Hasil untuk "Neoplasms. Tumors. Oncology. Including cancer and carcinogens"

Paula Díez, Pablo Juanes‐Velasco, Marina L. García‐Vaquero et al.

B‐cell chronic lymphocytic leukemia (B‐CLL) is characterized by highly heterogeneous genomic alterations and altered signaling pathways, with limited studies on its proteome. Our study presents a comprehensive analysis of the proteome and phosphoproteome in B‐CLL and CLL‐like monoclonal B‐cell lymphocytosis (MBL) primary cells. Using high‐resolution mass spectrometry, we identified 2970 proteins and 316 phosphoproteins across five tumor samples, including 55 newly identified phosphopeptides (ProteomeXchange‐PXD005997). Our multifaceted approach also integrated protein microarrays and western blotting for further data validation in a new patient cohort of 14 patients. Despite sharing 73% of their proteomes, the phosphoproteomes varied significantly among samples, independent of cytogenetic alterations and immunoglobulin heavy variable cluster (IGHV) mutational status. We identified common functional hallmarks in B‐CLL and MBL phosphoproteomes, notably tonic signaling (low‐level, constitutive signaling) of the B‐cell antigen‐specific receptor (BCR) and nuclear factor NF‐kappa‐B (NF‐kβ)/signal transducer and activator of transcription 3 (STAT3) pathways. Nine phosphoproteins involved in BCR signaling were further validated, showing a high correlation with early disease stages. Our study advances the field by providing a detailed perspective on the proteome and phosphoproteome of B‐CLL cells, revealing signaling pathways crucial for disease development and progression. Integrating diverse proteomics techniques and identifying novel phosphopeptides offers new insights into CLL biology, potentially informing future therapeutic strategies and biomarker development for early diagnosis and personalized treatment.

Xumin Zhou, Shilong Cheng, Zhongjie Chen et al.

Immunotherapy with checkpoint inhibitors produced significant clinical responses in a subset of cancer patients who were resistant to prior therapies. However, Castration-resistant prostate cancer (CRPC) is seriously lack of T cell infiltration, which greatly limits the clinical application of immunotherapy, but the mechanism is unclear. In the present study, in silico analyses and experimental data show that HnRNP L was significantly negatively correlated with CD4+ and CD8+ T cells infiltration in patients; besides, we found deficiency of HnRNP L recruites CD4+ and CD8+ T cells infiltration and impairs tumorigenesis. Mechanically, HnRNP L enhanced the translation of c-Myc and then promoted CXCL8 secretion via alternative splicing of EIF4G1. In vivo, inhibition of EIF4G1 by the inhibitor, SBI-0640756, attenuated HnRNP l-induced tumor progression and immunosuppressive activity. And most of all, therapeutic synergy between HnRNP L knockdown and Anti-PD-1 could significantly suppress xenograft prostate cancer growth. In summary, this study revealled the molecular mechanism of HnRNP L regulating the immune infiltration, which provides a new theoretical basis for overcoming the limitation of immunotherapy for CRPC.

Macarena Morillo-Huesca, Ignacio G. López-Cepero, Ryan Conesa-Bakkali et al.

Abstract Background Tumor resistance represents a major challenge in the current oncology landscape. Asparagine endopeptidase (AEP) overexpression correlates with worse prognosis and reduced overall survival in most human solid tumors. However, the underlying mechanisms of the connection between AEP and reduced overall survival in cancer patients remain unclear. Methods High-throughput proteomics, cellular and molecular biology approaches and clinical data from breast cancer (BC) patients were used to identify novel, biologically relevant AEP targets. Immunoblotting and qPCR analyses were used to quantify protein and mRNA levels. Flow cytometry, confocal microscopy, chemical inhibitors, siRNA- and shRNA-silencing and DNA repair assays were used as functional assays. In-silico analyses using the TCGA BC dataset and immunofluorescence assays in an independent cohort of invasive ductal (ID) BC patients were used to validate the clinical relevance of our findings. Results Here we showed a dual role for AEP in genomic stability and radiotherapy resistance in BC patients by suppressing ATR and PPP1R10 levels. Reduced ATR and PPP1R10 levels were found in BC patients expressing high AEP levels and correlated with worst prognosis. Mechanistically, AEP suppresses ATR levels, reducing DNA damage-induced cell death, and PPP1R10 levels, promoting Chek1/P53 cell cycle checkpoint activation, allowing BC cells to efficiently repair DNA. Functional studies revealed AEP-deficiency results in genomic instability, increased DNA damage signaling, reduced Chek1/P53 activation, impaired DNA repair and cell death, with phosphatase inhibitors restoring the DNA damage response in AEP-deficient BC cells. Furthermore, AEP inhibition sensitized BC cells to the chemotherapeutic reagents cisplatin and etoposide. Immunofluorescence assays in an independent cohort of IDBC patients showed increased AEP levels in ductal cells. These analyses showed that higher AEP levels in radioresistant IDBC patients resulted in ATR nuclear eviction, revealing AEPhigh/ATRlow protein levels as an efficient predictive biomarker for the stratification of radioresistant patients. Conclusion The newly identified AEP/ATR/PPP1R10 axis plays a dual role in genomic stability and radiotherapy resistance in BC. Our work provides new clues to the underlying mechanisms of tumor resistance and strong evidence validating the AEP/ATR axis as a novel predictive biomarker and therapeutic target for the stratification and treatment of radioresistant BC patients.

