MRI-cytometry: Mapping nonparametric cell size distributions using diffusion MRI.

PURPOSE: This report introduces and validates a new diffusion MRI-based method, termed MRI-cytometry, which can noninvasively map intravoxel, nonparametric cell size distributions in tissues. METHODS: MRI was used to acquire diffusion MRI signals with a range of diffusion times and gradient factors, and a model was fit to these data to derive estimates of cell size distributions. We implemented a 2-step fitting method to avoid noise-induced artificial peaks and provide reliable estimates of tumor cell size distributions. Computer simulations in silico, experimental measurements on cultured cells in vitro, and animal xenografts in vivo were used to validate the accuracy and precision of the method. Tumors in 7 patients with breast cancer were also imaged and analyzed using this MRI-cytometry approach on a clinical 3 Tesla MRI scanner. RESULTS: Simulations and experimental results confirm that MRI-cytometry can reliably map intravoxel, nonparametric cell size distributions and has the potential to discriminate smaller and larger cells. The application in breast cancer patients demonstrates the feasibility of direct translation of MRI-cytometry to clinical applications. CONCLUSION: The proposed MRI-cytometry method can characterize nonparametric cell size distributions in human tumors, which potentially provides a practical imaging approach to derive specific histopathological information on biological tissues.

Initial analysis of the dosimetric benefit and clinical resource cost of CBCT-based online adaptive radiotherapy for patients with cancers of the cervix or rectum.

PURPOSE: This provides a benchmark of dosimetric benefit and clinical cost of cone-beam CT-based online adaptive radiotherapy (ART) technology for cervical and rectal cancer patients. METHODS: An emulator of a CBCT-based online ART system was used to simulate more than 300 treatments for 13 cervical and 15 rectal cancer patients. CBCT images were used to generate adaptive replans. To measure clinical resource cost, the six phases of the workflow were timed. To evaluate the dosimetric benefit, changes in dosimetric values were assessed. These included minimum dose (Dmin) and volume receiving 95% of prescription (V95%) for the planning target volume (PTV) and the clinical target volume (CTV), and maximum 2 cc's (D2cc) of the bladder, bowel, rectum, and sigmoid colon. RESULTS: The average duration of the workflow was 24.4 and 9.2 min for cervical and rectal cancer patients, respectively. A large proportion of time was dedicated to editing target contours (13.1 and 2.7 min, respectively). For cervical cancer patients, the replan changed the Dmin to the PTVs and CTVs for each fraction 0.25 and 0.25 Gy, respectively. The replan changed the V95% by 9.2 and 7.9%. The D2cc to the bladder, bowel, rectum, and sigmoid colon for each fraction changed -0.02, -0.08, -0.07, and -0.04 Gy, respectively. For rectal cancer patients, the replan changed the Dmin to the PTVs and CTVs for each fraction of 0.20 and 0.24 Gy, respectively. The replan changed the V95% by 4.1 and 1.5%. The D2cc to the bladder and bowel for each fraction changed 0.02 and -0.02 Gy, respectively. CONCLUSIONS: Dosimetric benefits can be achieved with CBCT-based online ART that is amenable to conventional appointment slots. The clinical significance of these benefits remains to be determined. Managing contours was the primary factor affecting the total duration and is imperative for safe and effective adaptive radiotherapy.

Intergroup Randomized Phase III Study of Postoperative Oxaliplatin, 5-Fluorouracil, and Leucovorin Versus Oxaliplatin, 5-Fluorouracil, Leucovorin, and Bevacizumab for Patients with Stage II or III Rectal Cancer Receiving Preoperative Chemoradiation: A Trial of the ECOG-ACRIN Research Group (E5204).

