Re-irradiation of recurrent head and neck cancers using pulsed reduced dose rate radiotherapy: An institutional series.

PURPOSE/OBJECTIVE(S): Pulsed reduced dose rate (PRDR) radiation (RT) is a re-irradiation (Re-RT) technique that potentially overcomes dose/volume constraints in the setting of previous RT. There is minimal data for its use for recurrent or secondary primary head and neck squamous cell carcinoma (HNSCC). In this study, we report preliminary data from our institution of a consecutive cohort of HNSCC patients who received PRDR Re-RT. MATERIALS/METHODS: Nine patients received PRDR Re-RT from August 2020 to January 2023 and had analyzable data. Intensity modulated RT was used for treatment delivery and a wait time between 20 cGy arc/helical deliveries was used to achieve the effective low dose rate. Data collected included patient demographic information, prior interventions, diagnosis, radiation therapy dose and fractionation, progression free survival, overall survival, and toxicity rates. RESULTS: The median time to PRDR-RT from completion of initial RT was 13 months (range, 6-50 months). All but one patient underwent salvage surgery prior to PRDR-RT. The median follow-up after Re-RT was 7 months. The median OS from PRDR-RT was 7 months (range, 1-32 months). Median PFS was 7 months (range, 1-32 months). One patient (11.1 %) had acute grade 3 toxicity, and two patients (22.2 %) had late grade 3 toxicities. There were no grade 4+ toxicities. CONCLUSION: PRDR Re-RT is a feasible treatment strategy for patients with recurrent or second primary HNSCC. Initial findings from this retrospective review suggest reasonable survival outcomes and potentially improved toxicity; prospective data is needed to establish the safety and efficacy of this technique.

A Prospective Study Measuring Resident and Faculty Contour Concordance: A Potential Tool for Quantitative Assessment of Residents' Performance in Contouring and Target Delineation in Radiation Oncology Residency.

PURPOSE/OBJECTIVE(S): Accurate target delineation (ie, contouring) is essential for radiation treatment planning and radiotherapy efficacy. As a result, improving the quality of target delineation is an important goal in the education of radiation oncology residents. The purpose of this study was to track the concordance of radiation oncology residents' contours with those of faculty physicians over the course of 1 year to assess for patterns. MATERIALS/METHODS: Residents in postgraduate year (PGY) levels 2 to 4 were asked to contour target volumes that were then compared to the finalized, faculty physician-approved contours. Concordance between resident and faculty physician contours was determined by calculating the Jaccard concordance index (JCI), ranging from 0, meaning no agreement, to 1, meaning complete agreement. Multivariate mixed-effect models were used to assess the association of JCI to the fixed effect of PGY level and its interactions with cancer type and other baseline characteristics. Post hoc means of JCI were compared between PGY levels after accounting for multiple comparisons using Tukey's method. RESULTS: In total, 958 structures from 314 patients collected during the 2020-2021 academic year were studied. The mean JCI was 0.77, 0.75, and 0.61 for the PGY-4, PGY-3, and PGY-2 levels, respectively. The JCI score for PGY-2 was found to be lower than those for PGY-3 and PGY-4, respectively (all P < .001). No statistically significant difference of JCI score was found between the PGY-3 and PGY-4 levels. The average JCI score was lowest (0.51) for primary head and/or neck cancers, and it was highest (0.80) for gynecologic cancers. CONCLUSIONS: Tracking and comparing the concordance of resident contours with faculty physician contours is an intriguing method of assessing resident performance in contouring and target delineation and could potentially serve as a quantitative metric, which is lacking currently, in radiation oncology resident evaluation. However, additional study is necessary before this technique can be incorporated into residency assessments.

Opioid Use in Patients With Cervical Cancer at a Tertiary Academic Medical Center.