Prescilla Uijtewaal, Pim T.S. Borman, Peter L. Woodhead et al.

Background and purpose:: (Ultra-)hypofractionated radiotherapy is an effective treatment for localized prostate cancer, but intrafraction motion can increase toxicity and/or reduce treatment efficacy. Therefore, motion management is essential. This study explores magnetic resonance imaging (MRI)-guided multileaf collimator (MLC) tracking for 2-fraction prostate radiotherapy on an MR-linac. Materials and methods:: We compared two MRI-guided MLC centroid tracking workflows, each using a different motion manager to derive and stream target positions to our in-house MLC tracking software. The first workflow relies on interleaved 2D (2.5D) cine-MRI, introducing minimal latency. In contrast, the second workflow utilized 3D cine-MRI, which operates at a relatively lower imaging frequency that introduces more latency.For experimental validation, we used a motion phantom equipped with an integrated insert that combines film with plastic scintillation dosimetry. A 2x12 Gy 11-beam prostate intensity modulated radiotherapy plan was created for tracking deliveries. Results:: The signal latency introduced by the motion managers was 0.6 s for 2.5D cine-MRI and 6.3 s for 3D cine-MRI. Despite this latency, MLC tracking effectively restored the planned dose, improving the 2%/2mm local gamma pass-rates from 21% (due to linear drift) to 89% (2.5D) and 91% (3D). Plastic scintillator measurements showed reduced dose deviations at the periphery of the clinical target volume from 13–64% (no tracking) to 0–11% (2.5D) and 2–26% (3D). Conclusion:: Our experiments demonstrated the technical feasibility of 2.5D and 3D cine-MRI-based MLC tracking on an MR-linac for 2-fraction prostate radiotherapy, with both motion management strategies achieving comparable dosimetric improvements despite the difference in latency.

Dong-Shu Kang, Yu-Hao Lin, Jian-Qing Tian

Abstract Background It has been proven that the active surveillance (AS) is safe and feasible for low-risk papillary thyroid microcarcinomas (PTMC). There has been no bibliometric assessment of the scientific advancements in this field. We conducted this study to determine the characteristics and trends of published research on AS for PTMC. Methods In this study, articles on AS for PTMC published between 2014 and 2024 were identified using the Web of Science Core Collection database. Bibliometric analysis and visualization were conducted using VOSviewer and CiteSpace. Results 277 publications from 39 countries were identified, demonstrating a growth trend between 2014 and 2024. The United States of America dominated with the highest number of published papers, followed closely by South Korea and Japan. The most significant journal was *Thyroid*, and the leading author was Akira Miyauchi. Kuma Hospital and Memorial Sloan Kettering Cancer Center emerged as leading institutions. Keyword analysis revealed that, alongside the title-related terms of this study, “management,” “quality of life,” “lymph node metastasis,” “progression,” and “association guidelines” formed the core keywords in this field. Conclusion Active surveillance for low-risk PTMC has been endorsed and recommended by researchers in numerous countries. This study identified the current most active frontiers in this field and focused on candidate population profiling, tumor progression evaluation, cost-effectiveness of the active surveillance (AS) approach, and quality of life assessment for patients. This paper summarizes the controversial issues and provides a reference direction for researchers seeking to explore novel approaches in this field.

Wenfang Li, Qin Ou, Tian-xiang Zhang et al.

