Insights into microorganisms, associated factors, and the oral microbiome in infective endocarditis patients.

Introduction: Infective Endocarditis (IE) is a rare, life-threatening infection of the endocardium with multisystem effects. Culprit microorganisms derived from different niches circulate through the bloodstream and attach to the endocardium, particularly the heart valves. This study aimed to investigate culprit microorganisms among a cross-sectional cohort of IE patients, their associated factors, and to explore the potential relationship to the oral microbiome. Methods: In this observational study, we undertook a cross-sectional analysis of 392 medical records from patients diagnosed with IE. The primary outcome of this study was to analyse the association between the IE culprit microorganisms and the underlying anatomical types of IE (native valve (NVE), prosthetic valve (PVE), or cardiac device-related (CDE)). Secondary outcomes encompassed a comparative analysis of additional factors, including: the treatment approaches for IE, and the categorisation of blood cultures, extending to both genus and species levels. Additionally, we cross-referenced and compared the species-level identification of IE bacteraemia outcome measures with data from the expanded Human Oral Microbiome Database (eHOMD). Results: A culprit microorganism was identified in 299 (76.28%) case participants. Staphylococcal infections were the most common (p < 0.001), responsible for 130 (33.16%) hospitalisations. There were 277 (70.66%) cases of NVE, 104 (26.53%) cases of PVE, and 11 (2.81%) cases of CDE. The majority of PVE occurred on prosthetic aortic valves (78/104, 75%), of which 72 (93.5%) were surgical aortic valve replacements (SAVR), 6 (7.8%) were transcatheter aortic valve implants, and one transcatheter pulmonary valve implant. Overall, underlying anatomy (p = 0.042) as well as the treatment approaches for IE (p < 0.001) were significantly associated with IE culprit microorganisms. Cross-reference between IE bacteraemia outcomes with the eHOMD was observed in 267/392 (68.11%) cases. Conclusions: This study demonstrated that IE patients with a history of stroke, smoking, intravenous drug use, or dialysis were more likely to be infected with Staphylococcus aureus. CDE case participants and patients who had previous SAVR were most associated with Staphylococcus epidermidis. IE patients aged 78+ were more likely to develop enterococci IE than other age groups. Oral microorganisms indicated by the eHOMD are significantly observed in the IE population. Further research, through enhanced dental and medical collaboration, is required to correlate the presence of oral microbiota as causative factor for IE.

Impact of MRI resolution for Linac-based stereotactic radiosurgery.

Objective: Magnetic resonance imaging (MRI) is a standard imaging modality in intracranial stereotactic radiosurgery (SRS) for defining target volumes. However, wide disparities in MRI resolution exist, which could directly impact accuracy of target delineation. Here, sequences with various MRI resolution were acquired on phantoms to evaluate the effect on volume definition and dosimetric consequence for cranial SRS. Materials/Methods: Four T1-weighted MR sequences with increasing 3D resolution were compared, including two Spin Echo (SE) 2D acquisitions with 5mm and 3mm slice thickness (SE5mm, SE3mm) and two gradient echo 3D acquisitions (TFE, BRAVO). The voxel sizes were 0.4×0.4×5.0, 0.5×0.5×3.0, 0.9×0.9×1.25, and 0.4×0.4×0.5 mm3, respectively. Four phantoms with simulated lesions of different shape and volume (range, 0.53-25.0 cm3) were imaged, resulting in 16 total sets of MRIs. Four radiation oncologists provided contours on individual MR image set. All observer contours were compared with ground truth, defined on CT image according to the absolute dimensions of the target structure, using Dice similarity coefficient (DSC), Hausdorff distance (HD), mean distance-to-agreement (MDA), and the ratio between reconstructed and true volume (Ratiovol ). For dosimetric consequence, SRS plans targeting observer volumes were created. The true Paddick conformity index ( C I p a d d i c k t r u e ), calculated with true target volume, was correlated with quality of observer volume. Results: All measures of observer contours improved as increasingly higher MRI resolution was provided from SE5mm to BRAVO. The improvement in DSC, HD and MDA was statistically significant (p<0.01). Dosimetrically, C I p a d d i c k t r u e   strongly correlated with DSC of the planning observer volume (Pearson's r=0.94, p<0.00001). Conclusions: Significant improvement in target definition and reduced inter-observer variation was observed as the MRI resolution improved, which also improved the quality of SRS plans. Results imply that high resolution 3D MR sequences should be used to minimize potential errors in target definition, and multi-slice 2D sequences should be avoided.

