Trends in Androgen Deprivation Use in Men With Intermediate-Risk Prostate Cancer Who Underwent Radiation Therapy.

Purpose: Until 2018, National Cancer Comprehensive Network guidelines recommended androgen deprivation therapy (ADT) for all men with intermediate-risk prostate cancer who had undergone radiation therapy. Intermediate risk was stratified as favorable and unfavorable in 2018, and ADT recommendation was limited to men with unfavorable intermediate-risk prostate cancer. Data suggesting this stratification and treatment deintensification were first published in December 2013. This study characterizes US national trends for demographic, clinical, and socioeconomic factors associated with ADT use in men with intermediate-risk prostate cancer who have undergone definitive radiation therapy. Methods and Materials: This retrospective cohort study examined 108,185 men in the National Cancer Database who were diagnosed with intermediate-risk prostate cancer from 2004 to 2016. Temporal trends in demographic, clinical, and socioeconomic factors among men with intermediate-risk prostate cancer and associations with the use of ADT were characterized. Results: In total, 108,185 men diagnosed with intermediate-risk prostate cancer underwent radiation therapy from 2004 to 2016. Of these men, 41.09% received ADT. Among the 60,705 men with favorable intermediate-risk prostate cancer, 32.06% received ADT. Among the 47,480 men with unfavorable intermediate-risk prostate cancer, 52.64% received ADT. On multivariate analysis, use of ADT was associated with age and year of diagnosis; being a race other than White; having government-based insurance; having a higher prostate-specific antigen level, tumor stage, and Gleason score; receiving treatment at a nonacademic center; and receiving external beam radiation therapy alone. Conclusions: The findings highlight that ADT use is variable in men undergoing definitive radiation therapy for intermediate-risk prostate cancer, with the data suggesting that several clinical and socioeconomic disparities influence its use. The findings suggest that a significant proportion of men with favorable intermediate-risk prostate cancer receive ADT and remain candidates for treatment de-escalation, whereas a significant proportion of men with unfavorable intermediate-risk prostate cancer may be undertreated when ADT is omitted.

OdoriFy: A conglomerate of artificial intelligence-driven prediction engines for olfactory decoding.

The molecular mechanisms of olfaction, or the sense of smell, are relatively underexplored compared with other sensory systems, primarily because of its underlying molecular complexity and the limited availability of dedicated predictive computational tools. Odorant receptors (ORs) allow the detection and discrimination of a myriad of odorant molecules and therefore mediate the first step of the olfactory signaling cascade. To date, odorant (or agonist) information for the majority of these receptors is still unknown, limiting our understanding of their functional relevance in odor-induced behavioral responses. In this study, we introduce OdoriFy, a Web server featuring powerful deep neural network-based prediction engines. OdoriFy enables (1) identification of odorant molecules for wildtype or mutant human ORs (Odor Finder); (2) classification of user-provided chemicals as odorants/nonodorants (Odorant Predictor); (3) identification of responsive ORs for a query odorant (OR Finder); and (4) interaction validation using Odorant-OR Pair Analysis. In addition, OdoriFy provides the rationale behind every prediction it makes by leveraging explainable artificial intelligence. This module highlights the basis of the prediction of odorants/nonodorants at atomic resolution and for the ORs at amino acid levels. A key distinguishing feature of OdoriFy is that it is built on a comprehensive repertoire of manually curated information of human ORs with their known agonists and nonagonists, making it a highly interactive and resource-enriched Web server. Moreover, comparative analysis of OdoriFy predictions with an alternative structure-based ligand interaction method revealed comparable results. OdoriFy is available freely as a web service at https://odorify.ahujalab.iiitd.edu.in/olfy/.

Active Surveillance for Men with Intermediate Risk Prostate Cancer.