BackgroundMetaplastic carcinoma of the breast with mesenchymal differentiation (MCMD) is a type of metaplastic breast carcinoma (MpBC) that is very rare and aggressive. The present case provides valuable information for clinicians on this MpBC.Case presentationA 41-year-old woman visited our hospital for a palpable painless mass in the left breast. Core needle biopsy (CNB) was performed, and the pathological result was infiltrating ductal carcinoma. Epirubicin (100 mg/m2) + cyclophosphamide (600 mg/m2) for four cycles was given. Color Doppler ultrasound examination indicated no obvious change in the size of the left breast mass. We changed to paclitaxel (175 mg/m2) for two cycles. Re-examination on April 26, 2018 with color Doppler ultrasound indicated that the tumor diameter increased to 8.39 cm × 8.07 cm × 6.19 cm. Radical resection of the left breast carcinoma was performed on June 04, 2018. The postoperative pathological results showed that the left breast tumor was composed of carcinoma and sarcoma components, without nerves and vascular invasion. The immunohistochemistry results were as follows: ER: (−), PR: (−), HER2: (−), CK5/6 (+), CK7: (+), E-cadherin (+), Ki67: 40% (+), P120: (+), P53 diffuse +, P63: (+), and S100 partially positive, GATA-3: (+). Four cycles of vinorelbine (25 mg/m2) + cisplatin (40 mg/m2) were performed after the operation. Enhanced CT indicated a 6.0 cm × 4.6 cm mass in the liver on January 1, 2019 through regular review, and liver lobectomy confirmed that metastasis originated from sarcoma components, together with bone and cartilage differentiation. The immunohistochemistry results indicated the following: ER (−), PR (−), GATA-3 (−), CD34 (+), P63 (−), CK8 (−), P40: (−), and vimentin: (+). The patient received oral anlotinib 12 mg once a day, with 2 weeks on/1 week off for eight cycles. The patient survived and showed no signs of recurrence at the follow-up visit.ConclusionThis case indicated that CNB may not always give an accurate diagnosis for MCMD. Neoadjuvant chemotherapy with epirubicin, cyclophosphamide, or paclitaxel for MCMD may not be effective for patients showing no sensitivity to these drugs. In addition, regular postoperative follow-up plays an important role in the early detection of remote metastasis, and timely surgical excision of a single metastatic lesion in the liver can lead to long-term progression-free survival (PFS).

Zheng Yang, Yuhuan Lv, Meng Yu et al.

Background: GLP-1 receptor agonists (GLP-1RA) have demonstrated cardiovascular benefits, but the relationship between GLP-1RA and tumors is controversial. Recently, clinical trials reported higher rates of malignancy with semaglutide than control group. As real-world evidence of GLP-1RA-associated tumor risk is very limited, we explored the association of GLP-1RA and all types of neoplasms by mining the FDA Adverse Event Reporting System (FAERS) database. Methods: The FAERS data from the first quarter (Q1) of 2004 to the second quarter (Q2) of 2020 in the AERSMine were extracted to conduct disproportionality analysis, which was used by the proportional reporting ratio (PRR) to assess the relationship between GLP-1RA and all types of neoplasms. Then, the details of disproportionate GLP-1RA-associated tumor cases from Q1 2004 to Q2 2021 in the FAERS Public Dashboard were collected to analyze demographic characteristics. Results: A total of 8718 GLP-1RA-associated tumors were reported. Excluding cases with pre-existing tumors, other glucose-lowering drugs, and other GLP-1RA-related adverse events, diabetes cases with GLP-1RA as the main suspected drug were selected. GLP-1RA did not cause a disproportionate increase in all tumor cases (PRR 0.83) at the SOC level, and there was also no increase in most types of tumors associated with GLP-1RA at the HLGT/HLT levels. Significant signals were detected between GLP-1RA and certain tumors, including thyroid cancers [medullary thyroid cancer (PRR 27.43) and papillary thyroid cancer (PRR 8.68)], pancreatic neoplasms malignant (PRR 9.86), and islet cell neoplasms and APUDoma NEC (PRR 2.86). The combination of GLP-1RA with dipeptidyl-peptidase IV inhibitors (DPP4i) perhaps caused the increased reporting rate in some tumors. Conclusion: Our study provided new real-world evidence for oncology safety information of GLP-1RA. Given the wide use of GLP-1RA, clinicians should be well informed about important potential adverse events. Our pharmacovigilance analysis also prompted clinicians to raise concerns about potential tumor-related adverse effects when combining GLP-1RA with DPP4i.

Lindsay A. Bischoff, I. Ganly, L. Fugazzola et al.

Importance Oncocytic (Hürthle cell) thyroid carcinoma is a follicular cell-derived neoplasm that accounts for approximately 5% of all thyroid cancers. Until recently, it was categorized as a follicular thyroid carcinoma, and its management was standardized with that of other differentiated thyroid carcinomas. In 2022, given an improved understanding of the unique molecular profile and clinical behavior of oncocytic thyroid carcinoma, the World Health Organization reclassified oncocytic thyroid carcinoma as distinct from follicular thyroid carcinoma. The International Thyroid Oncology Group and the American Head and Neck Society then collaborated to review the existing evidence on oncocytic thyroid carcinoma, from diagnosis through clinical management and follow-up surveillance. Observations Given that oncocytic thyroid carcinoma was previously classified as a subtype of follicular thyroid carcinoma, it was clinically studied in that context. However, due to its low prevalence and previous classification schema, there are few studies that have specifically evaluated oncocytic thyroid carcinoma. Recent data indicate that oncocytic thyroid carcinoma is a distinct class of malignant thyroid tumor with a group of distinct genetic alterations and clinicopathologic features. Oncocytic thyroid carcinoma displays higher rates of somatic gene variants and genomic chromosomal loss of heterozygosity than do other thyroid cancers, and it harbors unique mitochondrial DNA variations. Clinically, oncocytic thyroid carcinoma is more likely to have locoregional (lymph node) metastases than is follicular thyroid carcinoma-with which it was formerly classified-and it develops distant metastases more frequently than papillary thyroid carcinoma. In addition, oncocytic thyroid carcinoma rarely absorbs radioiodine. Conclusions and Relevance The findings of this review suggest that the distinct clinical presentation of oncocytic thyroid carcinoma, including its metastatic behavior and its reduced avidity to radioiodine therapy, warrants a tailored disease management approach. The reclassification of oncocytic thyroid carcinoma by the World Health Organization is an important milestone toward developing a specific and comprehensive clinical management for oncocytic thyroid carcinoma that considers its distinct characteristics.