Dosimetric Evaluation of Fractionated Stereotactic Radiation Therapy for Skull Base Meningiomas Using HyperArc and Multicriteria Optimization.

PURPOSE: Treatment planning of skull based meningiomas can be difficult due to the irregular shaped target volumes and proximity to critical optic structures. This study evaluated the use of HyperArc (HA) radiosurgery optimization and delivery in conjunction with multicriteria optimization (MCO) to create conformal and efficient treatment plans for conventionally fractionated radiation therapy to difficult base-of-skull (BOS) lesions. METHODS AND MATERIALS: Twelve patients with BOS meningioma were retrospectively planned with HA-specific optimization algorithm, stereotactic normal tissue objective (SRS-NTO), and conventional automatic normal tissue objective to evaluate normal brain sparing (mean dose and V20 Gy). MCO was used on both SRS-NTO and automatic normal tissue objective plans to further decrease organ-at-risk doses and target dose maximum to within clinically acceptable constraints. Delivery efficiency was evaluated based on planned monitor units. RESULTS: The SRS-NTO in HA can be used to improve the mid- and low-dose spread to normal brain tissue in the irradiation of BOS meningiomas. Improvement in normal brain sparing can be seen in larger, more irregular shaped lesions and less so in smaller spherical targets. MCO can be used in conjunction with the SRS-NTO to reduce target dose maximum and dose to organ at risk without sacrificing the gain in normal brain sparing. CONCLUSIONS: HA can be beneficial both in treatment planning by using the SRS-NTO and in delivery efficiency through the decrease in monitor units and automated delivery.

Randomized prospective trial of fractionated stereotactic radiosurgery with chemotherapy versus chemotherapy alone for bevacizumab-resistant high-grade glioma.

PURPOSE: Outcomes for patients with recurrent high-grade glioma (HGG) progressing on bevacizumab (BEV) are dismal. Fractionated stereotactic radiosurgery (FSRS) has been shown to be feasible and safe when delivered in this setting, but prospective evidence is lacking. This single-institution randomized trial compared FSRS plus BEV-based chemotherapy versus BEV-based chemotherapy alone for BEV-resistant recurrent malignant glioma. MATERIALS AND METHODS: HGG patients on BEV with tumor progression after 2 previous treatments were randomized to 1) FSRS plus BEV-based chemotherapy or 2) BEV-based chemotherapy with irinotecan, etoposide, temozolomide, or carboplatin. FSRS was delivered as 32 Gy (8 Gy × 4 fractions within 2 weeks) to the gross target volume and 24 Gy (6 Gy × 4 fractions) to the clinical target volume (fluid-attenuated inversion recovery abnormality). The primary endpoints were local control (LC) at 2 months and progression-free survival (PFS). RESULTS: Of the 35 patients enrolled, 29 had glioblastoma (WHO IV) and 6 had anaplastic glioma (WHO III). The median number of prior recurrences was 3. Patients treated with FSRS had significantly improved PFS (5.1 vs 1.8 months, P < .001) and improved LC at 2 months (82% [14/17] vs 27% [4/15], P = .002). The overall median survival was 6.6 months (7.2 months with FSRS vs 4.8 months with chemotherapy alone, P = .11). CONCLUSIONS: FSRS combined with BEV-based chemotherapy in recurrent HGG patients progressing on BEV is feasible and improves LC and PFS when compared to treatment with BEV-based chemotherapy alone.

Disparities in the Use of Single-fraction Stereotactic Radiosurgery for the Treatment of Brain Metastases From Non-small Cell Lung Cancer.

PURPOSE: Radiation treatment patterns in patients with brain metastases from non-small cell lung cancer (NSCLC) have not been well elucidated. The National Cancer Database (NCDB) was used to evaluate trends in the use of whole brain radiation therapy (WBRT) and stereotactic radiosurgery (SRS) for brain metastasis from NSCLC. METHODS: This NCDB study included patients > 18 years old with metastatic NSCLC treated with single-fraction SRS or WBRT between 2004 and 2014. Chi-square, t-test, and multivariable logistic regression analyses were used to identify predictors of SRS versus WBRT. RESULTS: Of 40,803 patients, 34,183 (83.8%) received WBRT and 6,620 (16.2%) received SRS. SRS utilization increased from 7% (157 cases) in 2004 to 37% (1,346 cases) in 2014 (p < .001). SRS was utilized more by academic than community facilities (22% versus 13%, p < .001). The strongest independent predictors of SRS included year of diagnosis in 2010-2014 versus 2004-2009 (odds ratio [OR] 2.62, 95% CI 2.46-2.79, p < .0001), metropolitan versus rural (OR 2.26, CI 1.79-2.85, p < .0001), distance from cancer-reporting facility of ≥ 30 versus < 30 miles (OR 2.36, CI 2.18-2.56, p < .0001), private insurance versus non-insured patients (OR 1.96, CI 1.68-2.29, p < .0001), and academic versus community facility (OR 1.76, CI 1.66-1.87, p < .0001). CONCLUSION: SRS for NSCLC brain metastases has steadily increased in the United States; however, WBRT remains the most commonly used. Wide geographic and socioeconomic variations exist in the utilization of SRS and WBRT for this patient population.