BACKGROUND: The addition of bevacizumab to chemotherapy improved outcomes for patients with metastatic colon cancer. E5204 was designed to test whether the addition of bevacizumab to mFOLFOX6, following neoadjuvant chemoradiation and definitive surgery, could improve overall survival (OS) in patients with stage II/III adenocarcinoma of the rectum. SUBJECTS, MATERIALS, AND METHODS: Patients with stage II/III rectal cancer who had completed neoadjuvant 5-fluorouracil-based chemoradiation and had undergone complete resection were enrolled. Patients were randomized to mFOLFOX6 (Arm A) or mFOLFOX6 with bevacizumab (Arm B) administered every 2 weeks for 12 cycles. RESULTS: E5204 registered only 355 patients (17% of planned accrual goal) as it was terminated prematurely owing to poor accrual. At a median follow-up of 72 months, there was no difference in 5-year overall survival (88.3% vs. 83.7%) or 5-year disease-free survival (71.2% vs. 76.5%) between the two arms. The rate of treatment-related grade ≥ 3 adverse events (AEs) was 68.8% on Arm A and 70.7% on Arm B. Arm B had a higher proportion of patients who discontinued therapy early as a result of AEs and patient withdrawal than did Arm A (32.4% vs. 21.5%, p = .029).The most common grade 3-4 treatment-related AEs were neutropenia, leukopenia, neuropathy, diarrhea (without prior colostomy), and fatigue. CONCLUSION: At 17% of its planned accrual, E5204 did not meet its primary endpoint. The addition of bevacizumab to FOLFOX6 in the adjuvant setting did not significantly improve OS in patients with stage II/III rectal cancer. IMPLICATIONS FOR PRACTICE: At 17% of its planned accrual, E5204 was terminated early owing to poor accrual. At a median follow-up of 72 months, there was no significant difference in 5-year overall survival (88.3% vs. 83.7%) or in 5-year disease-free survival (71.2% vs. 76.5%) between the two arms. Despite significant advances in the treatment of rectal cancer, especially in improving local control rates, the risk of distant metastases and the need to further improve quality of life remain a challenge. Strategies combining novel agents with chemoradiation to improve both distant and local control are needed.

Magnetic resonance imaging of mean cell size in human breast tumors.

PURPOSE: Cell size is a fundamental characteristic of all tissues, and changes in cell size in cancer reflect tumor status and response to treatments, such as apoptosis and cell-cycle arrest. Unfortunately, cell size can currently be obtained only by pathological evaluation of tumor tissue samples obtained invasively. Previous imaging approaches are limited to preclinical MRI scanners or require relatively long acquisition times that are impractical for clinical imaging. There is a need to develop cell-size imaging for clinical applications. METHODS: We propose a clinically feasible IMPULSED (imaging microstructural parameters using limited spectrally edited diffusion) approach that can characterize mean cell sizes in solid tumors. We report the use of a combination of pulse sequences, using different gradient waveforms implemented on clinical MRI scanners and analytical equations based on these waveforms to analyze diffusion-weighted MRI signals and derive specific microstructural parameters such as cell size. We also describe comprehensive validations of this approach using computer simulations, cell experiments in vitro, and animal experiments in vivo and demonstrate applications in preoperative breast cancer patients. RESULTS: With fast acquisitions (~7 minutes), IMPULSED can provide high-resolution (1.3 mm in-plane) mapping of mean cell size of human tumors in vivo on clinical 3T MRI scanners. All validations suggest that IMPULSED provides accurate and reliable measurements of mean cell size. CONCLUSION: The proposed IMPULSED method can assess cell-size variations in tumors of breast cancer patients, which may have the potential to assess early response to neoadjuvant therapy.

National Cancer Institute (NCI) state of the science: Targeted radiosensitizers in colorectal cancer.

Colorectal cancer (CRC) represents a major public health problem as the second leading cause of cancer-related mortality in the United States. Of an estimated 140,000 newly diagnosed CRC cases in 2018, roughly one-third of these patients will have a primary tumor located in the distal large bowel or rectum. The current standard-of-care approach includes curative-intent surgery, often after preoperative (neoadjuvant) radiotherapy (RT), to increase rates of tumor down-staging, clinical and pathologic response, as well as improving surgical resection quality. However, despite advancements in surgical techniques, as well as sharpened precision of dosimetry offered by contemporary RT delivery platforms, the oncology community continues to face challenges related to disease relapse. Ongoing investigations are aimed at testing novel radiosensitizing agents and treatments that might exploit the systemic antitumor effects of RT using immunotherapies. If successful, these treatments may usher in a new curative paradigm for rectal cancers, such that surgical interventions may be avoided. Importantly, this disease offers an opportunity to correlate matched paired biopsies, radiographic response, and molecular mechanisms of treatment sensitivity and resistance with clinical outcomes. Herein, the authors highlight the available evidence from preclinical models and early-phase studies, with an emphasis on promising developmental therapeutics undergoing prospective validation in larger scale clinical trials. This review by the National Cancer Institute's Radiation Research Program Colorectal Cancer Working Group provides an updated, comprehensive examination of the continuously evolving state of the science regarding radiosensitizer drug development in the curative treatment of CRC.