Damir Grebić, Marin Oštrić, Laura Radoš et al.

Objective: The objective of this case report is to present a rare case of inflammatory undifferentiated pleomorphic sarcoma in a male breast. Case report: a 64-year-old man palpated a painless nodule on the left breast. Core needle biopsy did not reveal the final diagnosis as it was classified as B3 so an excisional biopsy of the tissue was performed, which revealed an undifferentiated pleomorphic sarcoma with a diameter of 4.5 cm, infiltrated with inflammatory cells. After we confirmed the sarcoma operation therapy was indicated. Stewart incision was performed and mastectomy was done. Pathohistological analysis confirmed negative surgical resection margins. After one month PET CT scan revealed lungs metastases and the patient underwent 6 chemotherapy cycles of doxorubicin with good response and contribution of lungs metastases remission. Three years later, the tumor recurred and infiltrated the thoracic wall. The patient underwent again to surgical procedure. We did the extirpation of tumor, resection of thoracic wall with large pectoral muscle and within fifth, sixth and seventh ribs resection and thoracoplasty with core matrix and bio-net was performed for reconstruction of the defect. On pathohistology findings distal resection margin was infiltrated by tumor cells so radiotherapy was performed. Larger thoracic resection was not possible as it would affect breathing mechanics. The postoperative course was normal, without paradoxical breathing. The patient has been in remission according to PET-CT examination for four years after them treatment. Conclusion: We have presented a rare case of undifferentiated pleomorphic sarcoma in the breast, its potential for recurrence and distant metastases, the possibilities of treatment, the importance and limitations of operative treatment as well as benefit of oncological procedures and unpredictable clinical course of disease.

M. I. Sokolova, V. I. Pavlova, A. Guz et al.

Introduction. metastases in the absence of a primary tumor (cancer of unknown primary (Cup) syndrome) are diagnosed in 2–4 % of malignant tumor cases. This pathology is characterized by early metastatic dissemination, weak response to conventional chemotherapy, and aggressive progression. The use of checkpoint inhibitors targeting programmed cell death protein 1 (pD-1) and its ligand (pD-L1) has shown good results in treatment of various cancers including oropharyngeal squamous cell carcinoma (OpSCC). In Cup syndrome, the effectiveness of checkpoint inhibitors is rarely investigated, and pD-L1 expression is often not measured.Aim. To compare the frequency of p16 and pD-L1 hyperexpression in OpSCC and Cup syndrome, and to analyze dependency of survival rates on the level of expression of p16, the most important prognostic marker.Materials and methods. The study included 121 patients (59 with OpSCC and 62 with Cup syndrome) who received medical treatment in the multidisciplinary medical Center “medical City” (Tyumen) and Chelyabinsk Oncological Center of Oncology and Nuclear medicine between 2019 and 2023. Immunohistochemical examination was performed using the vENTANA Benchmark gX with primary antibodies against pD-L1 (clone Sp263, uSA) and р16 (uS Biological, uSA). Statistical analysis of the data was performed using SpSS 26 software. Long-term treatment outcomes were evaluated using 1-, 3-, 5-year survival rates and median survival. Overall survival was analyzed using the kaplan-meier method. Statistical significance of the differences was evaluated using the Cox model.Results. The studied groups did not differ by sex (p = 0.472), age (р = 0.640), and N stage (р = 0.262). patient age in the whole population varied between 42 and 81 years (median age 61.89 ± 11.9 years; mean age 60.81 ± 9.8 years). pD-L1 expression rate was higher in Cup syndrome at 92 % compared to 73 % in OpSCC (statistically significant difference; р = 0.01). Analysis of the association of ORSCC and Cup syndrome with human papilloma virus showed statistically significant difference in p16 hyperexpression: patients with OpSCC had p16-positive status more frequently (53 % of cases) while patients with Cup syndrome mostly had p16-negative status (73 % of cases). mean life expectancy of patients with OpSCC and p16-positive status was 62.65 months (95 % confidence interval 54.98–70.31), minimal observation period was 12 months, maximal was 70 months. mean life expectancy of patients with Cup syndrome and positive p16 status was 66.22 months (95 % confidence interval 56.35–76.10), minimal observation period was 12 months, maximal was 70 months. No statistically significant differences in survival rates of patients with OpSCC and Cup syndrome were found (р = 0.999).Conclusion. The study showed higher pD-L1 expression in patients with Cup syndrome compared to patients with OpSCC: 92 and 73 %, respectively (р = 0.01). The obtained results highlight the importance of routine pD-L1 expression evaluation in patients with Cup syndrome. The frequency of p16 hyperexpression was higher in OpSCC compared to Cup syndrome: 53 % versus 27 % (р = 0.02) which agrees with the worldwide epidemiological data: among all malignant neoplasms of the head and neck, Hpv infection is most common in OpSCC. Therefore, it serves as an important sign of hidden oropharyngeal cancer in Cup syndrome.

