Magnetic-Resonance-Imaging Texture Analysis Predicts Early Progression in Rectal Cancer Patients Undergoing Neoadjuvant Chemoradiation.

BACKGROUND: We hypothesized that texture analysis (TA) from the preoperative MRI can predict early disease progression (ePD), defined as the percentage of patients who relapsed or showed distant metastasis within three months from the radical surgery, in patients with locally advanced rectal cancer (LARC, stage II and III, AJCC) undergoing neoadjuvant chemoradiotherapy (C-RT). METHODS: This retrospective monoinstitutional cohort study included 49 consecutive patients in total with a newly diagnosed rectal cancer. All the patients underwent baseline abdominal MRI and CT scan of the chest and abdomen to exclude distant metastasis before C-RT. Texture parameters were extracted from MRI performed before C-RT (T1, DWI, and ADC sequences) using LifeX Software, a dedicated software for extracting texture parameters from radiological imaging. We divided the cohort in a training set of 34 patients and a validation set of 15 patients, and we tested the data sets for homogeneity, considering the clinical variables. Then we performed univariate and multivariate analysis, and a ROC curve was also generated. RESULTS: Thirteen patients (26.5%) showed an ePD, three of whom with lung metastases and ten with liver relapse. The model was validated based on the prediction accuracy calculated in a previously unseen set of 15 patients. The prediction accuracy of the generated model was 82% (AUC = 0.853) in the training and 80% (AUC = 0.833) in the validation cohort. The only significant features at multivariate analysis was DWI GLCM Correlation (OR: 0.239, p < 0.001). CONCLUSION: Our results suggest that TA could be useful to identify patients that may develop early progression.

Putative Role of Circulating Human Papillomavirus DNA in the Development of Primary Squamous Cell Carcinoma of the Middle Rectum: A Case Report.

Here we present the case of a patient affected by rectal squamous cell carcinoma in which we demonstrated the presence of Human Papillomavirus (HPV) by a variety of techniques. Collectively, the virus was detected not only in the tumor but also in some regional lymph nodes and in non-neoplastic mucosa of the upper tract of large bowel. By contrast, it was not identifiable in its common sites of entry, namely oral and ano-genital region. We also found HPV DNA in the plasma-derived exosome. Next, by in vitro studies, we confirmed the capability of HPV DNA-positive exosomes, isolated from the supernatant of a HPV DNA positive cell line (CaSki), to transfer its DNA to human colon cancer and normal cell lines. In the stroma nearby the tumor mass we were able to demonstrate the presence of virus DNA in the stromal compartment, supporting its potential to be transferred from epithelial cells to the stromal ones. Thus, this case report favors the notion that human papillomavirus DNA can be vehiculated by exosomes in the blood of neoplastic patients and that it can be transferred, at least in vitro, to normal and neoplastic cells. Furthermore, we showed the presence of viral DNA and RNA in pluripotent stem cells of non-tumor tissue, suggesting that after viral integration (as demonstrated by p16 and RNA in situ hybridization positivity), stem cells might have been activated into cancer stem cells inducing neoplastic transformation of normal tissue through the inactivation of p53, p21, and Rb. It is conceivable that the virus has elicited its oncogenic effect in this specific site and not elsewhere, despite its wide anatomical distribution in the patient, for a local condition of immune suppression, as demonstrated by the increase of T-regulatory (CD4/CD25/FOXP3 positive) and T-exhausted (CD8/PD-1positive) lymphocytes and the M2 polarization (high CD163/CD68 ratio) of macrophages in the neoplastic microenvironment. It is noteworthy that our findings depicted a static picture of a long-lasting dynamic process that might evolve in the development of tumors in other anatomical sites.

3D bone texture analysis as a potential predictor of radiation-induced insufficiency fractures.

BACKGROUND: The aim of our work is to assess the potential role of texture analysis (TA), applied to computed tomography (CT) simulation scans, in relation to the development of insufficiency fractures (IFs) in patients undergoing radiation therapy (RT) for pelvic malignancies. METHODS: We analyzed patients undergoing pelvic RT from Jan-2010 to Dec-2016, 31 of whom had developed IFs of the pelvis. We analyzed CT simulation scans using LifeX Software©, and in particular we selected three regions of interest (ROI): L5 body, the sacrum and both the femoral heads. The ROI were automatically contoured using the treatment planning software Raystation©. TA parameters included parameters from the gray-level histogram, indices from sphericity and from the matrix of GLCM (gray level co-occurrence matrix). The IFs patients were matched (1:1 ratio) with control patients who had not developed IFs, and were matched for age, sex, type of tumor, menopausal status, RT dose and use of chemotherapy. Univariate and multivariate analyses (logistic regression) were used for statistical analysis. RESULTS: Significant TA parameters on univariate analysis included both parameters from the histogram distribution, as well from the matrix of GLCM. On logistic regression analysis the significant parameters were L5-energy [P=0.033, odds ratio (OR): 1.997, 95% CI: 1.059-3.767] and FH-Skewness (P=0.014, OR: 2.338, 95% CI: 1.191-4.591), with a R2: 0.268. A ROC curve was generated from the binary logistic regression, and the AUC was 0.741 (95% CI: 0.627-0.855, P=0.001, S.E.: 0.058). CONCLUSIONS: In our experience, 3D-bone CT TA can be used to stratify the risk of the patients to develop radiation-induced IFs. A prospective study will be conducted to validate these findings.