A phase I trial of concurrent sorafenib and stereotactic radiosurgery for patients with brain metastases.

We hypothesized that sorafenib (BAY 43-9006), an oral multi-kinase inhibitor, used in combination with SRS will improve overall intracranial control. This Phase I study assesses the safety, tolerability, and maximal tolerated dose of sorafenib administered with SRS to treat 1-4 brain metastases. This was an open label phase I dose escalation study with an expansion cohort. Eligible adults had 1-4 brain metastases from solid malignancies. Sorafenib was begun 5-7 days prior to SRS and continued for 14 days thereafter. Dose escalation of sorafenib was conducted via a "3 + 3" dose escalation design. Dose limiting toxicities (DLT) were determined 1 month after SRS and defined as ≥grade 3 neurologic toxicities. Twenty-three patients were enrolled. There were no DLTs at dose level 1 (400 mg per day) or dose level 2 (400 mg twice per day). An expansion cohort of 17 patients was treated at dose level 2. There were six grade 3 toxicities: hypertension (n = 2), rash (n = 1), lymphopenia (n = 1), hypokalemia (n = 1), fatigue (n = 1) and hand-foot syndrome (n = 1). All of these were attributable to sorafenib and not to the combination with SRS. The median time to CNS progression was 10 months, 1 year CNS progression-free survival was 46%, the median overall survival was 11.6 months and the 1 year overall survival was 46%. The use of sorafenib concurrent with SRS for the treatment of 1-4 brain metastases is safe and well tolerated at 400 mg twice a day. Our recommended phase II dose of concurrent sorafenib with SRS would be 400 mg twice daily.

Neoadjuvant Treatment for Locally Advanced Rectal Cancer: New Concepts in Clinical Trial Design.

OPINION STATEMENT: Treatment for locally advanced rectal cancer has evolved from surgery alone to surgery plus adjuvant therapy. Preoperative 5-fluorouracil- or capecitabine-based chemoradiation with standard fractionated radiation, surgery utilizing total mesorectal excision, and further chemotherapy has become the standard of care in the USA. Preoperative adjuvant chemoradiation treatment sequencing has allowed for decreased toxicity, more sphincter-sparing surgery, and improved local control rates as compared to delivering the chemoradiation postoperatively. Yet, given the heterogeneity of locally advanced disease, some patients may be over-treated with this approach, leading to unnecessary toxicity and costs, while others may have a propensity to develop distant metastases and may benefit from intensified therapy. Therefore, the trend in modern clinical trial design has been to individualize therapy. As such, current studies are examining shortening the duration of radiation, omitting preoperative chemoradiation in patients who have a robust response to induction chemotherapy alone, omitting or delaying surgery in patients who have a clinical complete response to preoperative chemoradiation, and completing all of the adjuvant treatment prior to surgery.

Towards real-time topical detection and characterization of FDG dose infiltration prior to PET imaging.