PURPOSE: Optimal treatment of intermediate risk prostate cancer remains unclear. National Comprehensive Cancer Network® guidelines recommend active surveillance, prostatectomy or radiotherapy. Recent trials demonstrated no difference in prostate cancer specific mortality for men undergoing active surveillance for low risk prostate cancer compared to prostatectomy or radiotherapy. The use of active surveillance for intermediate risk prostate cancer is less clear. In this study we characterize U.S. national trends for demographic, clinical and socioeconomic factors associated with active surveillance for men with intermediate risk prostate cancer. MATERIALS AND METHODS: This retrospective cohort study examined 176,122 men diagnosed with intermediate risk prostate cancer from 2010 to 2016 in the National Cancer Database. Temporal trends in demographic, clinical and socioeconomic factors among men with intermediate risk prostate cancer and association with the use of active surveillance were characterized. The analysis was performed in April 2020. RESULTS: In total, 176,122 men were identified with intermediate risk prostate cancer from 2010 to 2016. Of these men 57.3% underwent prostatectomy, 36.4% underwent radiotherapy and 3.2% underwent active surveillance. Active surveillance nearly tripled from 1.6% in 2010 to 4.6% in 2016 (p <0.001). On multivariate analysis use of active surveillance was associated with older age, diagnosis in recent years, lower Gleason score and tumor stage, type of insurance, treatment at an academic center and proximity to facility, and attaining higher education (p <0.05). Race and comorbidities were not associated with active surveillance. CONCLUSIONS: Our findings highlight increasing active surveillance use for men with intermediate risk prostate cancer demonstrating clinical and socioeconomic disparities. Prospective data and improved risk stratification are needed to guide optimal treatment for men with intermediate risk prostate cancer.

Radiotherapy and Immunotherapy Combinations for Lung Cancer.

PURPOSE OF REVIEW: Positive results from recent immunotherapy trials of non-small cell lung cancer (NSCLC) have coincided with a greater appreciation for the impact of radiation therapy (RT) on tumor immunity. Here, we summarize key clinical findings and ongoing efforts to combine immunotherapy and RT for the treatment of NSCLC. RECENT FINDINGS: The role of immunotherapy for NSCLC has expanded significantly following the pivotal approvals of nivolumab and pembrolizumab for metastatic NSCLC, maintenance durvalumab in unresectable stage III NSCLC, and atezolizumab for metastatic NSCLC. Several small early-phase trials have demonstrated the ability of RT to elicit clinically significant tumor immunity. These positive findings support current trial efforts combining RT with immunotherapy for NSCLC. Recently initiated trials of RT and immunotherapy hold significant promise in expanding the therapeutic options for NSCLC. Optimization of therapy will require careful patient selection to yield meaningful improvements in clinical outcomes.

The impact of quantitative CT-based tumor volumetric features on the outcomes of patients with limited stage small cell lung cancer.

INTRODUCTION: Limited stage small cell lung cancer (LS-SCLC) has a poor prognosis. Additional prognostic markers are needed for risk-stratification and treatment intensification. This study compares quantitative CT-based volumetric tumor measurements versus International Association for the Study of Lung Cancer (IASLC) TNM staging to predict outcomes. MATERIALS & METHODS: A cohort of 105 patients diagnosed with LS-SCLC and treated with chemoradiation (CRT) from 2000 to 2013 were analyzed retrospectively. Patients were staged by the Union for International Cancer Control (UICC) TNM Classification, 8th edition. Tumor volumes and diameters were extracted from radiation planning CT imaging. Univariable and multivariable models were used to analyze relationships between CT features and overall survival (OS), locoregional recurrence (LRR), in-field LRR, any progression, and distant metastasis (DM). RESULTS: Median follow-up was 21.3 months. Two-year outcomes were as follows: 38% LRR, 31% in-field LRR, 52% DM, 62% any progression, and 47% OS (median survival 16.5 months). On univariable analysis, UICC T-stage and N-stage were not associated with any clinical outcome. UICC overall stage was only statistically associated with in-field LRR. One imaging feature (3D maximum tumor diameter) was found to be significantly associated with LRR (HR 1.10, p = 0.003), in-field LRR (HR 1.10, p = 0.007), DM (HR 1.10, p = 0.02), any progression (HR 1.10, p = 0.008), and OS (HR 1.10, p = 0.03). On multivariable analysis, this feature remained significantly associated with all outcomes. CONCLUSION: For LS-SCLC, quantitative CT-based volumetric tumor measurements were significantly associated with outcomes after CRT and may be better predictors of outcome than TNM stage.

Use of frailty to predict survival in elderly patients with early stage non-small-cell lung cancer treated with stereotactic body radiation therapy.

