Onco

Gynecological malignancies (ovarian, endometrial, and cervical cancers), including disseminated intravascular coagulation (DIC), often provoke systemic coagulopathy. In recent years, tumor-derived, tissue factor–positive microparticles (TF⁺ MPs) have emerged as potent drivers of cancer-associated thrombosis and possibly DIC. These small (0.1–1 µm) membrane vesicles bud from cancer cell surfaces and carry procoagulant factors (phosphatidylserine and TF) on their surface. We review how TF⁺ MPs are generated by tumor cells and amplify the extrinsic coagulation cascade, potentially triggering DIC in patients with advanced gynecologic cancers. Clinical studies have linked el evated TF⁺ MP levels and activity to venous thromboembolism (VTE) in cancer, and small case series suggest dramatically high MP–TF activity in cancer-related DIC. We summarize evidence that TF⁺ MPs from ovarian tumors carry exceptionally high TF procoagulant activity (median ~80 pg/mL), and nearly all patients with cancer-associated VTE or DIC have MP–TF levels above normal. This review discusses diagnostic implications (e.g., measuring MP–TF activity as a biomarker) and treatment strategies (through the reduction in tumors, anticoagulation, and experimental TF inhibitors) in this setting. We also identify gaps in knowledge (standardized MP assays, prospective studies) and propose future directions (targeting MP formation or TF signaling). Two summary tables highlight recent studies of TF⁺ MPs in gynecologic cancer and their clinical outcomes. Illustrative figures depict the TF⁺ MP-triggered coagulation cascade and a conceptual framework for clinical management. Understanding TF⁺ MPs in gynecological cancer could improve the prediction and management of DIC and related thromboses. Full article

Conventional wisdom holds that nuclear oncogenes and tumor suppressors initiate malignant transformation. However, mounting research suggests that mitochondrial dysfunction—rooted in the unique evolutionary history and genetic autonomy of mitochondria—may serve as a more fundamental driver of oncogenesis. This paper proposes a “mitochondria-first” hypothesis of cancer, emphasizing the pivotal role of mitochondrial DNA (mtDNA) mutations, metabolic reprogramming, and immune evasion. By examining the evolutionary conflict between host and mitochondria, evaluating high mtDNA mutation rates, and highlighting the disruptive potential of mitochondrial transfer to immune cells, we outline robust mechanisms through which mitochondria could ignite cancer development. We also discuss emerging diagnostic and therapeutic approaches that target mitochondrial integrity, offering a potential paradigm shift in oncology. Full article

Background: Prostate cancer is a leading malignancy among men globally, with its incidence expected to rise due to aging populations and shifting lifestyles. While established risk factors include age, ethnicity, and genetics, the role of modifiable dietary factors, particularly sugar intake, remains less clear. Emerging evidence suggests that high sugar consumption may promote carcinogenesis through insulin resistance, chronic inflammation, and hormonal dysregulation. This systematic review aimed to evaluate the current evidence on the association between dietary sugar intake and prostate cancer risk. Methods: A systematic search was conducted across six databases for observational studies published between January 2005 and April 2025. Eligible studies assessed the associations between quantitative sugar intake and prostate cancer outcomes. Screening, data extraction, and a risk of bias assessment (using ROBINS-E) were performed independently by multiple reviewers. Results: Six studies met the inclusion criteria, comprising four prospective cohorts, one case–control study, and one cross-sectional study, with a combined sample of 11,583 men from the USA, Canada, Sweden, and France. Three studies reported a significant positive association between a high intake of dietary sugars and prostate cancer risk, two found no association, and one showed mixed findings depending on the type of sugar. Heterogeneity in the exposure assessments and confounder control limited the comparability. Conclusions: This review suggests a possible association between high dietary sugar intake and increased prostate cancer risk, especially from added sugars and sugar-sweetened beverages. However, inconsistent findings and methodological limitations highlight the need for robust, prospective studies with standardized assessments to understand this relationship better. Full article