BACKGROUND/AIM: Opioids are a common treatment for cancer-related pain and information is limited on the rates of opioid use for cervical cancer patients. This study aimed to analyze outpatient opioid use and various predictors among patients with cervical cancer at a tertiary academic medical center. PATIENTS AND METHODS: Data from patients with cervical cancer receiving treatment at a single institution, from August 2019 to July 2022, were retrospectively collected. Women with unrelated chronic opioid use or opioid use associated with acute inpatient stays were excluded. Charts were reviewed for patient demographics, disease characteristics, treatment characteristics, disease outcomes, and opioid prescriptions. The primary endpoint was duration of opioid use ≥6 months. Pearson's chi-squared testing, Welch's two-sample t-testing and Fisher's exact testing were used to determine predictors of opioid use ≥6 months. RESULTS: In total, 108 patients with cervical cancer (76.1%) of the 142 that received treatment were prescribed opioids. In women who were prescribed outpatient opioids, the median duration of opioid use was 69 days (interquartile range=5-359 days). In total, 40 (37.0%) had prescriptions for ≥180 days and 27 (25.0%) had prescriptions ≥365 days. On bivariate analysis, lower stage and receipt of surgery were associated with opioid use duration <6 months. Age, race, histology, substance/tobacco/alcohol use, depression/anxiety, and the receipt of brachytherapy/radiation were not associated with length of opioid prescriptions. CONCLUSION: This study demonstrated that 37% of patients with cervical cancer were using opioids for cancer-related pain longer than 6 months. Higher stage was associated with opioid use duration ≥6 months.

The Effects of the COVID-19 Pandemic on Cancer Staging in Patients Diagnosed With Head and Neck Cancer.

Purpose The healthcare system across the world was forced to implement new policies, guidelines, and procedures due to the coronavirus disease 2019 (COVID-19) pandemic, which led many patients to make an impossible choice about their health. For various reasons, many patients chose to remain at home and delay any interaction at medical facilities to protect themselves or others from the virus. Patients managing chronic diseases faced unprecedented challenges during this period, and the long-term effects on these patient populations remain unclear. Oncology patients, specifically those diagnosed with head and neck cancers, require prompt diagnosis and initiation of treatment for better outcomes. While the overall impact of how the pandemic has affected oncology patients is unknown, this retrospective study examined how the staging of head and neck tumors at our institution has been impacted since the beginning of the pandemic. Methods Available patient data (from August 1, 2019, through June 28, 2021) were collected from medical records and compared to determine statistical significance. Patients were categorized into a Pre-pandemic group, Pandemic group, and Vaccine-approved group, and patient and treatment characteristics were analyzed to look for patterns. The pre-pandemic period was defined as the period from August 1, 2019, to March 16, 2020, the pandemic period was defined as the period from March 17, 2020, to December 31, 2020, and the vaccine-approved period was defined as the period from January 1, 2021, to June 28, 2021.  Results Fisher's exact tests were used to compare tumor, node, metastasis (TNM) staging distributions between the three groups. In the Pre-pandemic group, out of 67 patients, 33 patients (55.0%) were diagnosed with a T stage of 0-2 and 27 patients (45.0%) were diagnosed with a T stage of 3-4. In the Pandemic and Vaccine-approved groups, out of 139 patients, 50 patients (39.1%) were diagnosed with a T stage of 0-2 and 78 patients (60.9%) were diagnosed with a T stage of 3-4; these differences were statistically significant (P-value = 0.0426). The Pre-pandemic group had 25 patients (41.7%) diagnosed with a group stage of 0-2 and 35 patients (58.3%) diagnosed with a group stage of 3-4. The Pandemic and Vaccine-approved groups had 36 patients (28.1%) diagnosed with a group stage of 0-2 and 92 patients (71.9%) diagnosed with a group stage of 3-4; these results trended to statistically significant (P-value = 0.0688). Conclusions Our findings suggest that there have been a higher number of patients with head and neck cancer diagnosed with a T stage of 3 or 4 since the start of the COVID-19 pandemic. The effects of the COVID-19 pandemic are ongoing and will need further evaluation to determine the overall effects on oncology patients. Increased morbidity and mortality rates may be a potential result in the years to come.