Texture analysis as a predictor of radiation-induced xerostomia in head and neck patients undergoing IMRT.

PURPOSE: Image texture analysis (TA) is a heterogeneity quantifying approach that cannot be appreciated by the naked eye, and early evidence suggests that TA has great potential in the field of oncology. The aim of this study is to evaluate parotid gland texture analysis (TA) combined with formal dosimetry as a factor for predicting severe late xerostomia in patients undergoing radiation therapy for head and neck cancers. METHODS: We performed a retrospective analysis of patients treated at our Radiation Oncology Unit between January 2010 and December 2015, and selected the patients whose normal dose constraints for the parotid gland (mean dose < 26 Gy for the bilateral gland) could not be satisfied due to the presence of positive nodes close to the parotid glands. The parotid gland that showed the higher V30 was contoured on CT simulation and analysed with LifeX Software©. TA parameters included features of grey-level co-occurrence matrix (GLCM), neighbourhood grey-level dependence matrix (NGLDM), grey-level run length matrix (GLRLM), grey-level zone length matrix (GLZLM), sphericity, and indices from the grey-level histogram. We performed a univariate and multivariate analysis between all the texture parameters, the volume of the gland, the normal dose parameters (V30 and Mean Dose), and the development of severe chronic xerostomia. RESULTS: Seventy-eight patients were included and 25 (31%) developed chronic xerostomia. The TA parameters correlated with severe chronic xerostomia included V30 (OR 5.63), Dmean (OR 5.71), Kurtosis (OR 0.78), GLCM Correlation (OR 1.34), and RLNU (OR 2.12). The multivariate logistic regression showed a significant correlation between V30 (0.001), GLCM correlation (p: 0.026), RLNU (p: 0.011), and chronic xerostomia (p < 0.001, R2:0.664). CONCLUSIONS: Xerostomia represents an important cause of morbidity for head and neck cancer survivors after radiation therapy, and in certain cases normal dose constraints cannot be satisfied. Our results seem promising as texture analysis could enhance the normal dose constraints for the prediction of xerostomia.

Radiotherapy plus rituximab as first-line regimen for localized follicular lymphoma.

Early-stage follicular lymphoma (FL) can be cured with involved-field radiotherapy (IF-RT); however, many patients relapse in non-irradiated areas. A combined association with chemotherapy could increase treatment efficacy, but toxic effects could be unacceptable. In vitro synergistic effect between rituximab (R) and RT has been observed, but clinical data are limited. We retrospectively analyzed 41 early-stage FL patients receiving R and IF-RT as first-line treatment. We administered R 375mg/m2 weekly for four courses, before or after IF-RT (median dose 24 Gy). Primary outcome was PFS, secondary endpoints were CR rate, OS and safety. All patients achieved CR, after a median follow-up of 46 months only three patients relapsed after 18, 26 and 42 months; estimated 5-year PFS was 90%. We suggest R in association with IF-RT could represent a feasible first-line treatment option for early-stage FL and could increase efficacy without additional toxicity compared to available data about RT alone.

Combining Abiraterone and Radiotherapy in Prostate Cancer Patients Who Progressed During Abiraterone Therapy.

BACKGROUND/AIM: This multicenter, retrospective, 'field-practice' study investigated treatment outcomes of ongoing abiraterone therapy with the addition of radiotherapy (RT) - initiated for oligoprogression or with a palliative intent. PATIENTS AND METHODS: Consecutive patients affected by metastatic castration-resistant prostate cancer (mCRPC) treated with abiraterone acetate were considered if they had received RT after the initiation of abiraterone treatment. RESULTS: A total of 32 patients were enrolled in the study. Median duration of abiraterone treatment was 13.0 months (range=3.8-40.9 months). Median duration of abiraterone treatment before RT was 5.9 months (range=0.4-40.0 months), and 7.2 months after RT (range=0.1-29.7 months). Median progression-free survival (PFS) was 12.6 months (95%CI=10.5-14.7) from the initiation of abiraterone treatment. From RT administration, PFS was 9.6 months (95%CI=6.4-12.9). Median overall survival (OS) since abiraterone initiation was 18.9 months (95%CI=4.7-33.0). CONCLUSION: RT prolongs abiraterone treatment in mCRPC patients leading to better clinical outcomes with this molecule.