Background: Hepatocellular carcinoma (HCC) remains a significant global health burden, particularly among vulnerable populations. This retrospective study investigates trends in HCC incidence and age at diagnosis within an urban medical center population, focusing on the impact of hepatitis C virus (HCV) treatment and racial disparities. Methods: The study includes 484 patients diagnosed with HCC between 2000 and 2023. Results: A significant decline in HCC incidence was observed with a peak in incidences between 2015 and 2017 (p < 0.02). The increase and subsequent decline were driven by a decline in HCV-related cases, particularly among the African American (AA) population. This trend was not seen for patients with other risk factors for HCC. An increase in age at diagnosis in HCV patients but not other risk patients was observed in AA (62 vs. 69 years p = 0.001) but not non-AA patients (66 vs. 67 p = 0.16). This increase in age for AA HCV patients could be due to an aging population, changing risk factor profiles, and/or limitations in surveillance and early detection of HCC. Conclusions: This study highlights the critical role of HCV treatment in reducing HCC incidence, particularly within the AA population. These findings emphasize the need for sustained efforts in surveillance, early detection, and targeted prevention strategies to address the evolving epidemiology of HCC and improve outcomes across all populations. Full article

Introduction: This article provides a comprehensive analysis of predictive models for individual cancer risk, examining their development, application, and evaluation. The study covers various cancer types, highlighting the diversity and sophistication of models over time. Methods: Utilizing data from PubMed, Web of Science, and Scopus, the research includes models developed for 22 cancer types, with significant emphasis on breast and colorectal cancers due to their prevalence and early detection benefits. Results: The analysis reveals an uneven distribution of models, often concentrated in the United States and the United Kingdom, with a notable gap in models for rarer cancers. Key methodologies such as logistic regression and Cox proportional hazards models dominate the field, reflecting a preference for established statistical techniques. The study underscores the importance of incorporating multiple risk factors, including genetic, environmental, lifestyle, and clinical data, to enhance predictive accuracy. Despite advancements, the article identifies a critical need for external validation and standardization in reporting practices to improve model reliability and generalizability. Conclusions The findings emphasize the potential of these models in personalized cancer prevention and early detection, while also calling for continued research and methodological harmonization to address existing gaps and challenges. Full article

Gliomas are incurable, heterogeneous brain tumors, with rare forms often constituting diagnostic and treatment challenges. Molecular diagnostics, mainly implemented through the World Health Organization (WHO) 2021 guidelines, have refined the classification, but highlight difficulties in diagnosing rare gliomas remain. This case series analyzes four patients with rare gliomas treated at the University Hospital, Ulm, between 2002 and 2024. Patients were selected based on unique histopathological features and long-term clinical follow-up. Clinical records, imaging, and histological data were reviewed. Molecular diagnostics followed WHO 2021 guidelines. Quality of life was assessed using standardized tools including the EQ-5D-5L, EQ VAS, the Distress Thermometer, and the Montreal Cognitive Assessment (MoCA). In the first case, a 51-year-old male’s diagnosis evolved from pleomorphic xanthoastrocytoma to a high-grade glioma with pleomorphic and pseudopapillary features, later identified as a neuroepithelial tumor with a PATZ1 fusion over 12 years. Despite multiple recurrences, extensive surgical interventions led to excellent outcomes. The second case involved a young female with long-term survival of astroblastoma, demonstrating significant improvements in both longevity and quality of life through personalized care. The third case involved a patient with oligodendroglioma, later transforming into glioblastoma, emphasizing the importance of continuous diagnostic reevaluation and adaptive treatment strategies, contributing to prolonged survival and quality of life improvements. Remarkably, the patient has achieved over 20 years of survival, including 10 years of being both therapy- and progression-free. The fourth case presents a young woman with neurofibromatosis type 1, initially misdiagnosed with glioblastoma based on histopathological findings. Subsequent molecular diagnostics revealed a subependymal giant cell astrocytoma-like astrocytoma, highlighting the critical role of early advanced diagnostic techniques. These cases underscore the importance of precise molecular diagnostics, individualized treatments, and ongoing diagnostic reevaluation to optimize outcomes. They also address the psychological impact of evolving diagnoses, stressing the need for comprehensive patient support. Even in complex cases, extensive surgical interventions can yield favorable results, reinforcing the value of adaptive, multidisciplinary strategies based on evolving tumor characteristics. Full article

Breast cancer is one of the most common and difficult-to-treat cancers affecting women globally. Long-term treatment success is still limited by problems like drug resistance, toxicity, and recurrence, even with advancements in conventional therapies. The application of substances derived from plants for medical purposes, or phytotherapy, has become a viable adjunctive approach to the treatment of breast cancer. An integrative approach to phytotherapy is examined in this review, focusing on how it can alter important molecular pathways implicated in the development, progression, and metastasis of breast cancer. By focusing on important signaling cascades like TGF-β, Wnt, Hedgehog, Notch, IL-6, Integrins, VEGF, HER2, EGFR, PI3K/Akt, and MAPK, and estrogen receptor pathways, a variety of phytochemicals, such as flavonoids, alkaloids, terpenoids, and polyphenols, demonstrate strong anticancer effects. This review also discusses how they affect immune modulation, angiogenesis, cell cycle regulation, and apoptosis. Moreover, it also emphasizes the challenges with these natural compounds’ bioavailability, standardization, and clinical translation while highlighting preclinical and clinical research that supports their therapeutic potential. This review attempts to give a thorough grasp of how plant-based compounds can support efficient and focused breast cancer treatments by fusing molecular insights with phytotherapeutic approaches. Full article