Impact of COVID-19 on public's interest in radiotherapy and other cancer treatments: a cross-sectional Google Trends analysis.

Background: COVID-19 has significantly impacted cancer care. While previous studies have emphasized treatment modification and prioritized the delivery of cancer care, few have examined this issue from the public perspective. Materials and methods: In the following study, we examine how public interest in various forms of cancer treatment has evolved during the pandemic using Google Trends. One-way ANOVA and linear regression tests were used to compare the mean search volume indices of three periods: pre-lockdown, lockdown, and reopening. Results/Conclusions: Our findings suggest that public interest in cancer treatments decreased during lockdown and returned after reopening but, in general, is still lower than pre-lockdown levels. Despite that, healthcare professionals should strive to provide timely cancer care, assuage patients' fears of healthcare settings, and encourage patients to continue proper cancer screenings.

Comparison of Survival Outcomes With/Without Adjuvant Radiation Therapy in Desmoplastic Melanoma.

BACKGROUND: Desmoplastic melanoma (DM) is a rare variant of cutaneous melanoma with a high rate of local recurrence. Recent studies have indicated a potential benefit in local control with the addition of adjuvant radiotherapy (RT). OBJECTIVE: This study sought to evaluate the outcomes of adjuvant RT for patients with DM. MATERIALS AND METHODS: The National Cancer Database was queried (2004-2015) for patients with newly diagnosed, nonmetastatic DM. Patients were divided into 2 groups based on the adjuvant therapy they received: RT or observation. Statistics included multivariable logistic regression to determine factors predictive of receiving adjuvant RT, Kaplan-Meier analysis to evaluate overall survival (OS), and Cox proportional hazards modeling to determine variables associated with OS. RESULTS: There was no difference in median OS between patients treated with RT when compared with patients observed (111.4 months vs 133.9 months, p = .1312). On multivariable analysis, older age, T stage ≥2, N stage ≥1, and no receipt of immunotherapy were associated with worse OS. CONCLUSION: In this large study evaluating efficacy of adjuvant RT in DM, no overall survival benefit was observed among patients receiving adjuvant RT.

The impact of HER2-directed targeted therapy on HER2-positive DCIS of the breast.

BACKGROUND: In invasive breast cancer, HER2 is a well-established negative prognostic factor. However, its significance on the prognosis of ductal carcinoma in situ (DCIS) of the breast is unclear. As a result, the impact of HER2-directed therapy on HER2-positive DCIS is unknown and is currently the subject of ongoing clinical trials. In this study, we aim to determine the possible impact of HER 2-directed targeted therapy on survival outcomes for HER2-positive DCIS patients. MATERIALS AND METHODS: The National Cancer Data Base (NCDB) was used to retrieve patients with biopsy-proven DCIS diagnosed from 2004-2015. Patients were divided into two groups based on the adjuvant therapy they received: systemic HER2-directed targeted therapy or no systemic therapy. Statistics included multivariable logistic regression to determine factors predictive of receiving systemic therapy, Kaplan-Meier analysis to evaluate overall survival (OS), and Cox proportional hazards modeling to determine variables associated with OS. RESULTS: Altogether, 1927 patients met inclusion criteria; 430 (22.3%) received HER2-directed targeted therapy; 1497 (77.7%) did not. Patients who received HER2-directed targeted therapy had a higher 5-year OS compared to patients that did not (97.7% vs. 95.8%, p = 0.043). This survival benefit remained on multivariable analysis. Factors associated with worse OS on multivariable analysis included Charlson-Deyo Comorbidity Score ≥ 2 and no receipt of hormonal therapy. CONCLUSION: In this large study evaluating HER2-positive DCIS patients, the receipt of HER2-directed targeted therapy was associated with an improvement in OS. The results of currently ongoing clinical trials are needed to confirm this finding.

