A population-based analysis of the impact of 1 vs. 2 doses of mitomycin on patterns of failure of anal cancer patients treated with concurrent chemoradiotherapy.

PURPOSE: We report the impact of 1 vs. 2 doses of mitomycin-C (MMC) based chemoradiation (CRT) on patterns of treatment failure and long-term patient outcomes in anal squamous cell carcinoma (ASCC) and the predictors for locoregional failure (LRF) and distant metastasis (DM). METHODS: In this population-based study, we identified all patients with anal cancer in our province treated radically with radiation and concurrent 5-Fluorouracil (5FU) and 1 vs. 2 doses of MMC between the years 2000-2019. The primary outcomes analyzed were locoregional recurrence (LRR), disease free survival (DFS), ASCC cancer-specific survival (ASCC-CSS) and overall survival (OS). RESULTS: 451 patients were identified. 272 (60%) patients received 1 cycle of MMC (MMC1) and 179 (40%) received 2 cycles (MMC2) as part of the CRT regimen. The median follow-up was 57 (36-252) and 97 (38-239) months for MMC1 and MMC2, respectively. Cox Regression analysis showed stage IIIb and IIIc were associated with worse locoregional recurrence free survival (RFS) (HR=2.851, p=<0.001) and distant RFS (HR=3.391, p=<0.001). Similarly, stage IIIb and IIIc patients had poorer DFS (HR 3.439, p=<0.001), ASCC-SS (HR 3.729, p=<0.001) and OS (2.230, p=<0.001). The use of MMC2 showed a positive impact on improved ASCC-SS (HR 0.569, p=0.029) and distant RFS (HR 0.555, p=0.040) in patients with stage IIIb and IIIc. CONCLUSIONS: Our analysis showed that 1 vs. 2 cycles of MMC along with 5FU and radiation is associated with comparable treatment outcomes in general. However, in patients with stage IIIb and IIIc cancer, 2 doses of MMC were associated with improved ASCC-SS and distant DFS.

Increasing prevalence of hot drought across western North America since the 16th century.

Across western North America (WNA), 20th-21st century anthropogenic warming has increased the prevalence and severity of concurrent drought and heat events, also termed hot droughts. However, the lack of independent spatial reconstructions of both soil moisture and temperature limits the potential to identify these events in the past and to place them in a long-term context. We develop the Western North American Temperature Atlas (WNATA), a data-independent 0.5° gridded reconstruction of summer maximum temperatures back to the 16th century. Our evaluation of the WNATA with existing hydroclimate reconstructions reveals an increasing association between maximum temperature and drought severity in recent decades, relative to the past five centuries. The synthesis of these paleo-reconstructions indicates that the amplification of the modern WNA megadrought by increased temperatures and the frequency and spatial extent of compound hot and dry conditions in the 21st century are likely unprecedented since at least the 16th century.

Design and Implementation of a New Orientation Program Based on Core Competencies and a Clinical Mentor Model.

A large pediatric hospital redesigned the traditional task-based orientation program to one based on the Synergy Model for Patient Care nurse competencies, enhanced identification of learning needs, critical thinking exercises, and use of experienced staff in the role of clinical mentor. Development of a role to coordinate the learning experiences of the new hire was essential to creation of a model built upon the framework of the core competencies needed to care for a unit's population of patients.

A multifault earthquake threat for the Seattle metropolitan region revealed by mass tree mortality.

Compound earthquakes involving simultaneous ruptures along multiple faults often define a region's upper threshold of maximum magnitude. Yet, the potential for linked faulting remains poorly understood given the infrequency of these events in the historic era. Geological records provide longer perspectives, although temporal uncertainties are too broad to clearly pinpoint single multifault events. Here, we use dendrochronological dating and a cosmogenic radiation pulse to constrain the death dates of earthquake-killed trees along two adjacent fault zones near Seattle, Washington to within a 6-month period between the 923 and 924 CE growing seasons. Our narrow constraints conclusively show linked rupturing that occurred either as a single composite earthquake of estimated magnitude 7.8 or as a closely spaced double earthquake sequence with estimated magnitudes of 7.5 and 7.3. These scenarios, which are not recognized in current hazard models, increase the maximum earthquake size needed for seismic preparedness and engineering design within the Puget Sound region of >4 million residents.

