nanoparticles effectively inhibited the growth of primary and recurrent tumors. These encouraging results highlight the potential of our nanocarrier system as an innovative therapeutic approach to address HCC primary tumor and postsurgical recurrence, providing hope for enhanced patient outcomes.

DNAR-10. PHASE I CLINICAL TRIAL OF PEPOSERTIB PLUS RADIOTHERAPY IN ADULTS WITH NEWLY-DIAGNOSED MGMT-UNMETHYLATED GLIOBLASTOMA

Abstract BACKGROUND DNA-dependent protein kinase (DNA-PK) is an attractive target in GBM because it promotes unwanted DNA repair and renders cancer cells less vulnerable to DNA damaging agents, such as radiotherapy (RT). Peposertib, a small molecule inhibitor of DNA-PK, has demonstrated pre-clinical efficacy in sensitizing GBM to RT, resulting in tumor regression. METHODS 21 patients with newly-diagnosed MGMT-unmethylated GBM received peposertib plus 6-weeks of RT to determine the maximum-tolerated dose (MTD) based on the Bayesian Optimal Interval design. The dose-limiting toxicity (DLT) period was 10-weeks. Patients received at least 6-cycles of adjuvant temozolomide (NCT04555577). Single-nuclei RNA-sequencing (snRNA-Seq) and spatial transcriptomics (Visium, 10x Genomics) were performed on matched pair primary-recurrent tumors and controls, incorporating tumor cell state and cell type definitions by automated cluster classification and differential expression of marker genes. RESULTS The MTD of peposertib in combination with RT was 300mg per RT fraction day. One DLT (G3 radiation necrosis @300mg) was observed. After a median follow-up of 15.4 months (interquartile-range 8.9-18.5), mPFS was 10.8 months (95%CI 8.33-NR) and mOS was 22.9 months (95%CI 16-NR). 6/21 (29%) patients have undergone re-resection to date. snRNA-Seq on 102,709 cells from 12 primary and 3 recurrent tumors revealed that pre-treatment tumor cell states were progenitor-like, while treatment with peposertib plus RT was associated with differentiated and inflammatory malignant cell states, along with macrophage infiltration. Spatial transcriptomics of 8 matched primary-recurrent tumors (20,793 transcriptomes) confirmed malignant cell differentiation and enrichment of pro-inflammatory macrophages after inhibition of DNA-PK. 5 patients will be enrolled into a window-of-opportunity expansion cohort to evaluate intratumoral drug concentration. CONCLUSION The combination of peposertib and intracranial RT was safe. Survival data for this MGMT-unmethylated GBM population was promising. Single nuclei and spatial transcriptomic analyses revealed enrichment of pro-inflammatory macrophages in the tumor microenvironmentafter DNA-PK inhibition. The study was supported by EMD-Serono (CrossRef Funder ID: 10.13039/100004755).

PATH-54. HIGH-THROUGHPUT SINGLE NUCLEAR DNA SEQUENCING OF HUMAN SPORADICNF1 MUTANT IDH-WILDTYPE GLIOBLASTOMAS REVEALS PATTERNS OF TUMOR EVOLUTION AND RECURRENCE