Radiation treatment for refractory endometriosis: a 38-year-old female presenting with vaginal bleeding.

BACKGROUND: Endometriosis is typically managed with a medical or surgical approach, though some patients have medically refractory disease and are poor surgical candidates. CASE PRESENTATION: A 39-year-old woman presented to our facility with uncontrolled bleeding and pain from an endometriotic mass at the vaginal cuff. She had a history of abdominal hysterectomy with bilateral salpingo-oophorectomy, now with medically refractive and inoperable disease due to prior history of vesicovaginal fistula. We prescribed 30 Gy in 10 fractions with 10 MV and 18 MV photons to the target. At follow-up our patient reported a complete resolution of bleeding and pelvic pain. CONCLUSION: Radiation treatment can be an effective treatment for refractory endometriosis.

The Use of Crowdfunding to Support Radiation Therapy Cancer Treatments.

BACKGROUND/AIM: The purpose of this study was to assess patients' use of a crowdfunding platform to raise funds for radiation treatment and to better understand the direct and indirect costs associated with treatments. MATERIALS AND METHODS: The GoFundMe crowdfunding database was queried for four unique categories related to radiation treatment campaigns. Covariates identified included clinical and demographic variables, and associations between amount raised and these predictors were analyzed using a generalized linear model. RESULTS: While 56% percent of campaigns cited direct costs associated with treatment, 73.4% of campaigns cited indirect costs related to treatment. Indirect expenses related to travel (31.7%) as well as living expenses (29.2%) were cited most often across all four treatment categories. CONCLUSION: This study enhances understanding regarding patients use of crowdfunding for radiation treatment. Increased focus should be placed on discussing the indirect costs of care with patients and their families.

Salvage Radiation Treatment for Primary Refractory Diffuse Large B-cell Lymphoma After Chimeric Antigen Receptor (CAR) T-cell Therapy: A Case Report.

BACKGROUND: Treatment of refractory/relapsing diffuse large B cell (R/R DLBCL) lymphoma remains a challenge. Radiation therapy (RT) has versatile roles in R/R DLBCL treatment: it can be used in the peri-transplant setting for transplant-eligible candidates, or as a salvage or palliation therapy depending on the extent of the disease in transplant-ineligible patients. The introduction of chimeric antigen receptor (CAR) T-cell therapy has changed the landscape of R/R DLBCL. RT has been used as a bridging therapy to CAR T-cell therapy in order to control disease progression during its manufacturing period. However, optimal RT and CAR T-cell therapy integration is still unknown. Salvage strategies for R/R DLBCL post-CAR T-cell therapy have been little studied. CASE REPORT: Here, we present a case of primary refractory DLBCL with residual disease post-CAR T-cell therapy successfully treated with salvage RT. CONCLUSION: Radiotherapy could be an effective salvage strategy for R/R DLBCL post-CAR T-cell therapy. Exact mechanisms await exploring.

First reported case of concurrent sonidegib and radiotherapy for recurrent, advanced basal cell carcinoma.

Basal cell carcinoma (BCC ) is the most common human malignancy. Systemic therapy with a sonic hedgehog (SHH) pathway inhibitor plays an important role in the treatment of advanced BCC . Literature on concurrent use of radiation therapy (RT ) with SHH inhibitors has been minimal and has solely been focused on vismodegib. We present a case report of a patient with recurrent basal cell carcinoma involving the high-risk area of the face, who was denied surgery due to comorbidities and difficulty in obtaining complete tumor removal without cosmetic or functional impairment. The patient received combined treatment of fractionated radiation with concurrent sonidegib and had complete clinical response with no significant toxicities. This is the first reported case on the use of concurrent RT with sonidegib for management of recurrent basal cell carcinoma of the head and neck.

Eye plaque brachytherapy versus enucleation for ocular melanoma: an analysis from the National Cancer Database.