Paloma Helena Sanches da Silva, Erick Ferry de Souza, Renato Dornas de Oliveira Pereira et al.

Background: Benign or malignant peripheral nerve sheath tumors originate from Schwann cells and the connective tissue that surrounds the nerve bundles. Malignant peripheral nerve sheath tumors are highly recurrent, despite its relative low metastatic potential. Although frequently diagnosed in the subcutaneous tissue, those tumours are rarely reported within nerve roots (somatic and autonomous), cranial or spinal nerves and its extensions  but are considered the main neoplasms from the peripheral nervous system. Clinical signs observed will vary according to the neurolocation and degree of tumour compression and the presumptive diagnosis can be based on the clinical characteristics and complementary tests such as radiography, myelography, computed tomography and especially magnetic resonance imaging for the excellent resolution of soft tissues. Tumor location at the brachial and lumbosacral plexus poses challenges in the diagnostic and therapeutic approach, mainly due to the impossibility of complete resection, which results in a poor prognosis, also considering the chemoresistance and radioresistance intrinsic to this histopathological type. There is limited evidence for chemotherapy at maximum tolerated dose or metronomic. Among new therapeutic strategies in veterinary oncology, immunotherapy stands out due to its relevant influence on the tumor microenvironment, being one of the innovative therapy modalities that have been developed in recent decades to treat cancer. Case: This study aimed to report the challenges faced in the diagnostic and therapeutic approach of a 12-year-old French Bulldog with a malignant peripheral nerve sheath tumor in the lumbosacral region, treated with decompressive surgery, adjuvant chemotherapy at maximum tolerated dose, metronomic chemotherapy and OncoTherad® nanoimmunotherapy. Disease progression occurred 5 months after surgery and the dog developed lung metastasis despite the efforts for its diagnosis, staging and treatment. Discussion: Peripheral nerve sheath tumors malignant can arise from spinal nerves, primarily in the brachial and lumbosacral plexus and their roots, but also from cranial nerves. In the patient's CT scan, the presence of soft density extradural neoformation was detected occupying more than half of the vertebral canal and compromising the cauda equina at the lumbosacral junction, thus corroborating the information found in the literature. The tumour was deemed unresectable, but surgery was performed for alleviating compression of the nerve roots and diagnosis. The definitive diagnosis can be reached by the histopathological examination performed in the presented case, after decompression surgery. For further characterization of the neoplasm, an immunohistochemical panel was performed, which confirmed the mesenchymal and neural origin, thus confirming neurofibrosarcoma. The prognosis was poor due to the involvement of nerve roots, psoas muscle and extradural canal affected by the neoplasm. Complete resection was impossible, resulting in permanence of macroscopic disease and also increasing the chances of local progression, which occurred 5 months after surgery despite multimodal treatment. Palliative care was performed as an attempt to assure quality of life and prolong life expectation including anti-inflammatory, analgesics, metronomic chemotherapy and immunotherapy with OncoTherad®. Keywords: peripheral nervous system, soft tissue sarcoma, oncology, immunotherapy, spinal decompression.