Abstract The advent of single cell techniques has advanced our understanding of glioblastoma (GBM) evolution and cell lineage relationships. However, study of mutational co-occurrence and clonal phylogeny has been hampered by limitations in single cell genotyping. Here, we perform semi-automated, rapid single nuclear dissociation followed by targeted single nucleus DNA sequencing (snDNA-seq) of eleven retrospectively identified somatic NF1 mutant IDH-wildtype glioblastomas. Bulk DNA sequencing was performed as part of routine clinical care using a CLIA-certified targeted sequencing panel. For snDNA-seq, tissue cores with greater than 30% tumor were dissociated on a S2 genomics S100 Singulator followed by snDNA-seq using a targeted 361 amplicon panel (Tapestri, Mission Bio, USA) to sequence for recurrently observed single nucleotide substitutions and copy number alterations. A mean of 3,661 cells were recovered per sample with a mean of 96 reads per cell per amplicon and 87% mean panel uniformity. SnDNA-seq validated point mutations and copy number alterations observed in bulk DNA-sequencing and revealed novel alterations and subclonal copy number alterations not detected on bulk analysis. Within individual samples, snDNA-seq based phylogenetic reconstruction identified mutually exclusive patterns of mutation between NF1 and PI3K signaling alterations, suggesting these events may occur in distinct tumor subclones. With regard to copy number alterations (CNAs), snDNA-seq demonstrated intra-tumoral heterogeneity for chromosome 9p loss, chromosome 7 gain, and chromosome 10 monosomy. Subclonal CNA clones not detected by bulk sequencing were identified in 5 samples. Analysis of a matched primary-recurrent tumor pair revealed expansion of a specific mutational clone (loss of 9p, 10p, gains of 1p, 7, 15, and 19q) at recurrence. SnDNA-seq recapitulated bulk DNA sequencing alterations and identified distinct patterns of mutational co-occurrence, CNAs, and tumor evolution over time. Reconstructing GBM phylogeny at single cell resolution has potential translational implications for understanding tumor evolution and treatment resistance.

Comparison of oral cancer versus competing factors as cause of death: Single institution experience with long-term follow up

Survivors of head and neck squamous cell carcinoma face excess mortality from multiple causes. However, impact and patterns of all-cause mortality remains unknown in oral cancer patients. The aim of this study was to analyse these patterns in long-term survivors. We retrospectively studied clinically node-negative (cN0) oral cancer patients primarily surgically treated at tertiary cancer center. A total of 152 patients were identified. Median follow-up of our cohort was 59 months. A total of 76 patients died. Thirty-four (22.4%) patients died from primary tumor recurrence and 42 (27.6%) patients died from competing causes. The most common competing causes of death were: cardiovascular disease (n = 18; 42.9%), followed by second primary cancer (SPC) (n = 11; 26.2%). Lung cancer accounted for 54.5% (6 of 11) of SPC associated deaths. Patients with cN0 oral cancer treated with up-front surgery are potentially highly curable for index cancer but face significant risks of mortality from causes other than disease recurrence. Nearly one-third of these patients died from competing causes of death which are major cause of mortality after the fourth year of follow-up period. This study highlights the importance of adjusted follow-up strategies addressing this population specific risks.

Size matters: Biomolecular compositions of small and large extracellular vesicles in the urine of glioblastoma patients.

The promise of urinary extracellular vesicles (uEVs) in biomarker discovery is emerging. However, the characteristics and compositions of different uEV subpopulations across normal physiological and pathological states require rigorous explication. We recently reported proteomic signatures of small (s)-uEVs (<200nm membranous nanoparticles) and described putative biomarkers corresponding to the diagnosis, tumour burden and recurrence of the lethal adult primary brain tumour, glioblastoma. Here, we comprehensively characterise uEV populations with significantly different mean and mode particle sizes obtained by differential centrifugation at 100,000×g (100K-uEVs; smaller) and 17,000×g (17K-uEVs; larger) using Fourier-transform infrared spectroscopy and quantitative data-independent acquisition mass spectrometry. We show distinct differences in protein and lipid content, prominent protein secondary structures, and proteome distributions between uEV populations that can distinguish glioblastoma patients from healthy controls and correspond to clinically relevant tumour changes (i.e., recurrence and treatment resistance). Among the key findings is a putative seven-protein biomarker panel associated with 17K-uEVs that could distinguish all glioblastoma patients from healthy controls and accurately classify 98.2% of glioblastoma samples. These novel, significant findings demonstrate that both uEV populations offer individual and combined biomarker potential. Further research is warranted to elucidate the complete diagnostic, prognostic, and predictive capabilities of often-neglected 17K-uEV populations.