Increased tissue modulus and hardness in the TallyHO mouse model of early onset type 2 diabetes mellitus.

Individuals with type 2 diabetes mellitus (T2DM) have a higher fracture risk compared to those without T2DM despite having higher bone mineral density (BMD). Thus, T2DM may alter other aspects of resistance to fracture beyond BMD such as bone geometry, microarchitecture, and tissue material properties. We characterized the skeletal phenotype and assessed the effects of hyperglycemia on bone tissue mechanical and compositional properties in the TallyHO mouse model of early-onset T2DM using nanoindentation and Raman spectroscopy. Femurs and tibias were harvested from male TallyHO and C57Bl/6J mice at 26 weeks of age. The minimum moment of inertia assessed by micro-computed tomography was smaller (-26%) and cortical porosity was greater (+490%) in TallyHO femora compared to controls. In three-point bending tests to failure, the femoral ultimate moment and stiffness did not differ but post-yield displacement was lower (-35%) in the TallyHO mice relative to that in C57Bl/6J age-matched controls after adjusting for body mass. The cortical bone in the tibia of TallyHO mice was stiffer and harder, as indicated by greater mean tissue nanoindentation modulus (+22%) and hardness (+22%) compared to controls. Raman spectroscopic mineral:matrix ratio and crystallinity were greater in TallyHO tibiae than in C57Bl/6J tibiae (mineral:matrix +10%, p < 0.05; crystallinity +0.41%, p < 0.10). Our regression model indicated that greater values of crystallinity and collagen maturity were associated with reduced ductility observed in the femora of the TallyHO mice. The maintenance of structural stiffness and strength of TallyHO mouse femora despite reduced geometric resistance to bending could potentially be explained by increased tissue modulus and hardness, as observed at the tibia. Finally, with worsening glycemic control, tissue hardness and crystallinity increased, and bone ductility decreased in TallyHO mice. Our study suggests that these material factors may be sentinels of bone embrittlement in adolescents with T2DM.

Does cardiac imaging surveillance strategy influence outcomes in patients with early breast cancer?

Background: Many patients with breast cancer receive therapies with the potential to cause cardiotoxicity. Echocardiography and multiple-gated acquisition (MUGA) scans are the most used modalities to assess cardiac function during treatment in high-risk patients; however, the optimal imaging strategy and the impact on outcome are unknown. Methods: Consecutive patients with stage 0-3 breast cancer undergoing pre-treatment echocardiography or MUGA were identified from a tertiary care cancer center from 2010-2019. Demographics, medical history, imaging data and clinical events were collected from hospital charts and administrative databases. The primary outcome is a composite of all-cause death or heart failure event. Clinical and imaging predictors of outcome were evaluated on univariable and multivariable analyses. Results: 1028 patients underwent pre-treatment MUGA and 1032 underwent echocardiography. The groups were well matched for most clinical characteristics except patients undergoing MUGA were younger, had more stage 3 breast cancer and more HER2 over-expressing and triple negative cases. Routine follow-up cardiac imaging scan was obtained in 39.3% of patients with MUGA and 38.0% with echocardiography. During a median follow-up of 2448 (1489, 3160) days, there were 194 deaths, including 7 cardiovascular deaths, and 28 heart failure events with no difference in events between the MUGA and echocardiography groups. There were no imaging predictors of the primary composite outcome or cardiac events. Patients without follow-up imaging had similar adjusted risk for the composite outcome compared to those with imaging follow-up, hazard ratio 0.8 (95% confidence interval 0.5,1.3), p=0.457. Conclusion: The selection of pretreatment echocardiography or MUGA did not influence the risk of death or heart failure in patients with early breast cancer. Many patients did not have any follow-up cardiac imaging and did not suffer worse outcomes. Cardiovascular deaths and heart failure event rates were low and the value of long-term cardiac imaging surveillance should be further evaluated.