Y. S. Chapko, D. Dubovichenko, A. A. Ruzhnikova et al.

Background. Granulocyte colony-stimulating factors (G-CSFs) are used in oncology practice for prevention of febrile neutropenia caused by cytotoxic chemotherapy. Despite the proven safety of G-CSFs use in randomized clinical trials and in real clinical practice, clinicians have questions about the tolerability of this group of drugs.Aim. To demonstrate the safety profile of a long-acting G-CSF produced in Russia which was used to prevent febrile neutropenia and maintain dose intensity of drug therapy in patients with various solid tumors undergoing chemotherapy at the Arkhangelsk Clinical Oncological Dispensary.Materials and methods. The retrospective analysis included patients with a confirmed diagnosis of malignant neoplasm who received various chemotherapy regimens that required the inclusion of G-CSF. For primary prevention of febrile neutropenia, patients were prescribed empegfilgrastim (Extimia®) at a dose of 7.5 mg subcutaneously once per course of chemotherapy.Results. Data of 151 patients were analyzed for the period from July 2021 to April 2023. The average age was 57 years (28–75). The group of elderly patients (over 65 years) consisted of 38 (25 %) patients. The majority of patients were diagnosed with breast cancer (56 (37 %) patients) and gastric cancer (37 (25 %) patients). The number of empegfilgrastim injections over the entire observation period was 773. Adverse reactions associated with the use of empegfilgrastim were registered in 13 (8.6 %) patients, the most common of which was grade 1–2 leukocytosis according to the CTCAE v.5 classification. One patient developed a serious adverse reaction: grade 4 neutropenia according to the CTCAE v.5 classification. A subgroup of patients with metastatic pancreatic cancer treated with FOLFIRINOX was analyzed separately to assess the relative dose intensity of the chemotherapy courses. Nine patients with metastatic pancreatic cancer received FOLFIRINOX therapy with a median of 8 (5–12) courses. A total of 69 chemotherapy cycles were administered to 9 patients with a median of 7.5 (2–13) cycles. The relative dose intensity of the chemotherapy courses was 83.71 ± 19.33.Conclusion. Empegfilgrastim has shown a favorable safety and tolerability profile in patients with various solid tumors in real-world clinical practice including the highly toxic FOLFIRINOX regimen.

Michel Alchoueiry, C. Labaki, Long Zhang et al.

Background: Chromophobe renal cell carcinoma (ChRCC) represents 5% of all kidney cancers. In contrast to clear cell RCC (ccRCC), the immune landscape of ChRCC and its response to immunotherapy remain poorly characterized. We sought to evaluate the clinical outcomes of patients with ChRCC treated with immuno-oncology (IO)-based regimens, and assess the immune cell composition, phenotypic state, and T cell specificity in the tumor microenvironment of ChRCC. Methods: Using real-world data from the International Metastatic RCC Database Consortium, we analyzed the survival outcomes and objective responses of patients with advanced ChRCC to currently adopted IO-based regimens (i.e. dual IO therapy or IO + vascular endothelial growth factor targeted therapy [VEGF-TT]) in the first-line setting, as compared to patients with ccRCC. Single-cell RNA sequencing (scRNA-seq) and single-cell T-cell receptor sequencing (scTCR-seq) were performed on ChRCC and related oncocytic neoplasms (i.e. renal oncocytoma [RO] and low-grade oncocytic tumor [LOT]) samples with matched normal kidney specimens. The infiltration of CD45+ immune cells in renal oncocytic tumors and ccRCC samples was quantified using immunohistochemistry (IHC). Results: Compared to patients with ccRCC (n=856) treated with first-line IO-based regimens, patients with ChRCC (n=31) had a lower overall survival (median: 24.7 vs. 50.5 months, p<0.001) and lower time to treatment failure (median: 4.5 vs. 11.0 months, p<0.001). Similarly, patients with ChRCC had a significantly lower overall response rate than those with ccRCC (12.0 vs. 47.1%, respectively; p<0.001). When evaluating immune cell infiltration, renal oncocytic tumors (ChRCC, RO, and LOT) exhibited a low density of CD45+ cells (mean: 739 ± 114 cells/mm2; n=5) compared to ccRCC (mean: 3,420 ± 1,979 cells/mm2; n=5) (p<0.05). Single-cell analysis was performed on 46,817 cells from 5 tumors (ChRCC: n=3, RO: n=1 and LOT: n=1) and 4 samples from adjacent normal kidney. Across all tumors, CD8+ T cell clusters displayed a lower expression of immune checkpoints (i.e. PDCD1, CTLA4, LAG3, HAVCR2, and TIGIT) as compared to CD8+ T-cells from ccRCC. This was further validated in the analysis of bulk RNA-seq data from the TCGA, with a significantly lower expression of all immune checkpoints in ChRCC compared to both ccRCC (p<0.01) and papillary RCC (pRCC; p<0.01). Analysis of the T cell receptor repertoire (scTCR-seq) of ChRCC, RO and LOT samples did not show any pattern of clonal expansion, and a higher proportion of T cells in ChRCC were inferred to have a viral specificity, compared to ccRCC (0.79 vs. 0.1%, respectively). Conclusions: Patients with metastatic ChRCC appear to display poor clinical outcomes when treated with IO-based regimens, compared to ccRCC. Renal oncocytic tumors, including ChRCC, exhibit a low infiltration of immune cells, and a non-exhausted immune phenotype. Citation Format: Michel Alchoueiry, Chris Labaki, Long Zhang, Yue Hou, Kevin Bi, Charbel Hobeika, J. Connor Wells, Kosuke Takemura, Ziad Bakouny, Sabrina Camp, Carmen Priolo, Damir Khabibullin, Nicholas Schindler, Renee Maria Saliby, Eddy Saad, Samer Salem, Melissa Daou, Rana McKay, Sumanta Pal, Daniel Heng, Eliezer Van Allen, Sachet Shukla, Toni Choueiri, David Braun, Elizabeth Henske. Clinical and molecular characterization of chromophobe renal cell carcinoma: A focus on immunotherapy based regimens and the tumor immune microenvironment [abstract]. In: Proceedings of the AACR Special Conference: Advances in Kidney Cancer Research; 2023 Jun 24-27; Austin, Texas. Philadelphia (PA): AACR; Cancer Res 2023;83(16 Suppl):Abstract nr B019.