7065 Eradication Of Metastatic ER-Positive Breast, Ovarian, Endometrial And Lung Cancer In Mouse Xenografts And Patient Derived Organoids

Abstract Disclosure: D.J. Shapiro: None. D. Duraki: None. S. Ghosh: None. J. Zhu: None. C. Mao: None. J. Kim: None. M. Jabeen: None. M.W. Boudreau: None. M.P. Mulligan: None. R. Romero: None. Y. Han: None. J. Zhang: None. E.R. Nelson: None. O. Olopade: None. G. Chang: None. P.J. Hergenrother: Advisory Board Member; Self; Systems Oncology. We described the tumor protective estrogen-ER activated anticipatory Unfolded Protein Response (a-UPR) pathway. Here we report a previously undescribed multistep pathway by which very rapid estrogen-ER activation of the a-UPR authorizes and regulates subsequent transcription of the estrogen-ER transcriptome. We repurposed the tumor protective a-UPR through identification and optimization of the small molecule ErSO and its family of agents. ErSO acts non-competitively with estrogen to induce lethal hyperactivation of the a-UPR. In orthotopic mouse xenografts containing wild type or mutant ER, ErSO often induced complete regression without recurrence of large primary breast tumors and of most lung, bone and liver metastases, near complete regression of normally lethal brain metastases and complete destruction of patient derived organoids (PDOs) in Matrigel. Six research teams in four locations have confirmed the remarkable effectiveness of ErSO in ER-positive breast cancer. We next evaluated ErSO in diverse ER containing cancers in which estrogen is not the primary driver of proliferation. ErSO often induced complete regression in multiple orthotopic xenograft models of primary and metastatic ovarian cancer. Using fresh ovarian cancer organoids immediately after removal from patients by paracentesis, ErSO destroyed the organoids from some patients with advanced stage III and stage IV disease. ErSO was effective in a mouse xenograft model of endometrial cancer and, surprisingly, even in ERalpha positive lung cancer. Our ongoing studies demonstrate ErSO induces complete, or near complete regression, of primary and metastatic lung cancer in mice. Studies of ErSO’s mechanism of action using genome-wide CRISPR screens with positive selection, and other techniques, unveil a novel death pathway in which ErSO activation of the a-UPR triggers rapid calcium release into the cell body. The calcium opens the plasma membrane TRPM4 sodium channel, leading to an influx of extracellular sodium. This swells the cells, resulting in osmotic stress that sustains lethal a-UPR activation. A little-studied cytoskeleton regulator we identified, FGD3, plays a pivotal role in whether the cells rupture their membranes, inducing necrotic cell death. Notably, medium from diverse cancer cells killed by ErSO-induced necrosis robustly activates human macrophage and induces their migration - potentially facilitating immunotherapy. These studies describe a pathway from a multiprotein ER-SRC-PLC complex, through the a-UPR, to a novel cell swelling and necrosis pathway, that we are exploiting to target diverse, therapeutically challenging, ER-positive human cancers. Presentation: 6/2/2024

Increased Distress in Neurooncological Patients, a Monocentric Longitudinal Study: When to Screen Which Patient?

Neurooncological patients are well-known to experience an increased psycho-oncological burden with a negative impact on distress, therapy adherence, quality of life, and finally survival. But still, psycho-oncological screening and support is rare, with ongoing discussion about specific screening time points and impact factors. Therefore, we analysed the psycho-oncologic treatment demand at specific disease-related time points throughout therapy. In this longitudinal, prospective, single-centre study, patients with malignant brain tumours were screened for increased distress (using the Distress Thermometer), anxiety, depression (Hospital Anxiety and Depression Scale questionnaire), and health-related quality of life interference (EORTC QLQ C30-BN20 questionnaire) at specific longitudinal time points during therapy. The results were correlated with sociodemographic and clinical data. From 2013 to 2017, 2500 prospective screening data points from 512 malignant brain tumour patients were analysed. DT was identified as a significant predictor for psycho-oncological treatment demand (p < 0.001). Particularly significant time points concerning psycho-oncological burden were primary diagnosis and tumour recurrence. Next to these known factors, here, patients < 65 years old and female patients (p = 0.018 and p = 0.017) reflected increased screening results, whereas partnership and professional activity (p = 0.043; p = 0.017) were identified as contributing factors to a significantly decreased treatment demand. The increased need for psycho-oncological support for neurooncological patients is underlined. Psycho-oncological support should particularly be offered at the time points of primary diagnosis and tumour recurrence. To support the positive effect of caregivers, they should be involved at an early stage.