Long-Term Patient-Reported Quality of Life of Anal Cancer Survivors Treated With Intensity Modulated Radiation Therapy and Concurrent Chemotherapy: Results From a Prospective Phase II Trial.

PURPOSE: Intensity modulated radiation therapy (IMRT) has confirmed its superiority in improving acute treatment-related toxicities in anal cancer, without compromising tumor control. However, the effect of IMRT on long-term quality of life (QOL) is poorly documented. The study prospectively evaluated the long-term patient-reported QOL after IMRT-based chemoradiation in anal cancer. METHODS AND MATERIALS: Fifty-eight patients treated with IMRT and concurrent 5 fluorouracil/mitomycin-C were enrolled in the study. A prespecified secondary endpoint was prospective evaluation of long-term QOL. Fifty-four patients underwent QOL evaluation at baseline, after treatment, and during follow-up until 60 months, with European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) scales and the Colorectal Cancer-Specific Quality Of Life Questionnaire (QLQ-CR29) scales. The QOL scores at baseline and posttreatment periods were compared. RESULTS: For QLQ-C30, at 60 months, the mean scores of global health status, all functional scales, and all symptoms except diarrhea had improved, indicating normalization of QOL. Clinically and statistically significant improvements in the global health status (15.4; P = .003), role functioning (19.3; P = .0017), emotional functioning (18.9; P = .008), and social functioning (29.8; P ≤ .001) were observed. Diarrhea persisted as a concern over the years (P = .172). For European Organization for Research and Treatment of Cancer QLQ-CR29, rectal pain (-38.6; P = .001), mucous or blood discharge per rectum (-22.8; P = .005), and perianal soreness (-37.3; P ≤ .001) were improved both clinically and statistically. Clinically significant fecal leakage was reported by 16% of patients (5.6; P = .421). Volumes receiving 45 and 54 Gy were independent predictors for fecal incontinence. Clinically and statistically significant urinary incontinence occurred in 21% of patients (17.5; P = .014). Deterioration of dyspareunia was clinically significant (26.7; P = .099) at 60 months. CONCLUSIONS: Compared with historical data, IMRT is associated with reduced long-term effects on QOL. The majority of patients treated with IMRT experienced clinically significant recovery of function and improvement in QOL over 5 years after completion of treatment. Specific toxicities such as chronic diarrhea, fecal incontinence, and urinary and sexual dysfunction were primarily responsible for deterioration of the long-term QOL. Future research aimed at reducing such toxicities is needed to further improve long-term QOL in anal cancer.

Obstetric and Newborn Weak D-Phenotype RBC Testing and Rh Immune Globulin Management Recommendations: Lessons From a Blinded Specimen-Testing Survey of 81 Transfusion Services.

CONTEXT.­: Modern RHD genotyping can be used to determine when patients with serologic weak D phenotypes have RHD gene variants at risk for anti-D alloimmunization. However, serologic testing, RhD interpretations, and laboratory management of these patients are quite variable. OBJECTIVE.­: To obtain interlaboratory comparisons of serologic testing, RhD interpretations, Rh immune globulin (RhIG) management, fetomaternal hemorrhage testing, and RHD genotyping for weak D-reactive specimens. DESIGN.­: We devised an educational exercise in which 81 transfusion services supporting obstetrics performed tube-method RhD typing on 2 unknown red blood cell challenge specimens identified as (1) maternal and (2) newborn. Both specimens were from the same weak D-reactive donor. The exercise revealed how participants responded to these different clinical situations. RESULTS.­: Of reporting laboratories, 14% (11 of 80) obtained discrepant immediate-spin reactions on the 2 specimens. Nine different reporting terms were used to interpret weak D-reactive maternal RhD types to obstetricians. In laboratories obtaining negative maternal immediate-spin reactions, 28% (16 of 57) performed unwarranted antiglobulin testing, sometimes leading to recommendations against giving RhIG. To screen for excess fetomaternal hemorrhage after a weak D-reactive newborn, 47% (34 of 73) of reporting laboratories would have employed a contraindicated fetal rosette test, risking false-negative results and inadequate RhIG coverage. Sixty percent (44 of 73) of laboratories would obtain RHD genotyping in some or all cases. CONCLUSIONS.­: For obstetric and neonatal patients with serologic weak D phenotypes, we found several critical problems in transfusion service laboratory practices. We provide recommendations for appropriate testing, consistent immunohematologic terminology, and RHD genotype-guided management of Rh immune globulin therapy and RBC transfusions.