PURPOSE: To dynamically detect and characterize 18F-fluorodeoxyglucose (FDG) dose infiltrations and evaluate their effects on positron emission tomography (PET) standardized uptake values (SUV) at the injection site and in control tissue. METHODS: Investigational gamma scintillation sensors were topically applied to patients with locally advanced breast cancer scheduled to undergo limited whole-body FDG-PET as part of an ongoing clinical study. Relative to the affected breast, sensors were placed on the contralateral injection arm and ipsilateral control arm during the resting uptake phase prior to each patient's PET scan. Time-activity curves (TACs) from the sensors were integrated at varying intervals (0-10, 0-20, 0-30, 0-40, and 30-40 min) post-FDG and the resulting areas under the curve (AUCs) were compared to SUVs obtained from PET. RESULTS: In cases of infiltration, observed in three sensor recordings (30 %), the injection arm TAC shape varied depending on the extent and severity of infiltration. In two of these cases, TAC characteristics suggested the infiltration was partially resolving prior to image acquisition, although it was still apparent on subsequent PET. Areas under the TAC 0-10 and 0-20 min post-FDG were significantly different in infiltrated versus non-infiltrated cases (Mann-Whitney, p < 0.05). When normalized to control, all TAC integration intervals from the injection arm were significantly correlated with SUVpeak and SUVmax measured over the infiltration site (Spearman ρ ≥ 0.77, p < 0.05). Receiver operating characteristic (ROC) analyses, testing the ability of the first 10 min of post-FDG sensor data to predict infiltration visibility on the ensuing PET, yielded an area under the ROC curve of 0.92. CONCLUSIONS: Topical sensors applied near the injection site provide dynamic information from the time of FDG administration through the uptake period and may be useful in detecting infiltrations regardless of PET image field of view. This dynamic information may also complement the static PET image to better characterize the true extent of infiltrations.

DCE-MRI analysis methods for predicting the response of breast cancer to neoadjuvant chemotherapy: pilot study findings.

PURPOSE: The purpose of this pilot study is to determine (1) if early changes in both semiquantitative and quantitative DCE-MRI parameters, observed after the first cycle of neoadjuvant chemotherapy in breast cancer patients, show significant difference between responders and nonresponders and (2) if these parameters can be used as a prognostic indicator of the eventual response. METHODS: Twenty-eight patients were examined using DCE-MRI pre-, post-one cycle, and just prior to surgery. The semiquantitative parameters included longest dimension, tumor volume, initial area under the curve, and signal enhancement ratio related parameters, while quantitative parameters included K(trans), v(e), k(ep), v(p), and τ(i) estimated using the standard Tofts-Kety, extended Tofts-Kety, and fast exchange regime models. RESULTS: Our preliminary results indicated that the signal enhancement ratio washout volume and k(ep) were significantly different between pathologic complete responders from nonresponders (P < 0.05) after a single cycle of chemotherapy. Receiver operator characteristic analysis showed that the AUC of the signal enhancement ratio washout volume was 0.75, and the AUCs of k(ep) estimated by three models were 0.78, 0.76, and 0.73, respectively. CONCLUSION: In summary, the signal enhancement ratio washout volume and k(ep) appear to predict breast cancer response after one cycle of neoadjuvant chemotherapy. This observation should be confirmed with additional prospective studies.

Feasibility and Tolerability of Adjuvant Capecitabine-Based Chemoradiation in Patients With Breast Cancer and Residual Disease After Neoadjuvant Chemotherapy: A Prospective Clinical Trial.

PURPOSE: Addition of adjuvant capecitabine improves overall survival for patients with breast cancer lacking pathologic complete response to standard-of-care neoadjuvant chemotherapy. Combining radiosensitizing capecitabine concurrent with radiation may further improve disease control, although the feasibility and tolerability of chemoradiation in this setting is unknown. This study aimed to determine the feasibility of this combination. Secondary objectives included the effect of chemoradiation on physician-reported toxicity, patient-reported skin dermatitis, and patient-reported quality of life compared with patients with breast cancer treated with adjuvant radiation. METHODS AND MATERIALS: Twenty patients with residual disease following standard neoadjuvant chemotherapy were enrolled in a prospective single-arm trial and treated with adjuvant capecitabine-based chemoradiation. Feasibility was defined as ≥75% of patients completing chemoradiation as planned. Toxicity was assessed using Common Terminology Criteria for Adverse Events version 5.0 and the patient-reported radiation-induced skin reaction scale. Quality of life was measured using the RAND Short-Form 36-Item Health Survey. RESULTS: Eighteen patients (90%) completed chemoradiation without interruption or dose reduction. The incidence of grade ≥3 radiation dermatitis was 5% (1 of 20 patients). Patient-reported radiation dermatitis did not show a clinically meaningful difference following chemoradiation (mean increase, 55 points) compared with published reports of patients with breast cancer treated with adjuvant radiation alone (mean increase, 47 points). On the other hand, patient-reported quality of life demonstrated a clinically meaningful decline at the end of chemoradiation (mean, 46; SD, 7) compared with the reference population of patients treated with adjuvant radiation alone (mean, 50; SD, 6). CONCLUSIONS: Adjuvant chemoradiation with capecitabine is feasible and tolerable in patients with breast cancer. Although current studies using adjuvant capecitabine for residual disease following neoadjuvant chemotherapy have specified sequential treatment of capecitabine and radiation, these results support the conduct of randomized trials in this setting to investigate the efficacy of concurrent radiation with capecitabine and provide patient-reported toxicity estimates for trial design.