Single institution experience treating adrenal metastases with stereotactic body radiation therapy.

OBJECTIVE: The objective of the study is to present our experience of treating adrenal metastases using stereotactic body radiation therapy (SBRT). MATERIALS AND METHODS: We retrospectively reviewed patients with adrenal metastases treated using SBRT from 2001 to 2014. Response Evaluation Criteria in Solid Tumors v1.1 was used. Maximum tumor response was defined as the greatest percentage tumor reduction noted on two or more post-SBRT CT scans. RESULTS: We identified 44 patients (median age 61.3 years, range: 25.8-85), with 54 adrenal metastases; primary diagnoses include non-small cell lung cancer (28 patients and 38 lesions), small cell lung cancer (1 patient), hepatocellular carcinoma (6 patients), and other (9 patients). Treatment was delivered in single (16 lesions, median dose 18 Gy [14-18]) or multiple fractions (38 lesions, median dose 30 Gy [16-40]). Median planning target volume was 49.65cc (3.21-984.54). Median response at first post-SBRT follow-up (median 1.65 months (m) (0.33-5.37), n = 46 lesions) was 10.8% with 91.3% local control. Median maximum tumor response was 31.8% (n = 32 lesions) at median follow-up of 5.4 m (0.9-44.8) with 96.6% local control. The response was comparable regardless of tumor histology or treatment fractionation. No patients experienced Grade 3/4 acute toxicities. One patient with a history of naproxen use required suturing with omental patch placement for perforated pyloric ulcer 14 m post-SBRT (18 Gy in single fraction) to the right adrenal metastasis; this region received <5 Gy. Ten patients treated for pain with available follow-up obtained relief. CONCLUSIONS: SBRT is a safe and efficacious treatment for adrenal metastases, demonstrating local tumor control. Further study of the impact on survival and quality of life is warranted.

On the improvement of CBCT image quality for soft tissue-based SRS localization.

PURPOSE: We explore the optimal cone-beam CT (CBCT) acquisition parameters to improve CBCT image quality to enhance intracranial stereotactic radiosurgery (SRS) localization and also assess the imaging dose levels associated with each imaging protocol. METHODS: Twenty-six CBCT acquisition protocols were generated on an Edge® linear accelerator (Varian Medical Systems, Palo Alto, CA) with different x-ray tube current and potential settings, gantry rotation trajectories, and gantry rotation speeds. To assess image quality, images of the Catphan 504 phantom were analyzed to evaluate the following image quality metrics: uniformity, HU constancy, spatial resolution, low contrast detection, noise level, and contrast-to-noise ratio (CNR). To evaluate the imaging dose for each protocol, the cone-beam dose index (CBDI) was measured. To validate the phantom results, further analysis was performed with an anthropomorphic head phantom as well as image data acquired for a clinical SRS patient. RESULTS: The Catphan data indicates that adjusting acquisition parameters had direct effects on the image noise level, low contrast detection, and CNR, but had minimal effects on uniformity, HU constancy, and spatial resolution. The noise level was reduced from 34.5 ± 0.3 to 18.5 ± 0.2 HU with a four-fold reduction in gantry speed, and to 18.7 ± 0.2 HU with a four-fold increase in tube current. Overall, the noise level was found to be proportional to inverse square root of imaging dose, and imaging dose was proportional to the product of total tube current-time product and the cube of the x-ray potential. Analysis of the anthropomorphic head phantom data and clinical SRS imaging data also indicates that noise is reduced with imaging dose increase. CONCLUSIONS: Our results indicate that optimization of the imaging protocol, and thereby an increase in the imaging dose, is warranted for improved soft-tissue visualization for intracranial SRS.

Corrigendum: "Training Global Oncologists: Addressing the Global Cancer Control Problem".