Bethany E. Monteith, Irwindeep Sandhu, Ann S. Lee

Multiple myeloma (MM) is a malignant clonal plasma cell disorder in the bone marrow and is the second-most common hematologic malignancy in adults. Although patients with MM have a moderate life expectancy, it remains a heterogeneous disease that often requires multiple lines of chemotherapy for durable control and long-term survival. This review outlines current management strategies for both transplant-eligible and transplant-ineligible patients as well as for relapsed and refractory disease. Advances in drug therapies have widened management options and improved survival. In this paper, we also discuss implications for special populations and survivorship care.

Bambara H. Aboubacar, Zerbo Nina Assanatou jumelle, Valerie Odero-Marah et al.

Purpose: Bisphosphonates have proven effective in reducing pain and skeletal events in bone metastases treatment. However, there is a long-term complication called osteonecrosis of the jaw, which has been reported for more than a decade. Despite various professional recommendations, there is no international consensus on the best therapeutic strategy. Prevention is crucial, and a multidisciplinary approach must be tailored to each stage of the condition. Design: We present a case of osteonecrosis of the jaw in a patient with metastatic breast cancer who was receiving 4 mg injectable zoledronic acid. Result: The patient stopped treatment with zoledronic acid and received systemic treatment (analgesics, antibiotics), with the resolution of symptoms. Conclusion: ONJ is a serious condition associated with taking BP that can impact oral health and quality of life. Our study highlights the effectiveness of systematic treatment in managing ONJ with BP-related alterations. Preventative measures, such as regular dental consultations, play a vital role in reducing the risk of ONJ. Multidisciplinary management is essential to addressing the different stages of the condition.

Minoru Miyashita, Joshua S. K. Bell, Stephane Wenric et al.

Abstract Background Endocrine-resistant HR+/HER2- breast cancer (BC) and triple-negative BC (TNBC) are of interest for molecularly informed treatment due to their aggressive natures and limited treatment profiles. Patients of African Ancestry (AA) experience higher rates of TNBC and mortality than European Ancestry (EA) patients, despite lower overall BC incidence. Here, we compare the molecular landscapes of AA and EA patients with HR+/HER2- BC and TNBC in a real-world cohort to promote equity in precision oncology by illuminating the heterogeneity of potentially druggable genomic and transcriptomic pathways. Methods De-identified records from patients with TNBC or HR+/HER2- BC in the Tempus Database were randomly selected (N = 5000), with most having stage IV disease. Mutations, gene expression, and transcriptional signatures were evaluated from next-generation sequencing data. Genetic ancestry was estimated from DNA-seq. Differences in mutational prevalence, gene expression, and transcriptional signatures between AA and EA were compared. EA patients were used as the reference population for log fold-changes (logFC) in expression. Results After applying inclusion criteria, 3433 samples were evaluated (n = 623 AA and n = 2810 EA). Observed patterns of dysregulated pathways demonstrated significant heterogeneity among the two groups. Notably, PIK3CA mutations were significantly lower in AA HR+/HER2- tumors (AA = 34% vs. EA = 42%, P < 0.05) and the overall cohort (AA = 28% vs. EA = 37%, P = 2.08e−05). Conversely, KMT2C mutation was significantly more frequent in AA than EA TNBC (23% vs. 12%, P < 0.05) and HR+/HER2- (24% vs. 15%, P = 3e−03) tumors. Across all subtypes and stages, over 8000 genes were differentially expressed between the two ancestral groups including RPL10 (logFC = 2.26, P = 1.70e−162), HSPA1A (logFC = − 2.73, P = 2.43e−49), ATRX (logFC = − 1.93, P = 5.89e−83), and NUTM2F (logFC = 2.28, P = 3.22e−196). Ten differentially expressed gene sets were identified among stage IV HR+/HER2- tumors, of which four were considered relevant to BC treatment and were significantly enriched in EA: ERBB2_UP.V1_UP (P = 3.95e−06), LTE2_UP.V1_UP (P = 2.90e−05), HALLMARK_FATTY_ACID_METABOLISM (P = 0.0073), and HALLMARK_ANDROGEN_RESPONSE (P = 0.0074). Conclusions We observed significant differences in mutational spectra, gene expression, and relevant transcriptional signatures between patients with genetically determined African and European ancestries, particularly within the HR+/HER2- BC and TNBC subtypes. These findings could guide future development of treatment strategies by providing opportunities for biomarker-informed research and, ultimately, clinical decisions for precision oncology care in diverse populations.