Time course of arthralgia among women initiating aromatase inhibitor therapy and a postmenopausal comparison group in a prospective cohort.

BACKGROUND: More than 80,000 postmenopausal breast cancer patients in the United States each year are estimated to begin a 5-year course of aromatase inhibitors (AIs) to prevent recurrence. AI-related arthralgia (joint pain and/or stiffness) may contribute to nonadherence, but longitudinal data are needed on arthralgia risk factors, trajectories, and background in postmenopause. This study sought to describe 1-year arthralgia trajectories and baseline covariates among patients with AI and a postmenopausal comparison group. METHODS: Patients initiating AIs (n = 91) were surveyed at the time of AI initiation and at 6 repeated assessments over 1 year. A comparison group of postmenopausal women without breast cancer (n = 177) completed concomitantly timed surveys. Numeric rating scales (0-10) were used to measure pain in 8 joint pair groups (bilateral fingers, wrists, elbows, shoulders, hips, knees, ankles, and toes). Poisson regression models were used to analyze arthralgia trajectories and risk factors. RESULTS: By week 6, the AI-initiating group had more severe arthralgia than did the comparison group (ratio of means = 1.8, 95% confidence interval = 1.24-2.7, P = .002), adjusting for baseline characteristics. Arthralgia then worsened further over 1 year in the AI group. Menopausal symptom severity and existing joint-related comorbidity at baseline among women initiating AI were associated with more severe arthralgia over time. CONCLUSIONS: Patients initiating AI should be told about the timing of arthralgia over the first year of therapy, and advised that it does not appear to resolve over the course of a year. Menopausal symptoms and joint-related comorbidity at AI initiation can help identify patients at risk for developing AI-related arthralgia.

Statistical comparison of dynamic contrast-enhanced MRI pharmacokinetic models in human breast cancer.

By fitting dynamic contrast-enhanced MRI data to an appropriate pharmacokinetic model, quantitative physiological parameters can be estimated. In this study, we compare four different models by applying four statistical measures to assess their ability to describe dynamic contrast-enhanced MRI data obtained in 28 human breast cancer patient sets: the chi-square test (χ(2)), Durbin-Watson statistic, Akaike information criterion, and Bayesian information criterion. The pharmacokinetic models include the fast exchange limit model with (FXL_v(p)) and without (FXL) a plasma component, and the fast and slow exchange regime models (FXR and SXR, respectively). The results show that the FXL_v(p) and FXR models yielded the smallest χ(2) in 45.64 and 47.53% of the voxels, respectively; they also had the smallest number of voxels showing serial correlation with 0.71 and 2.33%, respectively. The Akaike information criterion indicated that the FXL_v(p) and FXR models were preferred in 42.84 and 46.59% of the voxels, respectively. The Bayesian information criterion also indicated the FXL_v(p) and FXR models were preferred in 39.39 and 45.25% of the voxels, respectively. Thus, these four metrics indicate that the FXL_v(p) and the FXR models provide the most complete statistical description of dynamic contrast-enhanced MRI time courses for the patients selected in this study.

Controversies in radiation for upper rectal cancers.