The applicability of RHT in the treatment and supportive care of tumors has been discussed for years in many publications. There are hundreds of articles that have reported on the good acceptance and feasibility of HT, as well as its value in terms of controlling malignant diseases, enhancing response and, in some randomized controlled trials (RCTs), clear improvements in OS. Despite this, HT has never fully been accepted as a standard treatment among radiation and medical oncologists. The increased activity that HT offers in the context of chemotherapy (CHT), radiotherapy (RT), chemoradiotherapy (CRT), and immunotherapy, thus facilitating programmed cell death (PCD), has been documented in many studies. This aspect has been demonstrated in many tumors, including soft tissue sarcoma, cancers of the cervix, esophagus, stomach, colon/rectum, pancreas, breast, head and neck, and prostate, and bone metastases. HT improves cancer cell death through many modalities, targeting both the tumor microenvironment (TME) and the cancer cells directly. Targeted HT increases the temperature of the primary tumor and surrounding tissues to 39–43 °C, causing the tumor cells to become more immune-responsive. HT can also activate the immune response of the TME through inducing heat shock proteins (HSPs), which also promote an immunological response and PCD. HT can oxygenate hypoxic tumors, facilitating RT-induced DNA damage in cancer cells. At present, it seems that the combination of HT and RT, CHT, and immunotherapy might lead to immune enhancement effects in the TME, making cancer cells more responsive to immunotherapies. This narrative review presents the novel aspects of HT reported in recent years. Full article

Tumor cells and the tumor microenvironment (TME) produce factors, including neurotrophins, that induce axonogenesis and neurogenesis, and increase local nerve density. Proliferative growing cancer cell clusters and disseminated invasive tumor cells undergoing partial epithelial-to-mesenchymal transition (pEMT) can invade peripheral nerves. In the early stages of tumor–nerve interactions, Schwann cells (SCs) dedifferentiate, become activated and migrate to cancer cell nests; later, they induce pEMT in tumor cells and activate tumor cell migration along nerves. The SC–tumor–nerve interaction attracts myeloid-derived suppressor cells (MDSCs) and inflammatory monocytes, and the latter differentiate into macrophages. SCs and MDSCs are responsible for the activation of transforming growth factor-beta (TGF-beta) signaling. Intra-tumoral innervation is followed by perineural invasion (PNI), which has an unfavorable prognosis. What are the interventional options against PNI: local reduction in tumor nerves or inhibition of TGF-beta-related events, inhibition of downstream signaling of TGF-beta or immune activation, or intervention against immunosuppression? This systematic review is based on the Prisma 2009 search method and provides an overview of tumor–nerve interaction. Full article

Globally, women’s cancer-related morbidity and death are still caused mainly by gynecologic cancer. Antioxidant and anti-inflammatory drugs have shown promise in treating gynecologic cancer because of the complex interactions among oxidative stress, inflammation, and the development of tumors. This review focuses on how these drugs, which include polyphenols, terpenoids, and thiols-related phytochemical-derived compounds target different pathways associated with developing and progressing gynecologic cancer. We investigate what factors affect the tumor microenvironment, specifically how they affect immunological response and vasculogenesis. Through the review of recent studies, we have gained an extensive understanding of the molecular pathways that anti-inflammatory and antioxidant drugs use to achieve their therapeutic benefits. Gynecologic cancer is still a potent cause of cancer-related deaths and fatalities for women globally. Antioxidant and anti-inflammatory drugs have shown promise in treating gynecologic cancer because of the complex interactions among oxidative stress, inflammation, and the development of tumors. This review focuses on how these drugs target different pathways associated with developing and progressing gynecologic cancer. We investigate what factors affect the tumor microenvironment, specifically how they affect immunological response and vasculogenesis. Through the review of recent studies, we have gained an extensive understanding of the molecular pathways that anti-inflammatory and antioxidant drugs use to achieve their therapeutic benefits. Full article