Oral cavity squamous cell carcinoma (OCSCC) is a devastating disease, causing substantial morbidity and mortality. While many OCSCCs arise from an existing dysplastic lesion, not all oral premalignant lesions progress to OCSCC. Current methods for oral premalignancy and OCSCC diagnosis (visual and tactile exam followed by tissue biopsy and histologic evaluation) cannot discriminate between benign inflammatory changes and high-risk premalignant lesions that require interventions, underscoring the need for molecular-based biomarkers. The multi-step cancer progression from normal epithelium to premalignant lesion and invasive SCC is driven by the accumulation of genetic alterations, including changes in mitochondrial DNA (mtDNA). Due to the lack of protective histones and limited repair mechanisms, mtDNA is susceptible to damage by environmental carcinogens and reactive oxygen species, a byproduct of the oxidative phosphorylation system. As a result, mutation rate in mtDNA is ~10 times higher than in nuclear DNA, and may greatly facilitate the risk of mitochondrial dysfunction. Previous studies underscore that acquisition of somatic mtDNA mutations directly involved in tumorigenesis, and not merely epiphenomena. However, the impact of these studies is limited by an incomplete understanding of mitochondrial genomic alterations in the transition of preneoplastic lesions to invasive disease. In this study we used a unique cohort of 27 patients with matched longitudinally collected samples (histologically normal mucosa, dysplastic lesion, and SCC) coupled with novel ultra-deep mitochondrial sequencing (mtDNA-Seq) method to assess the mtDNA mutational landscape throughout the continuum of OCSCC progression. Using a custom bioinformatics workflow, somatic mutations were detected in a subset of the premalignant lesions, with overall higher mutational load observed in OCSCC specimens. While sequencing revealed a large degree of inter-patient heterogeneity, a panel of non-synonymous aberrations were present in both premalignant and invasive neoplasms. The majority of shared mutations showed an increase in fractional abundance in tumors, compared to the precursor lesions (suggesting a spatial expansion of these clones as they progressed histologically), and were enriched for coding mutations in complex-I subunits (critical region for ATP production), which is associated with an oncogenic phenotype. Additionally, mtDNA content increased in OCSCC tumor in a subset of patients, suggesting a cell compensation for defective oxidative phosphorylation and lower ATP production per mitochondria. Here we report the first comprehensive characterization of mitochondrial mutational landscape in dysplastic and invasive SCC lesions, and reveal key molecular events associated with the transition from non-invasive to invasive state. Citation Format: Alka Singh, Ashwin Lakshman Koppayi, Ping Wu, Mark Lingen, Vasudha Mishra, Alexander Pearson, Ari Rosenberg, Nishant Agrawal, Karthik Suresh, Evgeny Izumchenko. Ultra-deep sequencing of mitochondrial genome to explore the dynamic mutational changes associated with oral cavity squamous cell carcinoma progression. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4845.

J. Neglia, A. Meadows, L. Robison et al.

Bernadette Basilico, Ilaria Elena Palamà, Stefania D’Amone et al.

The complexity of the microenvironment effects on cell response, show accumulating evidence that glioblastoma (GBM) migration and invasiveness are influenced by the mechanical rigidity of their surroundings. The epithelial–mesenchymal transition (EMT) is a well-recognized driving force of the invasive behavior of cancer. However, the primary mechanisms of EMT initiation and progression remain unclear. We have previously showed that certain substrate stiffness can selectively stimulate human GBM U251-MG and GL15 glioblastoma cell lines motility. The present study unifies several known EMT mediators to uncover the reason of the regulation and response to these stiffnesses. Our results revealed that changing the rigidity of the mechanical environment tuned the response of both cell lines through change in morphological features, epithelial-mesenchymal markers (E-, N-Cadherin), EGFR and ROS expressions in an interrelated manner. Specifically, a stiffer microenvironment induced a mesenchymal cell shape, a more fragmented morphology, higher intracellular cytosolic ROS expression and lower mitochondrial ROS. Finally, we observed that cells more motile showed a more depolarized mitochondrial membrane potential. Unravelling the process that regulates GBM cells’ infiltrative behavior could provide new opportunities for identification of new targets and less invasive approaches for treatment.

O. V. Feger, R. Yu. Pogorilyak