Over the past few decades substantial improvement has occurred in the diagnosis and treatment of rectal cancers. This disease requires the close cooperation of a multidisciplinary team, including radiologists, gastroenterologists, surgeons, medical oncologists, and radiation oncologists, to provide optimum treatment with minimal morbidity. The widespread use of total mesorectal excision (TME) and improvements in chemotherapy and radiation delivery have resulted in decreases in locoregional recurrence. Large randomized studies have shown a benefit with the use of preoperative chemoradiation for most patients with transmural and/or node-positive disease. Controversy remains, however, regarding whether this treatment paradigm should be applied uniformly to all patients regardless of tumor location. As the risk of local recurrence decreases with high rectal tumors and the benefit in terms of sphincter preservation is not applicable to this subgroup of patients, up-front surgery to allow for more accurate pathologic staging prior to making final treatment decisions is recommended. In patients with pathologically staged T3,N0,M0 tumors of the upper rectum who have undergone TME with 12 or more nodes removed, the addition of chemoradiation has very little benefit.

Variation in Treatment Patterns of Patients with Early-Onset Gastric Cancer.

Background: Early-onset gastric cancer (EOGC), or gastric cancer in patients younger than 45 years old, is poorly understood and relatively uncommon. Similar to other gastrointestinal malignancies, the incidence of EOGC is rising in Western countries. It is unclear which populations experience a disproportionate burden of EOGC and what factors influence how patients with EOGC are treated. Methods: We conducted a retrospective, population-based study of patients diagnosed with gastric cancer from 2004 to 2018 using the National Cancer Database (NCDB). In addition to identifying unique demographic characteristics of patients with EOGC, we evaluated (using multivariable logistic regression controlling for year of diagnoses, primary site, and stage) how gender/sex, race/ethnicity, treatment facility type, payor status, and location of residence influenced the receipt of surgery, chemotherapy, and radiation. Results: Compared to patients 45−70 and >70 years of age with gastric cancer, patients with EOGC were more likely to be female, Asian/Pacific Islander (PI), African American (AA), Hispanic, uninsured, and present with stage IV disease. On multivariable analysis, several differences among subsets of patients with EOGC were identified. Female patients with EOGC were less likely to receive surgery and chemotherapy than male patients with EOGC. Asian/Pacific Islander patients with EOGC were more likely to receive chemotherapy and less likely to receive radiation than Caucasian patients with EOGC. African American patients were more likely to receive chemotherapy than Caucasian patients with EOGC. Hispanic patients were more likely to receive surgery and chemotherapy and less likely to receive radiation than Caucasian patients with EOGC. Patients with EOGC treated at community cancer centers were more likely to receive surgery and less likely to receive chemotherapy than patients with EOGC treated at academic centers. Uninsured patients with EOGC were more likely to receive surgery and less likely to receive chemotherapy than privately insured patients with EOGC. Patients with EOGC living in locations not adjacent to metropolitan areas were less likely to receive surgery compared to patients with EOGC who resided in metropolitan areas, Conclusions: Patients with EOGC are a demographically distinct population. Treatment of these patients varies significantly based on several demographic factors. Additional analysis is needed to elucidate why particular groups are more affected by EOGC and how treatment decisions are made for, and by, these patients.

ECOG-ACRIN Guideline for Contouring and Treatment of Early Stage Anal Cancer Using IMRT/IGRT.

PURPOSE: Previous anal cancer guidelines delineate target volumes similarly for all patients with squamous cell carcinoma of the anal canal and/or perianal skin (SCCA), regardless of disease stage. The purpose of this guideline is to provide customized radiation treatment recommendations for early stage (T1-2 N0 M0) anal cancer treated with intensity modulated and image guided radiation therapy (RT). METHODS AND MATERIALS: A contouring atlas and radiation treatment recommendations for the ongoing, randomized phase II trial of deintensified chemoradiation for early stage SCCA (EA2182) was created by an expert panel of radiation oncologists. A literature search was conducted to update and expand these recommendations into a guideline for routine clinical use. RESULTS: For the majority of cases, we recommend treatment in the supine, frog leg position with the use of a customized immobilization device and daily image guided RT to ensure optimal bone and soft tissue alignment. Vaginal dilators can be used daily during RT to maximize genitalia sparing. We recommend use of a 10-mm margin on the gross tumor plus including the anal complex to create the primary clinical target volume. To define the elective lymph node clinical target volume, we recommend starting with a 7-mm expansion on blood vessels, but then further refining these volumes based on the anatomic location. A 5- to 10-mm planning target volume (PTV) margin is suggested based on institutional setup and patient-specific factors. When using a simultaneous integrated boost technique, a dose of 50.4 Gy to primary PTV and 42 Gy to lymph node PTV, both delivered over 28 fractions, with chemotherapy is appropriate for early stage anal cancer. CONCLUSIONS: This guideline provides anatomic, clinical, and technical instructions to guide radiation oncologists in the planning and delivery of intensity modulated and image guided RT for early stage SCCA.