51311 Cutaneous Squamous Cell Carcinoma with Perineural Invasion: How is Perineural Invasion Detected Histopathologically? Biopsy vs Primary Management vs Tumor Recurrence

51311 Cutaneous Squamous Cell Carcinoma with Perineural Invasion: How is Perineural Invasion Detected Histopathologically? Biopsy vs Primary Management vs Tumor Recurrence

609. LONG-TERM OUTCOMES OF SALVAGE SURGERY AFTER PROTON BEAM THERAPY FOR ESOPHAGEAL SQUAMOUS CELL CANCER

Abstract Background Proton beam therapy (PBT) for esophageal cancer is a promising option for local control, reducing adverse events. The salvage surgery is sometimes performed for residual or recurrent lesion after PBT, however the long-term outcome has not been known for lack of previous reports. Methods Of 374 patients treated with radical PBT for squamous cell carcinoma of the thoracic esophagus at our institution from 2009 to 2018, we selected cases in which salvage surgery was performed. Salvage surgery was defined as surgical resection of recurrent primary tumor and/or lymph node metastases. The primary outcome was overall survival, and secondary outcomes and postoperative complications were investigated. Results Nineteen patients in whom salvage surgery was performed were included. Median age was 66 (55-80) years, male: female: 16:3, clinical stage at initial presentation was I:II:III = 3:6:10, and median time from PBT to relapse was 23.8 months. Esophagectomy were performed in 12 patients, and lymphadenectomy for recurrent lymph node were performed in 7 patients. During a median observation period of 26.5 months postoperatively, 14 cases were confirmed to have died of primary disease, and the median overall survival from salvage surgery was 38.3 months. 8/14 (57.1%) patients had Grade 3 or higher postoperative complications, and no operative mortality was observed. Conclusion We showed the long and short-term outcome of salvage surgery after PBT for esophageal squamous cell carcinoma. Although the risk of postoperative complications was high, some cases of long-term survival after salvage esophagectomy were observed.

Stereotactic Ablative Radiation Therapy (SABR) for Adolescent and Young Adult Malignancies.

There are limited studies examining local control (LC) and overall survival (OS) following stereotactic ablative radiation therapy (SABR) for adolescent and young adult (AYA) populations/histologies with local recurrences or metastatic disease. The RSSearch® Patient Registry, an international SABR registry, was evaluated for AYA patients treated with SABR. AYA patients with adult histologies/primaries were excluded. Kaplan-Meier analyses were employed to characterize LC and OS following SABR. Potential prognostic factors were assessed with log-rank tests for initial univariate analysis (UVA). For multivariate analyses (MVA), a Cox proportional hazards multivariate model was utilized. A total of 19 AYA patients with 39 lesions treated with SABR were identified and included in the analysis. Four lesions (10.3%) were treated with SABR for primary tumor recurrence and 35 lesions were treated for metastatic disease. The median patient age was 34 years (range: 16-39 years). Common lesion locations included lung (11 lesions; 28.2%), non-spinal bone (nine lesions; 23.1%), and spine (six lesions; 15.4%). The median biological effective dose (BED10) was 61.5 Gy (range: 26.4-180). One-year LC and OS following SABR were 77.7% (95% CI: 58.5-88.7) and 72.7% (95% CI: 46.3-87.6), respectively. On UVA, BED10 ≥ 60 Gy was associated with superior one-year LC (94.4% vs. 47.6%; p<0.0001) as were sarcoma primaries (two-year LC: 92.3% vs. 42.2%;p = 0.0002). Central nervous system (CNS) primaries had significantly poorer one-year LC (20% vs 87.5%; p<0.0001) as well as spinal metastases (33.3% vs. 87.0%; p<0.0001). On MVA, BED10 < 60 Gy was associated with inferior LC (hazard ratio (HR) = 5.51;p = 0.01) with sarcoma primaries associated with superior LC (HR = 0.04;p = 0.008). SABR with BED10 ≥ 60 Gy resulted in durable LC for AYA patients, particularly those with sarcoma primaries, though poor outcomes were noted in metastatic CNS malignancies.

