This study provides a rationale for the further development of PSMA-targeted imaging in breast cancer, especially in triple-negative tumors.

Vulvar cancer is rare but incidence rates are increasing due to an aging population and higher frequencies of young women being affected. In locally advanced, metastatic or recurrent disease prognosis is poor and new treatment modalities are needed. Immune checkpoint blockade of the PD-1/PD-L1 pathway is one of the most important advancements in cancer therapy in the last years. The clinical relevance of PD-L1 expression in vulvar cancer, however, has not been studied so far. We determined PD-L1 expression, numbers of CD3+ T cells, CD20+ B cells, CD68+ monocytes/macrophages, Foxp3+ regulatory T cells and CD163+ tumor-associated macrophages by immunohistochemistry in 103 patients. Correlation analysis with clinicopathological parameters was undertaken; the cause-specific outcome was modeled with competing risk analysis; multivariate Cox regression was used to determine independent predictors of survival. Membranous PD-L1 was expressed in a minority of tumors, defined by HPV-negativity. Its presence geographically correlated with immunocyte-rich regions of cancer islets and was an independent prognostic factor for poor outcome. Our data support the notion that vulvar cancer is an immunomodulatory tumor that harnesses the PD-1/PD-L1 pathway to induce tolerance. Accordingly, immunotherapeutic approaches might have the potential to improve outcome in patients with vulvar cancer and could complement conventional cancer treatment.

PurposeThe management of cervical cancer in pregnancy persists to be challenging. Therefore, identification of factors that influence the choice of therapeutic management is pivotal for an adequate patient counseling.MethodsWe present a literature review of 26 studies reporting 121 pregnancies affected by cervical cancer. Additionally, we add a retrospective case series of five patients with pregnancy-associated cervical cancer diagnosed and treated in our clinic between 2006 and 2013.ResultsThe literature review revealed that the therapeutic management during pregnancy varies according to the gestational age at diagnosis, while in the postpartum period no influence on the treatment choice could be detected. Also in our case series the choice of oncologic therapy was influenced by the gestational age, the wish to continue the pregnancy and the risks of delaying definitive treatment.ConclusionsThere are no standardized procedures concerning the treatment of cervical cancer in pregnancy. Therefore, in consultation with the patient and a multidisciplinary team, an adequate individualized treatment plan should be determined.Electronic supplementary materialThe online version of this article (doi:10.1007/s00404-015-3980-y) contains supplementary material, which is available to authorized users.

Objective: The effect of functional lung avoidance planning on radiation dose-dependent changes in regional lung perfusion is unknown. We characterized dose-perfusion response on longitudinal perfusion single photon emission computed tomography (SPECT)/CT in two cohorts of lung cancer patients treated with and without functional lung avoidance techniques. Methods: The study included 28 primary lung cancer patients: 20 from interventional (NCT02773238) (FLARE-RT) and eight from observational (NCT01982123) (LUNG-RT) clinical trials. FLARE-RT treatment plans included perfused lung dose constraints while LUNG-RT plans adhered to clinical standards. Pre- and 3 month post-treatment macro-aggregated albumin (MAA) SPECT/CT scans were rigidly co-registered to planning four-dimensional CT scans. Tumour-subtracted lung dose was converted to EQD2 and sorted into 5 Gy bins. Mean dose and percent change between pre/post-RT MAA-SPECT uptake (%ΔPERF), normalized to total tumour-subtracted lung uptake, were calculated in each binned dose region. Perfusion frequency histograms of pre/post-RT MAA-SPECT were analyzed. Dose–response data were parameterized by sigmoid logistic functions to estimate maximum perfusion increase (%ΔPERFmaxincrease), maximum perfusion decrease (%ΔPERFmaxdecrease), dose midpoint (Dmid), and dose-response slope (k). Results: Differences in MAA perfusion frequency distribution shape between time points were observed in 11/20 (55%) FLARE-RT and 2/8 (25%) LUNG-RT patients (p < 0.05). FLARE-RT dose response was characterized by >10% perfusion increase in the 0–5 Gy dose bin for 8/20 patients (%ΔPERFmaxincrease = 10–40%), which was not observed in any LUNG-RT patients (p = 0.03). The dose midpoint Dmid at which relative perfusion declined by 50% trended higher in FLARE-RT compared to LUNG-RT cohorts (35 GyEQD2 vs 21 GyEQD2, p = 0.09), while the dose-response slope k was similar between FLARE-RT and LUNG-RT cohorts (3.1–3.2, p = 0.86). Conclusion: Functional lung avoidance planning may promote increased post-treatment perfusion in low dose regions for select patients, though inter-patient variability remains high in unbalanced cohorts. These preliminary findings form testable hypotheses that warrant subsequent validation in larger cohorts within randomized or case-matched control investigations. Advances in knowledge: This novel preliminary study reports differences in dose-response relationships between patients receiving functional lung avoidance radiation therapy (FLARE-RT) and those receiving conventionally planned radiation therapy (LUNG-RT). Following further validation and testing of these effects in larger patient populations, individualized estimation of regional lung perfusion dose-response may help refine future risk-adaptive strategies to minimize lung function deficits and toxicity incidence.