Motion correction in diffusion-weighted MRI of the breast at 3T.

PURPOSE: To provide a quantitative assessment of motion and distortion correction of diffusion-weighted images (DWIs) of the breast and to evaluate the effects of registration on the mean apparent diffusion coefficient (mADC). MATERIALS AND METHODS: Eight datasets from four patients with breast cancer and eight datasets from six healthy controls were acquired on a 3T scanner. A 3D affine registration was used to align each set of images and principal component analysis was used to assess the results. Variance in tumor ADC measurements, tumor mADC values, and voxel-wise tumor mADC values were compared before and after registration for each patient. RESULTS: Image registration significantly (P = 0.008) improved image alignment for both groups and significantly (P < 0.001) reduced the variance across individual tumor ADC measurements. While misalignment led to potential under- and overestimation of mADC values for individual voxels, average tumor mADC values did not significantly change (P > 0.09) after registration. CONCLUSION: 3D affine registration improved the alignment of DWIs of the breast and reduced the variance between ADC measurements. Although the reduced variance did not significantly change tumor region-of-interest measures of mADC, it may have a significant impact on voxel-based analyses.

Safety considerations with new treatment regimens for anal cancer.

Introduction: Anal cancer is a rare malignancy, but incidence rates are rising. Primary chemoradiation is the standard of care for early disease with surgery reserved for salvage. Despite success in terms of survival, patients suffer significant morbidity. Research is underway to advance the field and improve outcomes for these patients.Areas covered: This review aims to discuss the safety and efficacy of new approaches to treat anal cancer. A literature search was performed from January 1950 through November 2020 via PubMed and ClinicalTrials.gov databases to obtain data from ongoing or published studies examining new regimens for the treatment of anal cancers. Pertinent topics covered include miniature drug conjugates, epidermal growth factor receptor inhibitors, checkpoint inhibitor combinations, and novel immunomodulators.Expert opinion: Based on emerging clinical data, the treatment paradigm for anal cancer is likely to shift in the upcoming years. One of the largest areas of investigation is the field of immunotherapy, which may emerge as an integral component of anal cancer for all treatment settings.

Preoperative concurrent paclitaxel-radiation in locally advanced breast cancer: pathologic response correlates with five-year overall survival.

We have previously demonstrated high pathologic response rates after neoadjuvant concurrent chemoradiation in patients with locally advanced breast cancer (LABC). We now report disease-free survival (DFS) and overall survival (OS) in the context of pathologic response. 105 LABC patients (White 46%, Non-White 54%) were treated with paclitaxel (30 mg/m² intravenously twice a week) for 10-12 weeks. Daily radiotherapy was delivered to breast, axillary, and supraclavicular lymph nodes during weeks 2-7 of paclitaxel treatment, at 1.8 Gy per fraction to a total dose of 45 Gy with a tumor boost of 14 Gy at 2 Gy/fraction. Pathological complete response (pCR) was defined as the absence of invasive cancer in breast and lymph nodes and pathological partial response (pPR) as the persistence of <10 microscopic foci of invasive carcinoma in breast or lymph nodes. Pathologic response (pCR and pPR) after neoadjuvant chemoradiation was achieved in 36/105 patients (34%) and was associated with significantly better DFS and OS. Pathological responders had a lower risk of recurrence or death (HR = 0.35, P = 0.01) and a longer OS (HR = 4.27, P = 0.01) compared with non-responders. Median DFS and OS were 57 and 84 months for non-responders, respectively, and have not yet been reached for responders. Importantly, pathologic response was achieved in 54% of patients with HR negative tumors (26/48). In conclusion, pathologic response to concurrent paclitaxel-radiation translated into superior DFS and OS. Half of the patients with HR negative tumors achieved a pathologic response.