Perilesional edema in brain metastasis from non-small cell lung cancer (NSCLC) as predictor of response to radiosurgery (SRS).

Radiosurgery (SRS) is widely used in the treatment of brain oligo-metastases from NSCLC. The aim of present study is to evaluate the extent of perilesional edema in brain metastases as predictive factor of treatment response. This single center retrospective study included 42 consecutive patients (January 2011-December 2014) with 1-2 brain metastasis from NSCLC treated with Radiosurgery (SRS). Extent of perilesional edema was measured as maximal extension from the edge of lesion and classified as minor (<10 mm) or major (≥10 mm). We analyzed Modality of Brain Recurrence (MBR), classified as in-field or out-of- field, and Brain Progression Free-Survival (BPFS) after treatment stratified according to extent of perilesional edema. Analyzing modality of brain recurrence and BPFS, after a median follow-up of 6 months, we found that patients with minor edema had a better radiological response to SRS with none in-field recurrences and a lower risk of the onset of new brain lesions (out-of-field recurrence). Instead, patients group with major edema had a worse response rate of lesions treated, further, a higher risk of out-of-field brain relapse. Extent of perilesional edema in brain metastasis from NSCLC could be a predictive factor of response and brain progression after SRS treatment alone.

Tumor infiltrating T lymphocytes expressing FoxP3, CCR7 or PD-1 predict the outcome of prostate cancer patients subjected to salvage radiotherapy after biochemical relapse.

Tumor immunologic microenvironment is strongly involved in tumor progression and the presence of tumor infiltrating lymphocytes (TIL) with different phenotypes has been demonstrated to be of prognostic relevance in different malignancies. We investigated whether TIL infiltration of tumor tissues could also predict the outcome of prostate cancer patients. To this end, we carried out a retrospective analysis correlating the outcome of locally advanced prostate cancer patients undergone salvage radiotherapy upon relapse after radical surgery with the infiltration by different TIL populations. Twenty-two patients with resectable prostate cancer, with a mean age of 67 (+/-3.93) years, who received salvage radiotherapy with a mean of 69.66 (+/- 3.178) Gy in 8 weeks, between June 1999 and January 2009 and with a median follow up of 123 (+/- 55.82) months, were enrolled in this study. We evaluated, by immunohistochemistry, the intratumoral (t) and peripheral stroma (p) infiltration by CD45, CD3, CD4, CD8, CCR7, FoxP3 or PD-1-positive cells on tumor samples taken at the diagnosis (d) and relapse times (R). We correlated these variables with patients' biochemical progression free survival (bPFS), post-radiotherapy progression free survival (PFS), and overall survival (OS). Substantial changes in the rate of TIL subsets were found between the first and the second biopsy with progressive increase in CD4, CCR7, FoxP3, PD-1+ cells. Our analysis revealed that higher CD8p,R+ and lower PD-1R+ TIL scores correlated to a longer bPFS. Higher CD8p,R+ and CCR7t,R+ TIL scores and lower CD45p,R+ and FoxP3p,R+ TIL scores correlated to a prolonged PFS and OS. These results suggest that the immunological microenvironment of primary tumor is strictly correlated with patient outcome and provide the rationale for immunological treatment of prostate cancer.

Phase Ib study of poly-epitope peptide vaccination to thymidylate synthase (TSPP) and GOLFIG chemo-immunotherapy for treatment of metastatic colorectal cancer patients.

Thymidylate synthase (TS) is a tumor-associated enzyme critical for DNA replication and main 5'-fluorouracil (5'-FU) target. TSPP/VAC1 is a multi-arm trial phase-Ib trial program aimed to investigate the toxicity and biomodulatory activity of a poly-epitope-peptide vaccine to TS (TSPP) in cancer patients (pts). Here, we present the results of the TSPP/VAC1/arm C trial aimed to evaluate TSPP in combination with chemo-immunotherapy in pretreated metastatic colo-rectal cancer (mCRC) pts. Twenty-nine pts, 14 males and 15 females, received poly-chemotherapy with gemcitabine [GEM; 1,000 mg/sqm, day-1], oxaliplatin [OX; 80 mg/sqm, day-2], levofolinate [100 mg/sqm, days 1-2], bolus/infusional 5'-FU [400 mg/800 mg/sqm, days 1-2], sargramostim [50 µg, days 3-7/q30], and interleukin-2 [sc. 0.5 MIU twice a day, days 8-14/18-30] [GOLFIG-regimen]. Seventeen pts received sc. TSPP injections at escalating dosage [3 pts, 100 µg (DL-1); 3 pts, 200 µg (DL-2) and 11pts, 300 µg (DL-3)] one week after each chemotherapy cycle (concomitant module), while 10 out 12 pts received TSPP (300 µg) after 12 GOLFIG courses [dose level (DL)-0] (sequential module). TSPP MTD was not achieved. Adverse events consisted in swelling/erythema at injection sites (17 cases), G1-2 haematological (16 cases) and gastro-enteric events (12), fever, rhinitis, conjunctivitis, and poly-arthralgia and rise in auto-antibodies [ANA, ENA, c-ANCA, p-ANCA in the DL1-3 pts]. Both treatment-modules showed immunomodulating and antitumor activity (disease-control-rate, DL1-3 and DL0 were 70.6% and 83.3%, respectively) with a better survival recorded in the second group [median OS DL1-3 vs. DL0 = 8 vs. 16 mo, p = 0.049]. The promising long-term survival produced by the sequential treatment module deserves further phase II evaluation.