In vitro comparison of CPD whole blood with conventional blood components.

INTRODUCTION: Resuscitation of severely injured trauma patients is commonly performed using red blood cells in additive solution supplemented with plasma and platelet concentrates. There is an increasing interest in the use of low anti-A titer Group O whole blood (LTOWB) in the early management of the resuscitation. It is unclear whether clinical outcome is improved using this approach. METHODS: Expired units of CPD-LTOWB were studied on Day 22 and expired units of thawed plasma on Day 6 and Day 7. LTOWB was assessed for hemoglobin content, clotting factor levels and platelet numbers and function using thromboelastography (TEG) and impedance aggregation. Assays of fibrinogen and FV, FVIII, FVII and FX were performed on the expired plasma. The LTOWB hemoglobin was compared to red cells in additive solution (AS-RBCs) and the clotting factor levels to those of expired thawed plasma. Platelet function was compared to fresh whole blood samples from healthy subjects. RESULTS: LTOWB contained slightly more hemoglobin than the AS-RBCs (Medians, 66 v 59 G), and the plasma content of fibrinogen was similar. Other clotting factors were reduced by approximately 15% except for FVIII which was 30% less. Both TEG and impedance aggregometry showed evidence of residual platelet function despite the prolonged period of refrigerator storage. CONCLUSION: LTOWB contains higher hemoglobin and adequate clotting factors, and residual platelet function is demonstrated indicating that this product would be expected to be at least equivalent to a single unit of each of the conventional components commonly used in trauma resuscitation.

The Effects of Modifying Amount and Type of Dietary Carbohydrate on Esophageal Acid Exposure Time and Esophageal Reflux Symptoms: A Randomized Controlled Trial.

INTRODUCTION: This is the first randomized controlled diet intervention trial to investigate both the amount and type of carbohydrate on symptomatic gastroesophageal reflux disease (GERD). METHODS: Ninety-eight veterans with symptomatic GERD were randomly assigned to high total/high simple, high total/low simple, low total/high simple, or low total/low simple carbohydrate diet for 9 weeks. The primary outcomes were esophageal acid exposure time (AET) and total number of reflux episodes derived from 24-hour ambulatory pH monitoring. Secondary outcomes were esophageal reflux symptoms rated using the Gastroesophageal Reflux Disease Questionnaire (GERDQ) and GERD Symptom Assessment Scale (GSAS). RESULTS: Half of the subjects were White and half African American (mean age, 60.0 ± 12.5 years; mean body mass index, 32.7 ± 5.4 kg/m 2 ). There was a significant main effect of diet treatment on AET ( P = 0.001) and on the total number of reflux episodes ( P = 0.003). The change in AET in the high total/low simple group (-4.3% ± 3.8%) differed significantly from the high total/high simple control group (+3.1% ± 3.7%), (P = 0.04). The reduction in simple sugar intake averaged 62 g less per day. Subjects' ratings of symptoms improved in all carbohydrate modification groups, including significant reductions in heartburn frequency, heartburn severity, acid taste in the mouth, lump/pain in the throat or chest, and sleep disturbance. DISCUSSION: A modification of dietary carbohydrate intake that targeted a substantial reduction in the intakes of simple sugars improved pH monitoring outcomes and symptoms of GERD that profoundly affect daily life. These findings provide a feasible and clinically applicable contribution to the limited objective data existing for efficacious dietary recommendations in the routine treatment and management of GERD.