Validation of an algorithm for the nonrigid registration of longitudinal breast MR images using realistic phantoms.

PURPOSE: The authors present a method to validate coregistration of breast magnetic resonance images obtained at multiple time points during the course of treatment. In performing sequential registration of breast images, the effects of patient repositioning, as well as possible changes in tumor shape and volume, must be considered. The authors accomplish this by extending the adaptive bases algorithm (ABA) to include a tumor-volume preserving constraint in the cost function. In this study, the authors evaluate this approach using a novel validation method that simulates not only the bulk deformation associated with breast MR images obtained at different time points, but also the reduction in tumor volume typically observed as a response to neoadjuvant chemotherapy. METHODS: For each of the six patients, high-resolution 3D contrast enhanced T1-weighted images were obtained before treatment, after one cycle of chemotherapy and at the conclusion of chemotherapy. To evaluate the effects of decreasing tumor size during the course of therapy, simulations were run in which the tumor in the original images was contracted by 25%, 50%, 75%, and 95%, respectively. The contracted area was then filled using texture from local healthy appearing tissue. Next, to simulate the post-treatment data, the simulated (i.e., contracted tumor) images were coregistered to the experimentally measured post-treatment images using a surface registration. By comparing the deformations generated by the constrained and unconstrained version of ABA, the authors assessed the accuracy of the registration algorithms. The authors also applied the two algorithms on experimental data to study the tumor volume changes, the value of the constraint, and the smoothness of transformations. RESULTS: For the six patient data sets, the average voxel shift error (mean +/- standard deviation) for the ABA with constraint was 0.45 +/- 0.37, 0.97 +/- 0.83, 1.43 +/- 0.96, and 1.80 +/- 1.17 mm for the 25%, 50%, 75%, and 95% contraction simulations, respectively. In comparison, the average voxel shift error for the unconstrained ABA was 0.46 +/- 0.29, 1.13 +/- 1.17, 2.40 +/- 2.04, and 3.53 +/- 2.89 mm, respectively. These voxel shift errors translate into compression of the tumor volume: The ABA with constraint returned volumetric errors of 2.70 +/- 4.08%, 7.31 +/- 4.52%, 9.28 +/- 5.55%, and 13.19 +/- 6.73% for the 25%, 50%, 75%, and 95% contraction simulations, respectively, whereas the unconstrained ABA returned volumetric errors of 4.00 +/- 4.46%, 9.93 +/- 4.83%, 19.78 +/- 5.657%, and 29.75 +/- 15.18%. The ABA with constraint yields a smaller mean shift error, as well as a smaller volume error (p = 0.031 25 for the 75% and 95% contractions), than the unconstrained ABA for the simulated sets. Visual and quantitative assessments on experimental data also indicate a good performance of the proposed algorithm. CONCLUSIONS: The ABA with constraint can successfully register breast MR images acquired at different time points with reasonable error. To the best of the authors' knowledge, this is the first report of an attempt to quantitatively assess in both phantoms and a set of patients the accuracy of a registration algorithm for this purpose.

Esophageal adenocarcinoma: treatment modalities in the era of targeted therapy.

Esophageal adenocarcinoma is an aggressive malignancy with a poor outcome, and its incidence continues to rise at an alarming rate. Current treatment strategies combining chemotherapy, radiation, and surgery are plagued with high rates of recurrence and metastasis. Multiple molecular pathways including the epidermal growth factor receptor, vascular endothelial growth factor, v-erb-b2 erythroblastic leukemia viral oncogene homolog (ERBB2), and Aurora kinase pathways are activated in many esophageal adenocarcinomas. In many cases, these pathways have critical roles in tumor progression. Research on the mechanisms by which these pathways contribute to disease progression has resulted in numerous biologic agents and small molecules with the potential to improve outcome. The promise of targeted therapy and personalized medicine in improving the clinical outcome is now closer than it has ever been.