QOL-42. ANALYSIS OF LATE EVENTS AFTER RADIATION THERAPY FOR PRIMARY PEDIATRIC BRAIN TUMORS

Abstract BACKGROUND Late events after radiation therapy for primary brain tumors consist of secondary malignant neoplasms (SMN) and tumor recurrences. The incidence and biology of late events are not very well described. Therefore, we aimed to identify late events in our institutional cohort and describe their biology. METHODS A retrospective chart review of all irradiated pediatric brain tumor patients treated between 2000 and 2015 at our institution was performed to obtain demographics and clinical data of late events. Late events were defined as intracranial intraaxial SMN or tumor recurrence occurring later than 3 years after radiation therapy. A whole-genome methylation array was employed to identify the methylation class of the late event. RESULTS In the observed period, 267 patients received some form of cranial radiotherapy for primary brain tumor; high-grade glioma (HGG, n=66), medulloblastoma (n=74), ependymoma (n=50), germ-cell tumors (GCT, n=22), low-grade glioma (LGG, n=24), and other diagnoses (n=31). Out of the 174 patients who were alive and without an event after 3 years from the radiation therapy, 30 developed late events (16.8%), and 27 of them were histologically verified. Verified late events consisted of 8 SMNs (29.6%) and 19 primary tumor recurrences. SMNs were mainly radiation-induced gliomas (RIG, n=7) and one atypical teratoid/rhabdoid tumor (ATRT) after craniopharyngioma. All RIG tumors clustered with the “pediatricHGG_RTK1” methylation class. Tumor recurrences consisted of medulloblastomas (Group 4 and Wnt), ependymomas (PFA and ST_ZFTA), GCTs, gliomas (one NF1-associated HGG, one H3-altered thalamic glioma, one diffuse astrocytoma with BRAF-V600E mutation), and craniopharyngiomas. The overall survival rate 5 years after a late event was 39.7%, with a worse survival rate for SMN patients (14.3%) compared to those with recurrences (44.9%) (p=0.05). CONCLUSIONS Late events affected 16.8% of long-term survivors. Strikingly, SMNs represented almost 30% of late events and were associated with a very poor prognosis.

Intentional Dural Resection during en bloc Spinal Resection Could Provide a Secure Surgical Margin for Patients with Recurrent Spinal Tumors.

It is always difficult to obtain a comfortable surgical margin for patients with recurrent malignant or invasive benign spinal tumors. Tumor intraspinal invasion and dural adhesion are the essential reasons. There are always residual tumor cells maintained at the edge of dura. Dural resection is a key point to obtain a comfortable surgical margin for such cases. Whether such patients benefit from this risky surgical procedure is unknown. This study aims to understand better the oncological results, associated risks, and neurological function of this risky surgical procedure. We retrospectively reviewed clinical data from six consecutive patients who registered spinal tumors in our institute and underwent dural resection during en bloc spinal resection from June 2013 to May 2020. The demographic and perioperative data, oncological outcomes, complications, and neurological status were collected and analyzed. All six patients were followed up for 24 to 46 months (mean follow-up time: 32.8 months). Local recurrence was detected in one patient (1/6, 16.7%) at 36 months postoperatively and in five patients with no evidence of disease at the last follow up (survival rate 83.3%). Eleven complications occurred in four patients (66.7%), and the dural resection-related complications included only four cases of cerebrospinal fluid leakage (CSFL), which accounted for 36.4% (4/11) of all complications. Neurologic status evaluated by the Frankel grade showed improvement of one grade in one case and deterioration of one to two grades in five patients immediately after surgery. All deterioration cases recovered to the preoperative level 6 months after the operation. Dural resection is significant for patients with dura matter invaded by recurrent primary malignant or invasive benign spinal tumors with the purpose of clinical cure. This study demonstrated that in strictly selected cases, intentional dural resection could provide satisfying local control and long-term disease-free survival with acceptable complications and satisfying neurological function.

Second primary squamous cell carcinoma of the oral cavity - a retrospective cohort study of therapeutic procedures and oncological outcome.