Potential areas where megavoltage computed tomography (MVCT) could be used are second- and third-phase treatment planning in 3D conformal radiotherapy and IMRT, adaptive radiation therapy, single fraction palliative treatment and for the treatment of patients with metal prostheses. A feasibility study was done on using MV cone beam CT (CBCT) images generated by proprietary 3D reconstruction software based on the FDK algorithm for megavoltage treatment planning. The reconstructed images were converted to a DICOM file set. The pixel values of megavoltage cone beam computed tomography (MV CBCT) were rescaled to those of kV CT for use with a treatment planning system. A calibration phantom was designed and developed for verification of geometric accuracy and CT number calibration. The distance measured between two marker points on the CBCT image and the physical dimension on the phantom were in good agreement. Point dose verification for a 10 cm x 10 cm beam at a gantry angle of 0 degrees and SAD of 100 cm were performed for a 6 MV beam for both kV and MV CBCT images. The point doses were found to vary between +/-6.1% of the dose calculated from the kV CT image. The isodose curves for 6 MV for both kV CT and MV CBCT images were within 2% and 3 mm distance-to-agreement. A plan with three beams was performed on MV CBCT, simulating a treatment plan for cancer of the pituitary. The distribution obtained was compared with those corresponding to that obtained using the kV CT. This study has shown that treatment planning with MV cone beam CT images is feasible.

Evidence is sparse regarding the clinical performance of luminescent oxygen channeling immunoassays-based tumor marker assays in gynecological cancer. Analyzing serum samples of 336 patients with Dimension™Vista1500, we investigated the diagnostic power of carbohydrate antigen 15-3, carbohydrate antigen 125, carcinoembryonic antigen, carbohydrate antigen 19-9, and alpha-fetoprotein in patients suffering from different types of gynecological cancer and precancerous gynecological diseases and compared findings to appropriate control groups. The cohort comprised 177 female patients with gynecological cancers (73 breast, 22 cervical, 16 endometrial, 17 vulva, and 49 ovarian cancers), 26 patients with precancerous gynecological diseases (11 vulva, 4 cervical, and 10 breast), 109 patients with benign gynecological diseases, and 24 healthy controls. Discriminative power was assessed by areas under the curve in receiver operating characteristic curves, and sensitivities were determined at a fixed specificity of 95%. Levels of biomarkers in healthy controls were in the expected ranges and a discriminative power between gynecological cancers and healthy controls was observed for several tumor markers. Established tumor type-associated markers were elevated in specific gynecological cancers and benign controls as well as within precancerous gynecological diseases and healthy control group. In ovarian cancer, carbohydrate antigen 125 and carbohydrate antigen 15-3 were significantly elevated compared to the respective benign diseases. Carbohydrate antigen 125 was the most conclusive marker (area under the curve = 0.86% and 77.6% sensitivity at 95% specificity). In breast cancer, carcinoembryonic antigen and carbohydrate antigen 15-3 were significantly higher than in the respective benign diseases. Carcinoembryonic antigen achieved the most conclusive area under the curve (0.65) with 31.5% sensitivity at 95% specificity. None of the investigated markers was found to be of value in discriminating benign and malignant cervical diseases. Carcinoembryonic antigen and alpha-fetoprotein distinguished precancerous breast and vulva diseases from healthy controls. These findings show that luminescent oxygen channeling immunoassays-based tumor marker assays provide reliable results in routine diagnostics.