Remote Dispensing of Emergency Release Red Blood Cells.

OBJECTIVES: Patients with acute bleeding are frequently transfused with emergency release (ER) group O RBCs. This practice has been reported to be safe with a low rate of acute hemolytic transfusion reactions (AHRs). METHODS: Records of patients who received ER RBCs over a 30-month period were examined at our hospitals. During this period, satellite refrigerators were on site in the emergency department (ED), which were electronically connected to the blood bank (electronically connected satellite refrigerator [ECSR]). Nurses accessing the refrigerator were required to give patient identification information, when known, prior to removal of the ER RBCs, allowing technologists the opportunity to check for previous serologic records and communicate directly with the ED if a serologic incompatibility was potentially present. RESULTS: In total, 935 patients were transfused with 1,847 units of ER RBCs. Thirty of these patients had a current (22/30) or historic (8/30) antibody. In 15 cases, incompatible RBCs were interdicted. In six cases, the transfusion was considered urgent, and an AHR occurred in four of these six (overall 0.4%), including one fatal AHR due to anti-KEL1. CONCLUSIONS: Use of KEL1-negative RBCs and ECSR merits consideration as approaches to mitigate the occurrence of ER RBC-associated AHRs.

A Review of Trastuzumab Biosimilars in Early Breast Cancer and Real World Outcomes of Neoadjuvant MYL-1401O versus Reference Trastuzumab.

The reduced cost of trastuzumab biosimilars has led to increased adoption for HER2-positive breast cancer. This review of trastuzumab biosimilars encompasses this development and real world clinical data in early breast cancer. In addition, we present a retrospective study evaluating the total pathological complete response (tpCR) rates (lack of residual invasive cancer in resected breast tissue and axillary nodes), of MYL-1401O to reference trastuzumab (TRZ) in the neoadjuvant setting for HER2+ early breast cancer (EBC) in Alberta, Canada. Neoadjuvant patients with HER2+ EBC treated with TRZ from November 2018-October 2019 and MYL-1401O from December 2019-September 2020 were identified. Logistic regression was used to control for variables potentially associated with tpCR: trastuzumab product, age, pre-operative T- and N-stage, grade, hormone receptor (HR)-status, HER2-status, chemotherapy regimen, and chemotherapy completion. tpCR was 35.6% in the MYL-1401O group (n = 59) and 40.3% in the TRZ (n = 77) group, p = 0.598. After controlling for clinically relevant variables, there was no significant difference in the odds of achieving tpCR in patients treated with TRZ versus MYL-1401O (OR 1.1, 95% CI 0.5-2.4, p = 0.850). tpCR rates were similar for patients treated with MYL-1401O compared to trastuzumab in our real world study of HER2+ neoadjuvant EBC and comparable to pivotal phase 3 trials.

Update to the Canadian clinical practice guideline for best-practice management of breast cancer-related lymphedema: study protocol.

BACKGROUND: One of the more frequent complications following treatment for breast cancer, lymphedema is a substantial swelling of the arm, breast and chest wall that occurs on the side where lymph nodes were removed. The aim of this work is to update recommendations on the prevention, diagnosis and management of lymphedema related to breast cancer. METHODS: We present the protocol for an update of the 2001 clinical practice guideline on lymphedema from the Steering Committee for Clinical Practice Guidelines for the Care and Treatment of Breast Cancer. We will use a patient-oriented research approach with a focus on self-management and the positive health model to inform the updated guideline development. The methods proposed will be undertaken with consideration of the standards outlined in the Appraisal of Guidelines for Research and Evaluation II (AGREE II) instrument. The literature will be appraised by evaluating existing guidelines from other countries, the evidence from systematic reviews and meta-analyses and direct evidence from clinical studies. We will manage competing interests according to Guidelines International Network principles. Recommendations will be presented using an actionable statement format and will be linked to the level of evidence along with any relevant considerations used in formulation. A draft of the guideline will be produced by the steering committee then sent out to international experts and stakeholder groups for feedback. INTERPRETATION: The primary benefit of this clinical guideline will be to improve the quality of care of women with breast cancer-related lymphedema. Findings will be disseminated at national and international conferences and through webinars and educational videos hosted on the websites of the supporting organizations.