In the presented study, the occurrence rates of second primary oral carcinomas and their prognostic relevance were analyzed. All patients with surgically treated oral squamous cell carcinomas within the years 2010 and 2022 in our department were included in this retrospective cohort study. Two groups were designed including patients with second primary carcinomas and patients with local tumor recurrences. Occurrence rates, tumor stages and applied therapies were assessed. Primary outcome was overall survival in dependence of the index tumor. Secondary outcomes were overall survival in dependence of local recurrences or second primary tumors. An overall number of 908 patients was included in the analysis. 98 patients (10.8%) developed a second primary oral squamous cell carcinoma. Patients with second primary tumors presented significantly (p < 0.001) better overall survival in dependence of the index tumor compared to patients suffering from local recurrences. There was no significant difference in overall survival (p = 0.4) in dependence of the date of second primary tumor or local recurrence. Patients with second primary tumors were more likely to receive surgery-based therapy compared to patients with local recurrences who more frequently received definitive radiotherapy. Our data indicates different clinical courses in terms of therapy and survival of patients suffering from second primary tumors compared to patients with local tumor recurrences. This may be due to a more aggressive biology of local recurrences and earlier detection of second primaries due to oncological follow-up of the index tumor. The differentiation of local tumor recurrences and second primary tumors is of clinical relevance, as applicable therapies and resulting prognosis may differ significantly.

Autophagy and senescence facilitate the development of antiestrogen resistance in ER positive breast cancer.

Estrogen receptor positive (ER+) breast cancer is the most common breast cancer diagnosed annually in the US with endocrine-based therapy as standard-of-care for this breast cancer subtype. Endocrine therapy includes treatment with antiestrogens, such as selective estrogen receptor modulators (SERMs), selective estrogen receptor downregulators (SERDs), and aromatase inhibitors (AIs). Despite the appreciable remission achievable with these treatments, a substantial cohort of women will experience primary tumor recurrence, subsequent metastasis, and eventual death due to their disease. In these cases, the breast cancer cells have become resistant to endocrine therapy, with endocrine resistance identified as the major obstacle to the medical oncologist and patient. To combat the development of endocrine resistance, the treatment options for ER+, HER2 negative breast cancer now include CDK4/6 inhibitors used as adjuvants to antiestrogen treatment. In addition to the dysregulated activity of CDK4/6, a plethora of genetic and biochemical mechanisms have been identified that contribute to endocrine resistance. These mechanisms, which have been identified by lab-based studies utilizing appropriate cell and animal models of breast cancer, and by clinical studies in which gene expression profiles identify candidate endocrine resistance genes, are the subject of this review. In addition, we will discuss molecular targeting strategies now utilized in conjunction with endocrine therapy to combat the development of resistance or target resistant breast cancer cells. Of approaches currently being explored to improve endocrine treatment efficacy and patient outcome, two adaptive cell survival mechanisms, autophagy, and "reversible" senescence, are considered molecular targets. Autophagy and/or senescence induction have been identified in response to most antiestrogen treatments currently being used for the treatment of ER+ breast cancer and are often induced in response to CDK4/6 inhibitors. Unfortunately, effective strategies to target these cell survival pathways have not yet been successfully developed. Thus, there is an urgent need for the continued interrogation of autophagy and "reversible" senescence in clinically relevant breast cancer models with the long-term goal of identifying new molecular targets for improved treatment of ER+ breast cancer.

Clinical and molecular study of radiation-induced gliomas

In this study, we provide a comprehensive clinical and molecular biological characterization of radiation-induced gliomas (RIG), including a risk assessment for developing gliomas. A cohort of 12 patients who developed RIG 9.5 years (3–31 years) after previous cranial radiotherapy for brain tumors or T-cell acute lymphoblastic leukemia was established. The derived risk of RIG development based on our consecutive cohort of 371 irradiated patients was 1.6% at 10 years and 3.02% at 15 years. Patients with RIG glioma had a dismal prognosis with a median survival of 7.3 months. We described radiology features that might indicate the suspicion of RIG rather than the primary tumor recurrence. Typical molecular features identified by molecular biology examination included the absence of Histon3 mutation, methylation profile of pedHGG-RTK1 and the presence of recurrent PDGFRA amplification and CDKN2A/B deletion. Of the two long-term surviving patients, one had gliomatosis cerebri, and the other had pleomorphic xanthoastrocytoma with BRAF V600E mutation. In summary, our experience highlights the need for tissue diagnostics to allow detailed molecular biological characterization of the tumor, differentiation of the secondary tumor from the recurrence of the primary disease and potentially finding a therapeutic target.