OBJECTIVES: Frailty has been shown to increase morbidity and mortality independent of age, but studies are lacking in radiation oncology. This study evaluates a modified frailty index (mFI) in predicting overall survival (OS) and non-cancer death for Stage I/II [N0M0] Non-Small-Cell Lung Cancer (NSCLC) patients treated with Stereotactic Body Radiation Therapy (SBRT). MATERIALS AND METHODS: Medical records for all patients with Stage I/II NSCLC treated at our institution with SBRT from 2009 to 2014 were reviewed. A validated mFI score, consisting of 11 variables was calculated, classifying patients as non-frail (0-1) or frail (≥2). Primary endpoint (OS) was analyzed using Kaplan-Meier method and log-rank. Secondary endpoint, non-cancer death, was analyzed using Fine-Gray's method, with death from lung cancer as a competing risk. RESULTS: Patient cohort consisted of 38 (27.3%) non-frail and 101 (72.7%) frail [median total mFI score 3.0 (range 0-7)]. Median age and pack-year history was 74 and 46years, respectively. Median follow-up among survivors was 38.5months (range 4.0-74.1months). Frailty was associated with a lower 3-year OS (37.3% vs. 74.7%; p=0.003) and 3-year cumulative incidence of non-cancer death (36.7% vs. 12.5%; p=0.02). Frailty remained significant in the multivariate model [OS HR for mFI ≥2: 2.25 (1.14-4.44); p=0.02]. CONCLUSION: Frailty is associated with lower OS in older patients with early stage NSCLC treated with SBRT, yet frail patients survived a median 2.5years, and were more likely to die of causes unrelated to the primary lung cancer, suggesting SBRT should be considered even in older patients deemed unfit for surgery.

Lymph node volume predicts survival but not nodal clearance in Stage IIIA-IIIB NSCLC.

BACKGROUND: Locally advanced non-small cell lung cancer (LA-NSCLC) patients have poorer survival and local control with mediastinal node (N2) tumor involvement at resection. Earlier assessment of nodal burden could inform clinical decision-making prior to surgery. This study evaluated the association between clinical outcomes and lymph node volume before and after neoadjuvant therapy. MATERIALS AND METHODS: CT imaging of patients with operable LA-NSCLC treated with chemoradiation and surgical resection was assessed. Clinically involved lymph node stations were identified by FDG-PET or mediastinoscopy. Locoregional recurrence (LRR), distant metastasis (DM), progression free survival (PFS) and overall survival (OS) were analyzed by the Kaplan Meier method, concordance index and Cox regression. RESULTS: 73 patients with Stage IIIA-IIIB NSCLC treated with neoadjuvant chemoradiation and surgical resection were identified. The median RT dose was 54 Gy and all patients received concurrent chemotherapy. Involved lymph node volume was significantly associated with LRR and OS but not DM on univariate analysis. Additionally, lymph node volume greater than 10.6 cm3 after the completion of preoperative chemoradiation was associated with increased LRR (p<0.001) and decreased OS (p = 0.04). There was no association between nodal volumes and nodal clearance. CONCLUSION: For patients with LA-NSCLC, large volume nodal disease post-chemoradiation is associated with increased risk of locoregional recurrence and decreased survival. Nodal volume can thus be used to further stratify patients within the heterogeneous Stage IIIA-IIIB population and potentially guide clinical decision-making.

Associations of Radiomic Data Extracted from Static and Respiratory-Gated CT Scans with Disease Recurrence in Lung Cancer Patients Treated with SBRT.

Radiomics aims to quantitatively capture the complex tumor phenotype contained in medical images to associate them with clinical outcomes. This study investigates the impact of different types of computed tomography (CT) images on the prognostic performance of radiomic features for disease recurrence in early stage non-small cell lung cancer (NSCLC) patients treated with stereotactic body radiation therapy (SBRT). 112 early stage NSCLC patients treated with SBRT that had static free breathing (FB) and average intensity projection (AIP) images were analyzed. Nineteen radiomic features were selected from each image type (FB or AIP) for analysis based on stability and variance. The selected FB and AIP radiomic feature sets had 6 common radiomic features between both image types and 13 unique features. The prognostic performances of the features for distant metastasis (DM) and locoregional recurrence (LRR) were evaluated using the concordance index (CI) and compared with two conventional features (tumor volume and maximum diameter). P-values were corrected for multiple testing using the false discovery rate procedure. None of the FB radiomic features were associated with DM, however, seven AIP radiomic features, that described tumor shape and heterogeneity, were (CI range: 0.638-0.676). Conventional features from FB images were not associated with DM, however, AIP conventional features were (CI range: 0.643-0.658). Radiomic and conventional multivariate models were compared between FB and AIP images using cross validation. The differences between the models were assessed using a permutation test. AIP radiomic multivariate models (median CI = 0.667) outperformed all other models (median CI range: 0.601-0.630) in predicting DM. None of the imaging features were prognostic of LRR. Therefore, image type impacts the performance of radiomic models in their association with disease recurrence. AIP images contained more information than FB images that were associated with disease recurrence in early stage NSCLC patients treated with SBRT, which suggests that AIP images may potentially be more optimal for the development of an imaging biomarker.