Approximately 5.4 million nonmelanoma skin cancers are treated each year in the US. Of this number 80 to 90% are basal cell carcinomas. In this study, we compare optical coherence tomography (OCT) images and vibrational optical coherence tomography (VOCT) measurements made on small and large nodular basal cell carcinomas (BCCs) using histopathology, OCT images, and VOCT physical measurements. OCT images were broken into green, blue, and red subchannel images and compared to histopathology conducted on the excised tissue. While our results suggest that both small and large BCCs have similar morphologies that include circular nodules with palisading cells surrounding the lesions, no part of the excised lesions appeared like normal skin. In the small lesion, the nodule is surrounded by tissue that may be considered to have “clear” margins even though the rete ridges are missing, and the ECM does not resemble normal skin. The edges of the lesion are free of palisading cells with only some inflammatory cells being present. In contrast, the mechanovibrational spectrum of the large lesion appeared to have an increased amount of large fibrotic peaks with decreased vibrations for normal cells and cancer-associated fibroblasts compared to the smaller nodule. These results indicate that it is possible to identify the location of the BCC nodules noninvasively using VOCT. The ability to noninvasively identify nodular BCCs using this technique makes it a useful adjunct to visual inspection and dermoscopy to identify cancerous lesions seen in the clinic. Since VOCT can be operated remotely, it can serve as a noninvasive screening tool to be used by general practitioners in areas where dermatologists are in short supply. Full article

Background: Our goal was to assess the diagnostic performance of the IOTA 3-step strategy for discriminating benign from malignant adnexal masses. Methods: Systematic review and meta-analysis design. A systematic search across three databases (Medline [PubMed], SCOPUS, and Web of Science) was conducted to identify primary studies reporting on the use of the IOTA three-step strategy from January 2012 to July 2024. Prospective cohort studies utilizing the three-step strategy, with histologic diagnosis or conservative management confirming spontaneous resolution or persistence in cases of benign-appearing masses for at least one year of follow-up, were used as the reference standard. Studies unrelated to the topic, those not addressing the IOTA three-step strategy, studies focusing on other prediction models, letters to the editor, commentaries, narrative reviews, consensus documents, and studies lacking data for constructing a 2 × 2 table were excluded. Quantitative synthesis was done, calculating the pooled sensitivity, specificity, and positive and negative likelihood ratios. Qualitative synthesis was done using QUADAS-2. Results: A total of 448 citations were initially identified, with 7 studies meeting inclusion criteria, comprising 5722 patients. The mean prevalence of ovarian malignancy was 28%. The quality of the studies was considered good. IOTA 3-step strategy showed a pooled sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio of the three-step strategy for adnexal mass classification were 94% (95% CI = 91–95%), 94% (95% CI = 91–97%), 17.0 (95% CI = 10–28.8), and 0.07 (95% CI = 0.05–0.1), respectively. Heterogeneity for sensitivity was moderate, and for specificity it was high. Conclusions: We conclude that the three-step strategy has good diagnostic performance, reducing the need for expert examiner evaluation. Full article

Background/Objectives: Multiple myeloma is a malignancy of plasma cells detected in the bone marrow, inducing symptoms like anemia, hypercalcemia, renal problems, and bone fractures in multiple myeloma patients, affecting their quality of life. The bone marrow microenvironment plays a crucial role in the prognosis and progression of the disease. The purpose of this study was to examine the relationship between the percentages of the major cell populations of the bone marrow, including immune cells, and physical function/quality of life in multiple myeloma patients after first-line treatment. Methods: Twenty-one multiple myeloma patients (N = 14 men, N = 7 women) participated in the study after completing first-line treatment. Bone marrow and blood samples were taken one hundred days after transplantation, while physical function (6 min walking test, handgrip test, maximal aerobic power, and isometric strength), health-related quality of life (QLQ-C30), and body composition (DXA) were assessed 2–5 days later. Flow cytometry was used to assess the percentages of plasma cells, mast cells, B cells (total, precursors, naïve, and memory), T cells (total, CD27− and CD27+), NK/NKT cells (total, CD27− and CD27+), eosinophils, monocytes, neutrophils, myeloid progenitors, erythroblasts, and erythroid progenitors, expressed as percentages of total nucleated cells of the bone marrow. Results: The percentage of CD27+ NK/NKT cells was correlated with five parameters of the quality of life questionnaire: physical function (r = 0.78, p = 0.005), role functioning (r = 0.69, p = 0.020), fatigue (r = −0.86, p = 0.000), pain (r = 0.68, p = 0.021), and dyspnea (r = −0.80, p = 0.003). Conclusions: In conclusion, stronger immune surveillance in the bone marrow from CD27+ NK/NKT cells is correlated with better quality of life in multiple myeloma patients. Full article