PURPOSE: There is no current randomized data comparing the efficacy of brachytherapy and enucleation for patients with larger sized tumors. The purpose of the present study was to use a large, contemporary database to determine current practice patterns and compare survival outcomes between different management options for patients with choroidal melanoma of various sizes. MATERIAL AND METHODS: The National Cancer Database was queried (2004-2014) for histologically-confirmed choroidal melanoma for patients treated with brachytherapy versus enucleation. Chi-square test was used to compare categorized demographic and clinical variables in both arms. Kaplan-Meier analysis evaluated overall survival (OS). Cox proportional hazards assessment determined variables associated with OS. Patients were divided into cohorts representing small, medium, and large tumors. Propensity scores matching (PSM) was utilized to compare more similar cohorts. RESULTS: A total of 7,096 patients met the selection criteria; 5,501 (78%) patients received brachytherapy and 1,595 (22%) patients were treated with enucleation. After PSM, 5-yr OS for small tumors was 87% vs. 64%, for medium tumors was 77% vs. 57%, and for large tumors was 68% vs. 46% for brachytherapy and enucleation, respectively (p < 0.001). Following PSM, multivariate Cox regression found older age (hazard ratio [HR] = 1.76, 95% confidence interval [CI] = 1.51-2.06), more comorbidities (HR = 1.46, 95% CI = 1.25-1.70), extraocular extension (EOE) (HR = 1.25, 95% CI = 1.06-1.48), ciliary body invasion (CBI) (HR = 1.20, 95% CI = 1.02-1.40), and larger size (HR = 1.52, 95% CI = 1.40-1.66) were negative prognosticators of survival. Brachytherapy was a positive prognosticator of survival (HR = 0.45, 95% CI = 0.40-0.51). CONCLUSIONS: Patients selected for brachytherapy had improved survival compared to enucleation in all size cohorts. EOE and CBI are significantly higher in the enucleation cohort and are important negative prognosticators for survival selected against patients having brachytherapy. Brachytherapy is a reasonable treatment option for certain patients with large size tumors.

Relationship Between Scholarly Activity and Postgraduate Career Choice: A Bibliometric Analysis of the 2017 Diplomates of the American Board of Dermatology.

BACKGROUND: Scholarly productivity is an assessment metric for dermatology residents and faculty. How the bibliometric h-index, a publicly available metric that incorporates the quantity and quality of publications, relates to early career choices of dermatologists has not been investigated. OBJECTIVE: We determined the h-indices of the 2017 diplomates of the American Board of Dermatology to ascertain its association with career choice. METHODS: A cross-sectional analysis was performed using the published list of the 2017 diplomates. Gender and PhD status were compiled. The Scopus database was queried for publications and h-indices. The primary outcome was the pursuit of an academic position, nonacademic position, or fellowship after board certification. RESULTS: Among 475 (96%) diplomates, the median (range) h-index was 2 (0-14). Those with MD and PhD degrees had greater h-indices (6.4 ± 3.1 vs. 2.3 ± 2.3, P < .05). There was a difference (P < .05) in h-index between diplomates pursuing an academic position (3.6 ± 3.1), non-procedural fellowship (3.3 ± 3.1), procedural fellowship (2.5 ± 2.0), and non-academic position (2.1 ± 2.1). CONCLUSIONS: The h-index quantifies academic productivity and may predict early career choices in dermatology.

Machine Segmentation of Pelvic Anatomy in MRI-Assisted Radiosurgery (MARS) for Prostate Cancer Brachytherapy.