Radiomic-Based Pathological Response Prediction from Primary Tumors and Lymph Nodes in NSCLC.

INTRODUCTION: Noninvasive biomarkers that capture the total tumor burden could provide important complementary information for precision medicine to aid clinical decision making. We investigated the value of radiomic data extracted from pretreatment computed tomography images of the primary tumor and lymph nodes in predicting pathological response after neoadjuvant chemoradiation before surgery. METHODS: A total of 85 patients with resectable locally advanced (stage II-III) NSCLC (median age 60.3 years, 65% female) treated from 2003 to 2013 were included in this institutional review board-approved study. Radiomics analysis was performed on 85 primary tumors and 178 lymph nodes to discriminate between pathological complete response (pCR) and gross residual disease (GRD). Twenty nonredundant and stable features (10 from each site) were evaluated by using the area under the curve (AUC) (all p values were corrected for multiple hypothesis testing). Classification performance of each feature set was evaluated by random forest and nested cross validation. RESULTS: Three radiomic features (describing primary tumor sphericity and lymph node homogeneity) were significantly predictive of pCR with similar performances (all AUC = 0.67, p < 0.05). Two features (quantifying lymph node homogeneity) were predictive of GRD (AUC range 0.72-0.75, p < 0.05) and performed significantly better than the primary features (AUC = 0.62). Multivariate analysis showed that for pCR, the radiomic features set alone had the best-performing classification (median AUC = 0.68). Furthermore, for GRD classification, the combination of radiomic and clinical data significantly outperformed all other feature sets (median AUC = 0.73). CONCLUSION: Lymph node phenotypic information was significantly predictive for pathological response and showed higher classification performance than radiomic features obtained from the primary tumor.

Inter-scan and inter-observer tumour volume delineation variability on cone beam computed tomography in patients treated with stereotactic body radiation therapy for early-stage non-small cell lung cancer.

INTRODUCTION: Quantification of volume changes on cone beam computed tomography (CBCT) during lung stereotactic body radiation therapy (SBRT) for non-small cell lung cancer (NSCLC) may provide a useful radiological marker for radiation response and for adaptive treatment planning. This study quantifies inter-scan and inter-observer variability in tumour volume delineation on CBCT. METHODS: Three clinicians independently contoured the primary gross tumour volume (GTV) manually on CBCTs taken immediately before SBRT treatment (pre) and after the same SBRT treatment (post) for 19 NSCLC patients. Relative volume differences (RVD) were calculated between the pre- and post-CBCTs for a given treatment and between any two of three observers for a given CBCT. Coefficient of variation (CV) was used to quantitatively measure and compare the extent of variability. RESULTS: Inter-observer variability had a significantly higher CV of 0.15 ± 0.13 compared to inter-scan CV of 0.03 ± 0.04 with P < 0.0001. The greatest variability was observed with tumours (<2 cm in diameter) versus larger tumours with 95% limit of agreement (LOA) (Mean ± Standard Deviation) of 1.90% ± 19.55% vs. -0.97% ± 12.26% for inter-scan RVD and 29.99% ± 73.84% vs. 9.37% ± 29.95% for inter-observer RVD respectively. CONCLUSIONS: Inter-observer variability was greater than inter-scan variability for tumour volume delineation on CBCT with greatest variability for small tumours (<2 cm in diameter). LOA for inter-scan variability (~12%) helps defines a threshold for clinically meaningful tumour volume change during SBRT treatment for tumours with diameter greater than 2 cm, with larger thresholds needed for smaller tumours.

Radiologic-pathologic correlation of response to chemoradiation in resectable locally advanced NSCLC.