[This corrects the article on p. 80 in vol. 5, PMID: 25905040.].

Intrafraction variability and deformation quantification in the breast.

PURPOSE: To evaluate intrafraction variability and deformation of the lumpectomy cavity (LC), breast, and nearby organs. METHODS AND MATERIALS: Sixteen left-sided postlumpectomy and 1 bilateral breast cancer cases underwent free-breathing CT (FBCT) and 10-phase 4-dimensional CT (4DCT). Deformable image registration was used for deformation analysis and contour propagation of breast, heart, lungs, and LC between end-exhale and end-inhale 4DCT phases. Respiration-induced motion was calculated via centroid analysis. Two planning target volumes (PTVs) were compared: PTV(FBCT) from the FBCT volume with an isotropic 10 mm expansion (5 mm excursion and 5 mm setup error) and PTV(4DCT) generated from the union of 4DCT contours with isotropic 5 mm margin for setup error. Volume and geometry were evaluated via percent difference and bounding box analysis, respectively. Deformation correlations between breast/cavity, breast/lung, and breast/heart were evaluated. Associations were tested between cavity deformation and proximity to chest wall and breast surface. RESULTS: Population-based 3-dimensional vector excursions were 2.5 ± 1.0 mm (range, 0.8-3.8 mm) for the cavity and 2.0 ± 0.8 mm (range, 0.7-3.0 mm) for the ipsilateral breast. Cavity excursion was predominantly in the anterior and superior directions (1.0 ± 0.8 mm and -1.8 ± 1.2 mm, respectively). Similarly, for all cases, LCs and ipsilateral breasts yielded median deformation values in the superior direction. For 14 of 17 patients, the LCs and breast interquartile ranges tended toward the anterior direction. The PTV(FBCT) was 51.5% ± 10.8% larger (P<.01) than PTV(4DCT). Bounding box analysis revealed that PTV(FBCT) was 9.8 ± 1.2 (lateral), 9.0 ± 2.2 (anterior-posterior), and 3.9 ± 1.8 (superior-inferior) mm larger than PTV(4DCT). Significant associations between breast and cavity deformation were found for 6 of 9 axes. No dependency was found between cavity deformation and proximity to chest wall or breast surface. CONCLUSIONS: Lumpectomy cavity and breast deformation and motion demonstrated large variability. A PTV(4DCT) approach showed value in patient-specific margins, particularly if robust interfraction setup analysis can be performed.

Deformable image registration based automatic CT-to-CT contour propagation for head and neck adaptive radiotherapy in the routine clinical setting.

PURPOSE: To evaluate the clinical potential of deformable image registration (DIR)-based automatic propagation of physician-drawn contours from a planning CT to midtreatment CT images for head and neck (H&N) adaptive radiotherapy. METHODS: Ten H&N patients, each with a planning CT (CT1) and a subsequent CT (CT2) taken approximately 3-4 week into treatment, were considered retrospectively. Clinically relevant organs and targets were manually delineated by a radiation oncologist on both sets of images. Four commercial DIR algorithms, two B-spline-based and two Demons-based, were used to deform CT1 and the relevant contour sets onto corresponding CT2 images. Agreement of the propagated contours with manually drawn contours on CT2 was visually rated by four radiation oncologists in a scale from 1 to 5, the volume overlap was quantified using Dice coefficients, and a distance analysis was done using center of mass (CoM) displacements and Hausdorff distances (HDs). Performance of these four commercial algorithms was validated using a parameter-optimized Elastix DIR algorithm. RESULTS: All algorithms attained Dice coefficients of >0.85 for organs with clear boundaries and those with volumes >9 cm(3). Organs with volumes <3 cm(3) and/or those with poorly defined boundaries showed Dice coefficients of ∼ 0.5-0.6. For the propagation of small organs (<3 cm(3)), the B-spline-based algorithms showed higher mean Dice values (Dice = 0.60) than the Demons-based algorithms (Dice = 0.54). For the gross and planning target volumes, the respective mean Dice coefficients were 0.8 and 0.9. There was no statistically significant difference in the Dice coefficients, CoM, or HD among investigated DIR algorithms. The mean radiation oncologist visual scores of the four algorithms ranged from 3.2 to 3.8, which indicated that the quality of transferred contours was "clinically acceptable with minor modification or major modification in a small number of contours." CONCLUSIONS: Use of DIR-based contour propagation in the routine clinical setting is expected to increase the efficiency of H&N replanning, reducing the amount of time needed for manual target and organ delineations.