Documenting patients' and providers' preferences when proposing a randomized controlled trial: a qualitative exploration.

BACKGROUND: With advances in cancer diagnosis and treatment, women with early-stage breast cancer (ESBC) are living longer, increasing the number of patients receiving post-treatment follow-up care. Best-practice survivorship models recommend transitioning ESBC patients from oncology-provider (OP) care to community-based care. While developing materials for a future randomized controlled trial (RCT) to test the feasibility of a nurse-led Telephone Survivorship Clinic (TSC) for a smooth transition of ESBC survivors to follow-up care, we explored patients' and OPs' reactions to several of our proposed methods. METHODS: We used a qualitative study design with thematic analysis and a two-pronged approach. We interviewed OPs, seeking feedback on ways to recruit their ESBC patients for the trial, and ESBC patients, seeking input on a questionnaire package assessing outcomes and processes in the trial. RESULTS: OPs identified facilitators and barriers and offered suggestions for study design and recruitment process improvement. Facilitators included the novelty and utility of the study and simplicity of methods; barriers included lack of coordination between treating and discharging clinicians, time constraints, language barriers, motivation, and using a paper-based referral letter. OPs suggested using a combination of electronic and paper referral letters and supporting clinicians to help with recruitment. Patient advisors reported satisfaction with the content and length of the assessment package. However, they questioned the relevance of some questions (childhood trauma) while adding questions about trust in physicians and proximity to primary-care providers. CONCLUSIONS: OPs and patient advisors rated our methods for the proposed trial highly for their simplicity and relevance then suggested changes. These findings document processes that could be effective for cancer-patient recruitment in survivorship clinical trials.

The influence of socialization agents on consumer responses to over-the-counter medicine advertising.

BACKGROUND: Despite the prevalence of over-the-counter medicine advertising (OTCA) in electronic and print media, scholarly focus has tended to concentrate on direct-to-consumer prescription medicine advertising (DTCA). OBJECTIVES: The purpose of this study is to examine the mechanisms through which attitudes toward OTCA in general and OTCA prompted behaviors are formed based on a consumer socialization framework. METHODS: An online survey was conducted as part of a larger medicine and pharmaceutical advertising project using the Qualtrics online panel. A total of 819 individuals who had taken a prescription medicine in the last six months participated in the survey and yielded 539 completed questionnaires (Completion rate: 65.8%). Of those, 304 responses from U.S. adults who had taken an OTC medicine and had seen an advertisement for OTC medicines in the past six months were analyzed to test the proposed model. A series of structural equation modeling analyses of the survey data was performed. RESULTS: The study results showed that consumers' use of mass media and professional interpersonal channels directly influenced attitudes toward OTCA and OTCA prompted behaviors. On the other hand, consumers' use of non-professional interpersonal channels indirectly influenced OTCA outcomes through their use of mass media and professional interpersonal channels. Younger respondents were more likely to obtain OTC medicine information from non-professional interpersonal and mass media sources whereas older respondents were more likely to obtain OTC medicine information from physicians and pharmacists. CONCLUSIONS: Application of the consumer socialization framework in the context of OTCA provides expanded understanding of the mechanisms through which responses to OTCA are formed. The findings of this study provide implications for pharmaceutical marketers, health professionals, and consumers of OTC medicines.

No evidence of disease versus residual disease in long-term responders to first-line HER2-targeted therapy for metastatic breast cancer.