In this study we have attempted to optimize a PET based adaptive threshold segmentation method for delineating small tumors, particularly in a background of high tracer activity. The metabolic nature of pituitary adenomas and the constraints of MRI imaging in the postoperative setting to delineate these tumors during radiosurgical procedures motivated us to develop this method. Phantom experiments were done to establish a relationship between the threshold required for segmenting the PET images and the target size and the activity concentration within the target in relation to its background. The threshold was developed from multiple linear regression of the experimental data optimized for tumor sizes less than 4 cm3. We validated our method against the phantom target volumes with measured target to background ratios ranging from 1.6 to 14.58. The method was tested on ten retrospective patients with residual growth hormone‐secreting pituitary adenomas that underwent radiosurgery and compared against the volumes delineated by manual method. The predicted volumes against the true volume of the phantom inserts gave a correlation coefficient of 99% (p<0.01). In the ten retrospective patients, the automatically segmented tumor volumes against volumes manually delineated by the clinicians had a correlation of 94% (p<0.01). This adaptive threshold segmentation showed promising results in delineating tumor volumes in pituitary adenomas planned for stereotactic radiosurgery, particularly in the postoperative setting where MR and CT images may be associated with artifacts, provided optimization experiment is carried out.PACS number: 87.57.nm, 87.57.uk

Purpose of the Report We evaluated the reliability of 18F-FDG PET imaging biomarkers to classify early response status across observers, scanners, and reconstruction algorithms in support of biologically adaptive radiation therapy for locally advanced non–small cell lung cancer. Patients and Methods Thirty-one patients with unresectable locally advanced non–small cell lung cancer were prospectively enrolled on a phase 2 trial (NCT02773238) and underwent 18F-FDG PET on GE Discovery STE (DSTE) or GE Discovery MI (DMI) PET/CT systems at baseline and during the third week external beam radiation therapy regimens. All PET scans were reconstructed using OSEM; GE-DMI scans were also reconstructed with BSREM-TOF (block sequential regularized expectation maximization reconstruction algorithm incorporating time of flight). Primary tumors were contoured by 3 observers using semiautomatic gradient-based segmentation. SUVmax, SUVmean, SUVpeak, MTV (metabolic tumor volume), and total lesion glycolysis were correlated with midtherapy multidisciplinary clinical response assessment. Dice similarity of contours and response classification areas under the curve were evaluated across observers, scanners, and reconstruction algorithms. LASSO logistic regression models were trained on DSTE PET patient data and independently tested on DMI PET patient data. Results Interobserver variability of PET contours was low for both OSEM and BSREM-TOF reconstructions; intraobserver variability between reconstructions was slightly higher. ΔSUVpeak was the most robust response predictor across observers and image reconstructions. LASSO models consistently selected ΔSUVpeak and ΔMTV as response predictors. Response classification models achieved high cross-validated performance on the DSTE cohort and more variable testing performance on the DMI cohort. Conclusions The variability FDG PET lesion contours and imaging biomarkers was relatively low across observers, scanners, and reconstructions. Objective midtreatment PET response assessment may lead to improved precision of biologically adaptive radiation therapy.