PURPOSE: To investigate machine segmentation of pelvic anatomy in magnetic resonance imaging (MRI)-assisted radiosurgery (MARS) for prostate cancer using prostate brachytherapy MRIs acquired with different pulse sequences and image contrasts. METHODS AND MATERIALS: Two hundred 3-dimensional (3D) preimplant and postimplant prostate brachytherapy MRI scans were acquired with a T2-weighted sequence, a T2/T1-weighted sequence, or a T1-weighted sequence. One hundred twenty deep machine learning models were trained to segment the prostate, seminal vesicles, external urinary sphincter, rectum, and bladder using the MRI scans acquired with T2-weighted and T2/T1-weighted image contrast. The deep machine learning models consisted of 18 fully convolutional networks (FCNs) with different convolutional encoders. Both 2-dimensional and 3D U-Net FCNs were constructed for comparison. Six objective functions were investigated: cross-entropy, Jaccard distance, focal loss, and 3 variations of Tversky distance. The performance of the models was compared using similarity metrics, including pixel accuracy, Jaccard index, Dice similarity coefficient (DSC), 95% Hausdorff distance, relative volume difference, Matthews correlation coefficient, precision, recall, and average symmetrical surface distance. We selected the highest-performing architecture and investigated how the amount of training data, use of skip connections, and data augmentation affected segmentation performance. In addition, we investigated whether segmentation on T1-weighted MRI was possible with FCNs trained on only T2-weighted and T2/T1-weighted image contrast. RESULTS: Overall, an FCN with a DenseNet201 encoder trained via cross-entropy minimization yielded the highest combined segmentation performance. For the 53 3D test MRI scans acquired with T2-weighted or T2/T1-weighted image contrast, the DSCs of the prostate, external urinary sphincter, seminal vesicles, rectum, and bladder were 0.90 ± 0.04, 0.70 ± 0.15, 0.80 ± 0.12, 0.91 ± 0.06, and 0.96 ± 0.04, respectively, after model fine-tuning. For the 5 T1-weighted images, the DSCs of these organs were 0.82 ± 0.07, 0.17 ± 0.15, 0.46 ± 0.21, 0.87 ± 0.06, and 0.88 ± 0.05, respectively. CONCLUSIONS: Machine segmentation of the prostate and surrounding anatomy on 3D MRIs acquired with different pulse sequences for MARS low-dose-rate prostate brachytherapy is possible with a single FCN.

Early evidence of pulmonary dysfunction in survivors of childhood Hodgkin lymphoma.

Survivors of childhood Hodgkin lymphoma (HL) are at risk for pulmonary late effects, but whether survivors also experience pulmonary dysfunction early off therapy is not well understood. We determined the incidence of pulmonary dysfunction in children/adolescents with HL at entry into survivorship, as well as risk factors related to this outcome. Survivors in clinical remission and with a pulmonary function test (PFT) obtained 2-6 years off therapy were included. Seventy-five of 118 subjects met eligibility criteria (mean age at diagnosis: 13 years, mean time off therapy: 40 months). Survivors of HL had a higher than expected incidence of pulmonary dysfunction at entry into survivorship (40/75 [53%] had an abnormal DLCO and/or a restrictive or obstructive impairment). Evidence for diffusion impairment was associated with female sex (odds ratio [OR] = 3.19, p = .04). Longitudinal follow-up studies are needed to determine if early evidence of pulmonary dysfunction predicts risk for later onset pulmonary outcomes.

Long-Term Institutional Experience With Telemedicine Services for Radiation Oncology: A Potential Model for Long-Term Utilization.

PURPOSE: With the development of the coronavirus disease 2019 (COVID-19) pandemic, health care practices and radiation oncology departments have begun to incorporate telemedicine services to practice social distancing and minimize the chances of disease spread. Given the severity of this pandemic, it will likely fundamentally affect the use of these services for years to come. Our institution and radiation oncology department have used telemedicine services for many years; we would like to report on our departmental experience to guide other radiation oncology practices on its long-term use for clinical evaluation and patient care. METHODS AND MATERIALS: Our institution's telemedicine program provides clinical services for a number of remote locations and represents the largest telehealth network in the world, with over 300 sites and 60,000 patient encounters a year. RESULTS: Specifically for our radiation oncology department, over 200 patient encounters occur via telemedicine a year. Patients report great appreciation and satisfaction with these encounters, as they eliminate the time and energy needed for travel from long distances. It has resulted in improved efficiency and cost-effectiveness as well. CONCLUSIONS: Based on our institutional experience, our long-term vision for telemedicine (after COVID-19 pandemic has hopefully subsided) is as an excellent and cost-efficient tool to provide long-term follow-up for patients, especially for those who live far away in rural or underserved areas.