BACKGROUND: Long-term response to HER2-targeted therapies is infrequent in metastatic breast cancer (MBC). We evaluated clinical characteristics of HER2-positive MBC patients with no evidence of disease (NED) vs residual disease (RES) experiencing long-term response to first-line HER2-targeted therapy. METHODS: Patients receiving first-line chemotherapy-trastuzumab (CT) or taxane-trastuzumab-pertuzumab (THP) with response duration ≥2-fold higher than in phase II/III trials (CT [18.2 months]; THP [40.4 months]) were included. Clinical characteristics and radiographic review for NED or RES was evaluated by Cox-regression (hazard ratio; HR) or Kaplan-Meier (log-rank). Characteristics associated with NED were evaluated by logistic regression (Odds; OR). RESULTS: From 01/2005-01/2016, N = 103 (4.6%) patients were identified. In multivariate analyses, NED (N = 46) showed improved progression-free (PFS) and overall survival (OS) [p < 0.001] versus RES (N = 57), with high 5-year PFS/OS for NED (93.2%/97.4%) relative to RES (10.6%/61.3%). Premenopausal status (p = 0.006), de-novo metastases (p = 0.002), and no palliative radiotherapy (p = 0.01) were associated with NED. Overall, 6/7 (85.7%) patients with NED were alive and disease-free after discontinuing HER2 treatment (≥1 year) versus 1/17 (5.9%) with RES. CONCLUSIONS: Long-term responders with NED have better survival compared to RES. Premenopausal status and de novo metastatic disease are associated with NED. Prospective studies of HER2 therapy discontinuation with NED in MBC are warranted.

Rationale and design of the Diet Restriction and Exercise-induced Adaptations in Metastatic breast cancer (DREAM) study: a 2-arm, parallel-group, phase II, randomized control trial of a short-term, calorie-restricted, and ketogenic diet plus exercise during intravenous chemotherapy versus usual care.

BACKGROUND: An underlying cause of solid tumor resistance to chemotherapy treatment is diminished tumor blood supply, which leads to a hypoxic microenvironment, dependence on anaerobic energy metabolism, and impaired delivery of intravenous treatments. Preclinical data suggest that dietary strategies of caloric restriction and low-carbohydrate intake can inhibit glycolysis, while acute exercise can transiently enhance blood flow to the tumor and reduce hypoxia. The Diet Restriction and Exercise-induced Adaptations in Metastatic Breast Cancer (DREAM) study will compare the effects of a short-term, 50% calorie-restricted and ketogenic diet combined with aerobic exercise performed during intravenous chemotherapy treatment to usual care on changes in tumor burden, treatment side effects, and quality of life. METHODS: Fifty patients with measurable metastases and primary breast cancer starting a new line of intravenous chemotherapy will be randomly assigned to usual care or the combined diet and exercise intervention. Participants assigned to the intervention group will be provided with food consisting of 50% of measured calorie needs with 80% of calories from fat and ≤ 10% from carbohydrates for 48-72 h prior to each chemotherapy treatment and will perform 30-60 min of moderate-intensity cycle ergometer exercise during each chemotherapy infusion, for up to six treatment cycles. The diet and exercise durations will be adapted for each chemotherapy protocol. Tumor burden will be assessed by change in target lesion size using axial computed tomography (primary outcome) and magnetic resonance imaging (MRI)-derived apparent diffusion coefficient (secondary outcome) after up to six treatments. Tertiary outcomes will include quantitative MRI markers of treatment toxicity to the heart, thigh skeletal muscle, and liver, and patient-reported symptoms and quality of life. Exploratory outcome measures include progression-free and overall survival. DISCUSSION: The DREAM study will test a novel, short-term diet and exercise intervention that is targeted to mechanisms of tumor resistance to chemotherapy. A reduction in lesion size is likely to translate to improved cancer outcomes including disease progression and overall survival. Furthermore, a lifestyle intervention may empower patients with metastatic breast cancer by actively engaging them to play a key role in their treatment. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03795493 , registered 7 January, 2019.