A novel approach for establishing benchmark CBCT/CT deformable image registrations in prostate cancer radiotherapy.

Deformable image registration (DIR) is an integral component for adaptive radiation therapy. However, accurate registration between daily cone-beam computed tomography (CBCT) and treatment planning CT is challenging, due to significant daily variations in rectal and bladder fillings as well as the increased noise levels in CBCT images. Another significant challenge is the lack of 'ground-truth' registrations in the clinical setting, which is necessary for quantitative evaluation of various registration algorithms. The aim of this study is to establish benchmark registrations of clinical patient data. Three pairs of CT/CBCT datasets were chosen for this institutional review board approved retrospective study. On each image, in order to reduce the contouring uncertainty, ten independent sets of organs were manually delineated by five physicians. The mean contour set for each image was derived from the ten contours. A set of distinctive points (round natural calcifications and three implanted prostate fiducial markers) were also manually identified. The mean contours and point features were then incorporated as constraints into a B-spline based DIR algorithm. Further, a rigidity penalty was imposed on the femurs and pelvic bones to preserve their rigidity. A piecewise-rigid registration approach was adapted to account for the differences in femur pose and the sliding motion between bones. For each registration, the magnitude of the spatial Jacobian (|JAC|) was calculated to quantify the tissue compression and expansion. Deformation grids and finite-element-model-based unbalanced energy maps were also reviewed visually to evaluate the physical soundness of the resultant deformations. Organ DICE indices (indicating the degree of overlap between registered organs) and residual misalignments of the fiducial landmarks were quantified. Manual organ delineation on CBCT images varied significantly among physicians with overall mean DICE index of only 0.7 among redundant contours. Seminal vesicle contours were found to have the lowest correlation amongst physicians (DICE = 0.5). After DIR, the organ surfaces between CBCT and planning CT were in good alignment with mean DICE indices of 0.9 for prostate, rectum, and bladder, and 0.8 for seminal vesicles. The Jacobian magnitudes |JAC| in the prostate, rectum, and seminal vesicles were in the range of 0.4-1.5, indicating mild compression/expansion. The bladder volume differences were larger between CBCT and CT images with mean |JAC| values of 2.2, 0.7, and 1.0 for three respective patients. Bone deformation was negligible (|JAC| = ∼ 1.0). The difference between corresponding landmark points between CBCT and CT was less than 1.0 mm after DIR. We have presented a novel method of establishing benchmark DIR accuracy between CT and CBCT images in the pelvic region. The method incorporates manually delineated organ surfaces and landmark points as well as pixel similarity in the optimization, while ensuring bone rigidity and avoiding excessive deformation in soft tissue organs. Redundant contouring is necessary to reduce the overall registration uncertainty.

Endometrial carcinoma in the baby boomer generation. Tumor characteristics and clinical outcome.

BACKGROUND: Baby boomers (BB) entering retirement represent a significant burden on medical resources. The unique lifestyle characteristics engendered by the BB may lead to different endometrial cancer characteristics that bear understanding. We sought to characterize BB with endometrioid carcinoma after hysterectomy and compare the results to those of prior to the baby boomers (PB). PATIENTS AND METHODS: After reviewing our prospectively maintained database of 1,450 patients with endometrial cancer, we identified 595 patients who underwent hysterectomy for 1988 International Federation of Gynecologic Oncology (FIGO) stage I-II uterine endometrioid carcinomas, who were born between 1926 and 1964. Their medical records were reviewed in this Institutional review board (IRB)-approved study. Patients with non-endometrioid carcinoma and those who received preoperative therapy were excluded. Patients were defined as BB (born 1946-1964) or PB (born in 1926-1945). The two groups were compared regarding patients' demographics, tumor characteristics and survival. Following a univariate analysis, multivariable modeling was carried out using Cox regression analysis. RESULTS: All patients underwent hysterectomy with a minimum of two years' follow-up. There were 234 patients (39%) in the BB group and 361 patients (61%) in the PB group. Median follow-up for the study cohort was 56 months. BB had higher body mass index (p=0.027), lower tumor grade (p=0.002), earlier FIGO stage (p=0.023), higher number of dissected lymph nodes (p=0.008), less lymphvascular space involvement (p=<0.034), less utilization of adjuvant therapy (p=<0.001), and younger age at diagnosis (p=0.002). However, there was no significant difference found between the BB and PB in regards to local control, disease-specific survival and overall survival. For the study cohort, FIGO stage and tumor grade were independent predictors of recurrence-free and disease-specific survival. There was a trend towards shorter overall survival for the PB women (p=0.063). CONCLUSION: Although tumor characteristics were more favorable in the BB group of women, local control and survival end-points were not statistically different compared to those of the PB group. As more BB are diagnosed with endometrial carcinoma, further research is warranted to further elucidate the characteristic differences in endometrial carcinoma, if any, in this generation.