OBJECTIVES: Accurate assessment of tumor response to chemoradiation has the potential to guide clinical decision-making regarding surgical resection and/or dose escalation for patients. Early assessment has implications for Optimal local therapy for operable locally advanced non-small cell lung cancer (LA-NSCLC) is controversial. This study evaluated quantitative CT-based tumor measurements to predict pathologic response. MATERIALS AND METHODS: Patients with operable LA-NSCLC treated with chemoradiation followed by surgical resection were assessed. Tumor diameter and volume were quantified from CT imaging obtained prior to chemoradiation and post-chemoradiation prior to surgical resection. Univariate and multivariate logistic regression were used to determine association with the primary endpoint of pathologic complete response (pCR). Overall survival, locoregional recurrence, and distant metastasis were assessed as secondary endpoints. RESULTS: 101 LA-NSCLC patients were identified and treated with preoperative chemoradiation and surgical resection. The median RT dose was 54Gy (range, 46-70) and 98% of patients received concurrent chemoradiation as part of their preoperative treatment. Reduction of CT-defined tumor volume was associated with pCR (OR 1.06 [1.02-1.09], p=0.002) and LRR (HR 1.01 [1.00-1.02], p=0.048). Conventional response assessment determined by RECIST (p=0.213) was not associated with pCR or any secondary endpoints. CONCLUSION: CT-measured reductions in tumor volume after chemoradiation are associated with pCR and provide greater clinical information about tumor response than conventional response assessment (RECIST) or absolute tumor sizes or volumes. This study demonstrates that change in tumor volumes provides better radiologic-pathologic correlation and is thus an additional tool to assess tumor response following chemoradiation.

CT-based radiomic analysis of stereotactic body radiation therapy patients with lung cancer.

BACKGROUND: Radiomics uses a large number of quantitative imaging features that describe the tumor phenotype to develop imaging biomarkers for clinical outcomes. Radiomic analysis of pre-treatment computed-tomography (CT) scans was investigated to identify imaging predictors of clinical outcomes in early stage non-small cell lung cancer (NSCLC) patients treated with stereotactic body radiation therapy (SBRT). MATERIALS AND METHODS: CT images of 113 stage I-II NSCLC patients treated with SBRT were analyzed. Twelve radiomic features were selected based on stability and variance. The association of features with clinical outcomes and their prognostic value (using the concordance index (CI)) was evaluated. Radiomic features were compared with conventional imaging metrics (tumor volume and diameter) and clinical parameters. RESULTS: Overall survival was associated with two conventional features (volume and diameter) and two radiomic features (LoG 3D run low gray level short run emphasis and stats median). One radiomic feature (Wavelet LLH stats range) was significantly prognostic for distant metastasis (CI=0.67, q-value<0.1), while none of the conventional and clinical parameters were. Three conventional and four radiomic features were prognostic for overall survival. CONCLUSION: This exploratory analysis demonstrates that radiomic features have potential to be prognostic for some outcomes that conventional imaging metrics cannot predict in SBRT patients.

Radiomic phenotype features predict pathological response in non-small cell lung cancer.

BACKGROUND AND PURPOSE: Radiomics can quantify tumor phenotype characteristics non-invasively by applying advanced imaging feature algorithms. In this study we assessed if pre-treatment radiomics data are able to predict pathological response after neoadjuvant chemoradiation in patients with locally advanced non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: 127 NSCLC patients were included in this study. Fifteen radiomic features selected based on stability and variance were evaluated for its power to predict pathological response. Predictive power was evaluated using area under the curve (AUC). Conventional imaging features (tumor volume and diameter) were used for comparison. RESULTS: Seven features were predictive for pathologic gross residual disease (AUC>0.6, p-value<0.05), and one for pathologic complete response (AUC=0.63, p-value=0.01). No conventional imaging features were predictive (range AUC=0.51-0.59, p-value>0.05). Tumors that did not respond well to neoadjuvant chemoradiation were more likely to present a rounder shape (spherical disproportionality, AUC=0.63, p-value=0.009) and heterogeneous texture (LoG 5mm 3D - GLCM entropy, AUC=0.61, p-value=0.03). CONCLUSION: We identified predictive radiomic features for pathological response, although no conventional features were significantly predictive. This study demonstrates that radiomics can provide valuable clinical information, and performed better than conventional imaging features.

Modelling kidney disease with CRISPR-mutant kidney organoids derived from human pluripotent epiblast spheroids.

Human-pluripotent-stem-cell-derived kidney cells (hPSC-KCs) have important potential for disease modelling and regeneration. Whether the hPSC-KCs can reconstitute tissue-specific phenotypes is currently unknown. Here we show that hPSC-KCs self-organize into kidney organoids that functionally recapitulate tissue-specific epithelial physiology, including disease phenotypes after genome editing. In three-dimensional cultures, epiblast-stage hPSCs form spheroids surrounding hollow, amniotic-like cavities. GSK3ß inhibition differentiates spheroids into segmented, nephron-like kidney organoids containing cell populations with characteristics of proximal tubules, podocytes and endothelium. Tubules accumulate dextran and methotrexate transport cargoes, and express kidney injury molecule-1 after nephrotoxic chemical injury. CRISPR/Cas9 knockout of podocalyxin causes junctional organization defects in podocyte-like cells. Knockout of the polycystic kidney disease genes PKD1 or PKD2 induces cyst formation from kidney tubules. All of these functional phenotypes are distinct from effects in epiblast spheroids, indicating that they are tissue specific. Our findings establish a reproducible, versatile three-dimensional framework for human epithelial disease modelling and regenerative medicine applications.