Prognostic Value of MR Imaging Texture Analysis in Brain Non-Small Cell Lung Cancer Oligo-Metastases Undergoing Stereotactic Irradiation.

UNLABELLED: BACKGROUND : Stereotactic irradiation is widely used in brain oligo-metastases treatment. The aim of this study is to evaluate the prognostic value of magnetic resonance imaging (MRI) texture analysis (TA) of brain metastases (BM) of non-small cell lung cancer (NSCLC). MATERIALS AND METHODS : This study included thirty-eight consecutive patients undergoing stereotactic irradiation, that is, stereotactic fractionated radiotherapy (SRT) or radiosurgery (SRS), from January 2011 to December 2014 for 1-2 brain BM from NSCLC. Whole-brain radiotherapy (WBRT) was not delivered. The diagnostic MRI DICOM (Digital Imaging and Communications in Medicine) images were collected and analyzed with a homemade ImageJ macro, and typical TA parameters (mean, standard deviation, skewness, kurtosis, entropy, and uniformity) were evaluated for: brain progression-free survival; modality of brain metastatic progression (local progression or/and new metastases); and overall survival, after SRT/SRS. RESULTS: After SRT/SRS 14 patients (36.8%) experienced recurrence in the brain, with a recurrence in the irradiated site (five patients, 13.2%), new metastases (11 patients, 28.9%), local recurrence and new metastases (two patients, 5.25%). Nineteen patients (50%) died of tumor progression or other causes. Entropy and uniformity were significantly associated with local progression, whereas kurtosis was significantly associated with both local progression and new brain metastases. CONCLUSIONS : These results appear promising, since the knowledge of factors correlated with the modality of brain progression after stereotactic irradiation of brain oligo-metastatic foci of NSCLC might help in driving the best treatment in these patients (association of SRT/SRS with WBRT? Increase of SRT/SRS dose?). Our preliminary data needs confirmation in large patient series.

Diffusion-weighted magnetic resonance diagnosis of local recurrences of prostate cancer after radical prostatectomy: preliminary evaluation on twenty-seven cases.

OBJECTIVES: To assess the diagnostic performance of diffusion-weighted MR imaging (DWI) in patients affected by prostatic fossa (PF) relapse after radical prostatectomy (RP) for prostatic carcinoma (PC). METHODS: Twenty-seven patients showing a nodular lesion in the PF at T2-weighted MR imaging after RP, with diagnosis of PC relapse established by biopsy or PSA determinations, were investigated by DWI. Two readers evaluated the DWI results in consensus and the apparent diffusion coefficient (ADC) of the nodules, separately; a mean value was obtained (ADCm). RESULTS: Relapses did not significantly differ in size in respect of postsurgical benign nodules. The DWI qualitative evaluation showed sensitivity, specificity, accuracy, ppv, and npv values, respectively, of 83.3%, 88.9%, 85.2%, 93.7%, and 72.7% (100%, 87.5%, 95.6%, 93.7%, and 100%, for nodules >6 mm). The intraclass correlation coefficient (ICC) for ADC evaluation between the two readers was 0.852 (95% CI 0.661-0.935; P = 0.0001). The ADCm values for relapses and benign nodules were, respectively, 0.98 ± 0.21 × 10(-3) mm(2)/sec and 1.24 ± 0.32 × 10(-3) mm(2)/sec (P = 0.006). Sensitivity, specificity, accuracy, ppv and npv of ADCm were, respectively, 77.8%, 88.9%, 81.8%, 93.3%, and 66.7% (93.3%, 87.5%, 85.4%, 93.3%, and 87.5% for nodules >6 mm). CONCLUSIONS: Diffusion-weighted MR imaging is a promising tool in the management of a hyperintense nodule detected by T2-weighted sequences. This might have a relevant importance in contouring radiotherapy treatment volumes.