Background: Adult granulosa cell tumours (AGCT) of the ovary account for 2–5% of ovarian tumours, with 30% occurring in women of childbearing age. Despite a good prognosis, up to 25% recur. There is a paucity of high-quality evidence to guide management. Objective: To describe management of AGCT across multiple gynaecological cancer centres. Methods: Retrospective analysis of electronic patient records from six gynaecological cancer centres in Southwest England between 2000 and 2021 (n = 119). Results: We included 107 patients with a median follow-up of 60 months (0–261 months). Most (97/107; 90.7%) were diagnosed with stage I disease (31.8% stage Ic). Primary management was staging surgery in 33/107 (30.8%), hysterectomy and bilateral salpingo-oophorectomy (BSO) (28/107; 26.2%), or conservation of an ovary (17/107; 15.9%). Three had a subsequent pregnancy. A quarter (27/107; 25.2%) were diagnosed with recurrent disease. Fifteen patients (15/107; 14%) had multiple recurrences. Recurrence was more likely if cyst rupture was reported at surgery (38.7%) compared with no rupture (14.3%; p < 0.001). The recurrence rate was higher with ovarian conservation (6/17; 35.3%) compared with BSO (21/90; 23.3%; p < 0.01), and all recurrences involved the residual ovary. Of the 11 deaths, 6 (54.5%) were attributed to progressive disease. Conclusions: Although survival with early-stage disease is good, ovarian cystectomy or unilateral ovarian conservation was associated with increased risk of recurrence. There is no conclusive evidence to support a contralateral oophorectomy in pre-menopausal women, but completion surgery should at least be considered, either immediately or after childbearing/assisted reproductive treatment. Full article

Background: Adult B-cell acute lymphoblastic leukaemia (aB-ALL) is characterised by abnormal differentiation and proliferation of lymphoid progenitors. Despite a significant improvement in relapse-free and overall survival for children with B-ALL, aB-ALL has a particularly poor prognosis with a 5-year survival rate of 20%. First remission is achieved for most patients, but relapse is common with a high associated mortality. New treatments such as immunotherapy offer an opportunity to extend remission and prevent relapse. Methods: aB-ALL antigens were identified using different sources—immunoscreening, protoarrays, two microarrays and one cancer-testis antigen database, and a review of the genomic analyses of aB-ALL. A total of 385 aB-ALL-associated gene products were examined for their association with patient survival. Results: We identified 87 transcripts with differential expression between aB-ALL and healthy volunteers (peripheral blood, bone marrow and purified CD19⁺ cells), and 42 that were associated with survival. Enrichr analysis showed that the Transforming Growth Factor-β (TGFβ), Wnt and Hippo pathways were highly represented (p < 0.02). We found that SOX4 and ROCK1 were upregulated in all types of B-ALL (ROCK1 having a p < 0.001 except in t(8;14) patients), as well as SMAD3 and TEAD4 upregulation being associated with survival (p = 0.0008, 0.05 and 0.001, respectively). Expression of each aB-ALL antigen was verified by qPCR, but only TEAD4 showed significant transcript upregulation in aB-ALL compared to healthy volunteer CD19+ cells (p = 0.01). Conclusions: We have identified a number of antigens and their pathways that play key roles in aB-ALL and may act as useful targets for future immunotherapy strategies. Full article

Breast cancer is a complex disease that is one of the leading causes of cancer-related mortality in women worldwide. Of the subtypes of breast cancer, the most aggressive subtype is triple negative breast cancer (TNBC) due to its lack of targets that could be leveraged for treatment in other subtypes. Current treatment options for both local and metastatic TNBC include radiation therapy, chemotherapy, surgery, targeted therapy, and immunotherapy, which has been gaining popularity in recent years. The role of targeted therapy in TNBC is somewhat limited due to the paucity of therapeutic personalized targets, and, due to the heterogeneity of the disease, the effectiveness of these different modalities varies from patient to patient. These unique elements are the foundation of personalized medicine where genomics and transcriptomics play a critical role in increasing granularity in patients’ disease and treatment. The purpose of these molecular tools is to identify biomarkers that could be used to further characterize each patient’s unique disease features and to predict how certain treatment modalities will affect patient survival and prognosis. The interplay between these biomarkers and molecular pathways involved in treatment response with disease progression and aggressiveness is a complex phenomenon. In this review, we describe the current state of the literature in regard to biomarkers that show promise in the clinical setting to predict response to treatments such as chemotherapy, radiation, and surgery in locally advanced and metastatic TNBC. Full article