Brain and Brain Stem Necrosis After Reirradiation for Recurrent Childhood Primary Central Nervous System Tumors: A PENTEC Comprehensive Review

Reirradiation is increasingly used in children and adolescents/young adults (AYA) with recurrent primary central nervous system tumors. The Pediatric Normal Tissue Effects in the Clinic (PENTEC) reirradiation task force aimed to quantify risks of brain and brain stem necrosis after reirradiation. A systematic literature search using the PubMed and Cochrane databases for peer-reviewed articles from 1975 to 2021 identified 92 studies on reirradiation for recurrent tumors in children/AYA. Seventeen studies representing 449 patients who reported brain and brain stem necrosis after reirradiation contained sufficient data for analysis. While all 17 studies described techniques and doses used for reirradiation, they lacked essential details on clinically significant dose-volume metrics necessary for dose-response modeling on late effects. We, therefore, estimated incidences of necrosis with an exact 95% CI and qualitatively described data. Results from multiple studies were pooled by taking the weighted average of the reported crude rates from individual studies. Treated cancers included ependymoma (n = 279 patients; 7 studies), medulloblastoma (n = 98 patients; 6 studies), any CNS tumors (n = 62 patients; 3 studies), and supratentorial high-grade gliomas (n = 10 patients; 1 study). The median interval between initial and reirradiation was 2.3 years (range, 1.2-4.75 years). The median cumulative prescription dose in equivalent dose in 2-Gy fractions (EQD22; assuming α/β value = 2 Gy) was 103.8 Gy (range, 55.8-141.3 Gy). Among 449 reirradiated children/AYA, 22 (4.9%; 95% CI, 3.1%-7.3%) developed brain necrosis and 14 (3.1%; 95% CI, 1.7%-5.2%) developed brain stem necrosis with a weighted median follow-up of 1.6 years (range, 0.5-7.4 years). The median cumulative prescription EQD22 was 111.4 Gy (range, 55.8-141.3 Gy) for development of any necrosis, 107.7 Gy (range, 55.8-141.3 Gy) for brain necrosis, and 112.1 Gy (range, 100.2-117 Gy) for brain stem necrosis. The median latent period between reirradiation and the development of necrosis was 5.7 months (range, 4.3-24 months). Though there were more events among children/AYA undergoing hypofractionated versus conventionally fractionated reirradiation, the differences were not statistically significant (P = .46). Existing reports suggest that in children/AYA with recurrent brain tumors, reirradiation with a total EQD22 of about 112 Gy is associated with an approximate 5% to 7% incidence of brain/brain stem necrosis after a median follow-up of 1.6 years (with the initial course of radiation therapy being given with conventional prescription doses of ≤2 Gy per fraction and the second course with variable fractionations). We recommend a uniform approach for reporting dosimetric endpoints to derive robust predictive models of late toxicities following reirradiation.

An online rectal cancer tumoroid biorepository: A resource to facilitate multimodal data integration.