Analysis of patent innovation in the field of brachytherapy.

PURPOSE: To characterize inventions and assess trends in brachytherapy innovation based on brachytherapy-related patents awarded across the past 2 decades and provide insights that will help inform future research and entrepreneurship in the field. METHODS: The United States Patent and Trademark Office database was searched for patents awarded between 1999 and 2018 with a classification code corresponding to the broadest brachytherapy search category. Patent characteristics were stratified and compared by geographic location, affiliation, and theme of invention. RESULTS: There were 202 brachytherapy-related patents awarded from 2009 to 2018, which indicates a 56% increase in patent productivity and brachytherapy innovation compared with the previous decade from 1999 to 2008. Patents had an industry affiliation in 83% of cases from 1999 to 2008 and in 76% of cases from 2009 to 2018. Meanwhile, academic participation in brachytherapy patent innovation rose from 4% to 11% in that time. The focus and theme of inventions evolved across time, with radiation sources being the most common theme from 1999 to 2008 and falling to third place in 2009-2018. Conversely, development of brachytherapy-related patents involving exogenous agents such as drug-conjugates, radiosensitizers, and adjuncts to treatment increased substantially in the subsequent decade. While no collaboration was observed between academia and industry between 1999 and 2008, notable partnerships emerged in the subsequent decade which amounted to almost 5% of all patents awarded between 2009 and 2018. CONCLUSIONS: There has been an increase in overall brachytherapy patent production over time, and this has been accompanied by a greater variety of distinct patent themes. Collaboration between industry and academia is rare. Knowledge of brachytherapy patents may inform future research innovation in this field.

Prenatal risk factors for internalizing and externalizing problems in childhood.

BACKGROUND: A growing body of research has documented the effects of prenatal risk factors on a wide spectrum of adverse offspring health outcomes. Childhood behavior problems, such as externalizing and internalizing problems, are no exception. This comprehensive literature review aims to summarize and synthesize current research about commonly experienced prenatal risk factors associated with internalizing and externalizing problems, with a focus on their impact during childhood and adolescence. Potential mechanisms as well as implications are also outlined. DATA SOURCES: The EBSCO, Web of Science, PubMed, Google Scholar, and Scopus databases were searched for studies examining the association between prenatal risk factors and offspring internalizing/externalizing problems, using keywords "prenatal" or "perinatal" or "birth complications" in combination with "internalizing" or "externalizing". Relevant articles, including experimental research, systematic reviews, meta-analyses, cross-sectional and longitudinal cohort studies, and theoretical literature, were reviewed and synthesized to form the basis of this integrative review. RESULTS: Prenatal risk factors that have been widely investigated with regards to offspring internalizing and externalizing problems encompass health-related risk factors, including maternal overweight/obesity, substance use/abuse, environmental toxicant exposure, maternal infection/inflammation, as well as psychosocial risk factors, including intimate partner violence, and anxiety/depression. Collectively, both epidemiological and experimental studies support the adverse associations between these prenatal factors and increased risk of emotional/behavioral problem development during childhood and beyond. Potential mechanisms of action underlying these associations include hormonal and immune system alterations. Implications include prenatal education, screening, and intervention strategies. CONCLUSIONS: Prenatal risk factors are associated with a constellation of offspring internalizing and externalizing problems. Identifying these risk factors and understanding potential mechanisms will help to develop effective, evidence-based prevention, and intervention strategies.