Organoid culture is an emerging and promising 3D culture system by which three-dimensional cell aggregates have been produced from different organs and tissues. This new innovative culture technology preserves parental gene expression, as well as the biological features of parental cells in vitro and ensures maintenance of three-dimensional cell culture for prolonged periods, opening new encouraged scientific scenarios and making them a functioning and valid system for testing new drugs for tissue engineering studies and precision oncology medicine. Various research focused on organoids has been performed in perfusion bioreactors, an advanced device able to mimic the tumor environment, providing a physiological growth state and a long-term culture viability. Perfusion bioreactors have been used for the maintenance and growth of organoids as well as for tumor patient samples improving proliferation while supporting the development of extracellular matrix (ECM). The ability to mimic the tumor environment and to maintain patient-derived biopsies for a long time makes perfusion bioreactors an essential model for preclinical testing. Full article

Peritoneal carcinomatosis is a common presentation found in advanced-stage gastrointestinal (GI) and gynecological cancers. Combined cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is associated with significant survival benefits for select patients. CRS/HIPEC is not currently provided in Newfoundland and Labrador (NL). The Canadian HIPEC Collaborative Group recommends that centres complete a minimum of one case monthly to maintain competency and achieve good outcomes. Thus, we aimed to demonstrate that the annual patient volume in NL justifies the feasibility of implementing a combined surgical and gynecological oncology CRS/HIPEC program. Methods: A retrospective chart review of the NL Cancer Care Registry identified patients with stage IV colorectal, appendiceal, or gastric cancer and stage III to IV epithelial ovarian cancer over a 1-year period (1 January 2020–31 December 2020) to identify the number of patients meeting the criteria for CRS/HIPEC and/or those referred out of province to receive the treatment. The results are presented as proportions and percentages. Results: Thirty-one patients were eligible to receive CRS/HIPEC during the study period (11 GI, 20 gynecological). Of the GI patients, 63% were referred out of province for the procedure. Gynecological patients underwent CRS and systemic therapy +/− outpatient intraperitoneal chemotherapy in NL. Conclusions: Allowing patients to receive this standard of care treatment near home reduces financial, social, and emotional stressors. Our results confirm a sufficient patient volume to support a combined CRS/HIPEC program in NL. The implementation of this program will require multidisciplinary collaboration, specialized training, equipment, and protocol development. Full article

Background: Few studies have compared the risk of reoperation by timing in breast reconstruction surgery after mastectomy. We evaluated the first and total number of reoperations by reconstruction timing in women with breast cancer undergoing primary mastectomy. Methods: A cohort study of 23,301 primary mastectomies in women with breast cancer undergoing either immediate breast reconstruction (IBR) or delayed reconstruction was carried out within Kaiser Permanente between 2010 and 2022. The first reoperation rate was calculated using cause-specific Cox Proportional Hazards Models, while Multiplicative Cox Proportional Hazards Models were used to account for mortality and timing in reoperation. Patients were continuously monitored for death, outcome of interest, loss to follow-up through healthcare membership termination, or study end date (31 December 2022). Results: In total, 78.4% (n = 18,276) of the cohort underwent IBR. The average follow-up time was 5.9 years (±3.8). The following covariates were imbalanced (standardized mean difference [SMD] ≥ 0.20) between IBR and delayed groups: BMI, smoking status, year of mastectomy, bilateral procedures, and reconstruction type. The crude incidence of first reoperation was 33.04% vs. 31.72% in IBR vs. delayed patients and the risk of reoperation was 18% higher in IBR patients (HR = 1.18, 95% CI = 1.12–1.25). There was no difference in the risk of reoperation by timing (p > 0.05) when assessing multiple reoperations. The reoperation risk was the highest for IBR patients who did not complete reconstruction or single-stage reconstruction. In addition, the first reoperation rate of IBR patients was higher in those who underwent expander–implant-based reconstruction. Conclusions: The first reoperation rate was higher in IBR patients compared to those who delayed reconstruction, although we failed to detect a difference for multiple returns to surgery, except in certain subgroups. Assessing reoperation risk by timing among different reconstruction modalities can aid patients in making informed decisions about the type of breast reconstruction to undergo. Full article