A comparison of clinical and dosimetric outcomes in patients receiving partial breast irradiation with photon-only versus mixed photon/electron treatment plans.

Several series evaluating external-beam partial breast irradiation (PBI) have linked negative cosmetic outcomes to large normal tissue treatment volumes. We compared patients treated with PBI whose treatment plans included only photons to those whose plans incorporated electrons. Twenty-seven patients were identified: median age 67 years, pT1 82%, pN0 56%, margin negative 100%. All received 38.5 Gy using 3-5 noncoplanar photon beams (6-15X). Electrons (9-20 MeV) were included in 59%. Median follow-up was 22 months. Ninety percent experienced good/excellent cosmetic outcomes. Two patients had fair cosmesis, and both were treated with a mixed photon/electron approach. Median conformity index for photon-only treatment plans was 1.7 (range, 0.9-2.0) and for photon/electron plans, 1.0 (0.3-1.4). Median percent ipsilateral breast volume receiving 100% and 50% of prescription dose was 19 and 50 for photon-only plans vs. 10 and 38 for photon/electron plans (p < 0.05). Median percent target volume receiving 100% and 95% of prescription dose was 93 and 98 for photon-only plans vs. 75 and 94 for photon/electron plans (p < 0.05). A mixed photon/electron, noncoplanar technique decreases the volume of treated normal breast tissue at the cost of slightly decreased tumor bed coverage. Further study is needed to determine whether this results in a more favorable therapeutic ratio than photon-only approaches.

A safety and survival analysis of neoadjuvant bevacizumab with standard chemoradiation in a phase I/II study compared with standard chemoradiation in locally advanced rectal cancer.

INTRODUCTION: Bevacizumab is increasingly being tested with neoadjuvant regimens in patients with localized cancer, but its effects on metastasis and survival remain unknown. This study examines the long-term outcome of clinical stage II/III rectal cancer patients treated in a prospective phase II study of bevacizumab with chemoradiation and surgery. As a benchmark, we used data from an analysis of 42 patients with locally advanced rectal cancer treated with a contemporary approach of preoperative fluoropyrimidine-based radiation therapy. MATERIALS AND METHODS: Outcome analyses were performed on 32 patients treated prospectively with neoadjuvant bevacizumab, 5-fluorouracil, radiation therapy, and surgery as well as 42 patients treated with standard fluoropyrimidine-based chemoradiation. RESULTS: Overall survival, disease-free survival, and local control showed favorable trends in patients treated with bevacizumab with chemoradiation followed by surgery. Acute and postoperative toxicity appeared acceptable. CONCLUSIONS: Neoadjuvant bevacizumab with standard chemoradiation and surgery shows promising long-term efficacy and safety profiles in locally advanced rectal cancer patients.

Plasma soluble VEGFR-1 is a potential dual biomarker of response and toxicity for bevacizumab with chemoradiation in locally advanced rectal cancer.

We explored plasma and urinary concentrations of two members of the vascular endothelial growth factor (VEGF) family and their receptors as potential response and toxicity biomarkers of bevacizumab with neoadjuvant chemoradiation in patients with localized rectal cancer. The concentrations of VEGF, placental growth factor (PlGF), soluble VEGF receptor 1 (sVEGFR-1), and sVEGFR-2 were measured in plasma and urine at baseline and during treatment. Pretreatment values and changes over time were analyzed as potential biomarkers of pathological response to treatment as well as for acute toxicity in patients with locally advanced rectal cancer treated prospectively in 2002-2008 with neoadjuvant bevacizumab, 5-fluorouracil, radiation therapy, and surgery in a phase I/II trial. Of all biomarkers, pretreatment plasma sVEGFR-1-an endogenous blocker of VEGF and PlGF, and a factor linked with "vascular normalization"-was associated with both primary tumor regression and the development of adverse events after neoadjuvant bevacizumab and chemoradiation. Based on the findings in this exploratory study, we propose that plasma sVEGFR-1 should be further studied as a potential biomarker to stratify patients in future studies of bevacizumab and/or cytotoxics in the neoadjuvant setting.