159 Background: Advancing genetic and computational technologies have increased the complexity and quantity of data available in the field of rectal cancer research. As such, there is a need for a centralized source of data to aid and organize current research efforts. To this end, our team has created a unique online biorepository of rectal cancer tumoroids which may serve as a resource for a community of researchers. Methods: The rectal cancer tumoroid biorepository was created in cBioPortal in 2015. Organoids were derived from patient tumor samples (tumoroids). These samples represented multiple treatment timepoints and included primary, recurrent, and metastatic tumors. These tumoroids were further analyzed by various assays such as MSK-IMPACT and IC50 (to fluorouracil, FOLFOX, and FOLFIRI) to obtain patient-specific genomic and chemosensitivity data. A tumoroid profile was then created in cBioPortal for each sample. Clinical information was collected by chart review and annotated into the tumoroid profiles using the unique features of cBioPortal. These included interactive filters and graphical depictions of patient demographics, clinical and pathologic staging, treatment course, clinical response, overall survival, and disease-free survival. Results were organized in an intuitive visual display for convenient analysis. Novel features such as chemosensitivity plots and an interactive patient timeline were incorporated as well. Results: In total, 401 rectal cancer tumoroids have been derived from 177 unique patients. Approximately 32% of the tumoroids were from patients 50 years or younger, and 63% of patients have a treatment naïve sample in our repository. Ten percent of tumoroids were derived from T1-T2 tumors, 56% from T3 tumors, and 17% from T4 tumors. Additionally, 14% of tumoroids were derived from primary tumor recurrences while 6% were derived from metastases. Of the 78% of tumoroids with completely annotated clinical data, 8% were MSI-H, 11% were clinical complete responders, and 5.5% were pathologic complete responders. Lastly, complete IC50 data with clinical correlates has been established for 20% of tumoroids. These data show that tumoroids with a high sensitivity to chemotherapy (FOLFOX) correlated with a 3.3-fold increase in clinical complete response rates in the corresponding patients (p=0.0263). Conclusions: Integrating histopathological, clinicogenomic, and tumoroid response data, this expanding online resource provides a platform to identify valid biomarkers for patient treatment response. This publicly available biorepository built within cBioPortal is intuitive and flexible to accommodate and organize a wide range of data and has the potential to serve as an important resource in rectal cancer research.

Salvage Strategies for Local Recurrences of Squamous Cell Carcinoma of the Nasal Vestibule: A Single-Center Experience of 22 Years.

Squamous cell carcinomas of the nasal vestibule are an extremely rare neoplastic disease. Although brachytherapy is gaining popularity for primary treatment, surgery remains the best option in case of recurrences. The aim of this paper is to outline our treatment experience of local recurrence of SCCNVs over the past 22 years. We retrospectively reviewed the clinical data of the patients who underwent surgical treatment for local recurrence of SCCNV: data regarding age, sex, primary tumor treatment, recurrence location and time of appearance, surgical resection, type of reconstruction, postoperative complication, surgical revision, and re-recurrence rate were analyzed. Twenty patients were included in the study. The median period for recurrence appearance was 17 months, and the prevalent location of recurrence was the nasal alae. Prevalent reconstructive procedures were the nasolabial flap and paramedian forehead flap. No postoperative complications were observed, and one case of re-recurrence was detected at 12-months of follow-up. Based on our experience, salvage surgical procedures for SCCNV recurrences must be individualized and carefully planned, taking into account the peculiar pattern of tumor spread and the presence of scar and heavily radiotherapy damaged tissue from previous treatment; delayed reconstruction should be considered for all the cases with skeletal involvement.

Boosted photo-immunotherapy via near-infrared light excited phototherapy in tumor sites and photo-activation in sentinel lymph nodes.

Phototherapy is a promising modality that could eradicate tumor and trigger immune responses via immunogenic cell death (ICD) to enhance anti-tumor immunity. However, due to the lack of deep-tissue-excitable phototherapeutic agents and appropriate excitation strategies, the utility of phototherapy for efficient activation of the immune system is challenging. Herein, we report functionalized ICG nanoparticles (NPs) with the capture capability of tumor-associated antigens (TAAs). Under near-infrared (NIR) light excitation, the ICG NPs exhibited high-performance phototherapy, i.e., synergistic photothermal therapy and photodynamic therapy, thereby efficiently eradicating primary solid tumor and inducing ICD and subsequently releasing TAAs. The ICG NPs also captured TAAs and delivered them to sentinel lymph nodes, and then the sentinel lymph nodes were activated with NIR light to trigger efficient T-cell immune responses through activation of dendritic cells with the assistance of ICG NP generated reactive oxygen species, inhibiting residual primary tumor recurrence and controlling distant tumor growth. The strategy of NIR light excited phototherapy in tumor sites and photo-activation in sentinel lymph nodes provides a powerful platform for active immune systems for anti-tumor photo-immunotherapy.