Resolution by unassisted Top3 points to template switch recombination intermediates during DNA replication.

The evolutionarily conserved Sgs1/Top3/Rmi1 (STR) complex plays vital roles in DNA replication and repair. One crucial activity of the complex is dissolution of toxic X-shaped recombination intermediates that accumulate during replication of damaged DNA. However, despite several years of study the nature of these X-shaped molecules remains debated. Here we use genetic approaches and two-dimensional gel electrophoresis of genomic DNA to show that Top3, unassisted by Sgs1 and Rmi1, has modest capacities to provide resistance to MMS and to resolve recombination-dependent X-shaped molecules. The X-shaped molecules have structural properties consistent with hemicatenane-related template switch recombination intermediates (Rec-Xs) but not Holliday junction (HJ) intermediates. Consistent with these findings, we demonstrate that purified Top3 can resolve a synthetic Rec-X but not a synthetic double HJ in vitro. We also find that unassisted Top3 does not affect crossing over during double strand break repair, which is known to involve double HJ intermediates, confirming that unassisted Top3 activities are restricted to substrates that are distinct from HJs. These data help illuminate the nature of the X-shaped molecules that accumulate during replication of damaged DNA templates, and also clarify the roles played by Top3 and the STR complex as a whole during the resolution of replication-associated recombination intermediates.

High mitochondrial priming sensitizes hESCs to DNA-damage-induced apoptosis.

Human embryonic stem cells (hESCs) are highly sensitive to DNA damage and have low survival ability relative to differentiated cells. We investigated the source of this difference by comparing damage response pathways in hESCs and differentiated cells. We found that hESCs undergo more rapid p53-dependent apoptosis after DNA damage than differentiated cells do. However, p53 localization and function are similar between hESCs and differentiated cells, suggesting that p53 alone cannot explain the difference in sensitivity. Instead, we show that mitochondrial readiness for apoptosis, known as mitochondrial priming, differs between hESCs and differentiated cells. Specifically, the balance between proapoptotic and antiapoptotic proteins is shifted closer to the apoptotic threshold in hESCs than in differentiated cells. Altering this balance in differentiated cells increases their sensitivity and results in cell death, suggesting that manipulation of mitochondrial priming could potentially alter the sensitivity of other stem cells, including cancer stem cells.

Homologous recombination-dependent rescue of deficiency in the structural maintenance of chromosomes (Smc) 5/6 complex.

The essential and evolutionarily conserved Smc5-Smc6 complex (Smc5/6) is critical for the maintenance of genome stability. Partial loss of Smc5/6 function yields several defects in DNA repair, which are rescued by inactivation of the homologous recombination (HR) machinery. Thus HR is thought to be toxic to cells with defective Smc5/6. Recent work has highlighted a role for Smc5/6 and the Sgs1 DNA helicase in preventing the accumulation of unresolved HR intermediates. Here we investigate how deletion of MPH1, encoding the orthologue of the human FANCM DNA helicase, rescues the DNA damage sensitivity of smc5/6 but not sgs1Δ mutants. We find that MPH1 deletion diminishes accumulation of HR intermediates within both smc5/6 and sgs1Δ cells, suggesting that MPH1 deletion is sufficient to decrease the use of template switch recombination (TSR) to bypass DNA lesions. We further explain how avoidance of TSR is nonetheless insufficient to rescue defects in sgs1Δ mutants, by demonstrating a requirement for Sgs1, along with the post-replicative repair (PRR) and HR machinery, in a pathway that operates in mph1Δ mutants. In addition, we map the region of Mph1 that binds Smc5, and describe a novel allele of MPH1 encoding a protein unable to bind Smc5 (mph1-Δ60). Remarkably, mph1-Δ60 supports normal growth and responses to DNA damaging agents, indicating that Smc5/6 does not simply restrain the recombinogenic activity of Mph1 via direct binding. These data as a whole highlight a role for Smc5/6 and Sgs1 in the resolution of Mph1-dependent HR intermediates.