Intensified Total Neoadjuvant Therapy in Patients With Locally Advanced Rectal Cancer: A Phase II Trial.

AIMS: We assessed the efficacy and safety of total neoadjuvant therapy, including targeted agent plus FOLFOXIRI (5-fluorouracil, leucovorin, oxaliplatin and irinotecan) induction chemotherapy followed by intensified chemoradiotherapy (CRT) and surgical resection, in patients with locally advanced rectal cancer. MATERIALS AND METHODS: This was a single-arm, single-centre phase II trial. Eligible patients had non-metastatic locally advanced rectal adenocarcinoma. Based on Ras-BRAF status, patients were treated with bevacizumab (mutated Ras-BRAF) or panitumumab/cetuximab (wild-type Ras-BRAF) plus FOLFOXIRI regimen followed by oxaliplatin-5-fluorouracil-based CRT and surgery. The primary end point was pathological complete response rate. Secondary end points were toxicity, compliance, tumour downstaging, complete resection, surgical complications, local and distant failures and overall survival. The sample size was planned to expect an absolute 20% improvement in pathological complete response rate over historical literature data with an α error of 0.05 and a power of 80%. RESULTS: Between October 2015 and September 2019, 28 patients (median age 66 years) were enrolled. All patients had regional lymph node involvement at diagnosis. FOLFOXIRI plus bevacizumab was administered in 11 mutated Ras-BRAF patients, whereas the 17 wild-type Ras-BRAF patients received FOLFOXIRI plus panitumumab/cetuximab. Overall, total neoadjuvant therapy was well tolerated and 26 patients (92.9%) completed the programmed strategy. A complete response was achieved in nine cases (32.1%) and a nearly pathological complete response (ypT1 ypN0) in two patients (7.2%). There was no evidence of febrile neutropenia and no grade 4 adverse events were recorded. Radical resection was achieved in all cases. CONCLUSION: FOLFOXIRI plus targeted agent-based induction chemotherapy and intensified CRT before surgery showed promising clinical activity and was well tolerated in locally advanced rectal cancer patients. This phase II trial provides a strong rationale for phase III studies.

Stereotactic ablative radiotherapy in castration-resistant prostate cancer patients with oligoprogression during androgen receptor-targeted therapy.

OBJECTIVES: To report outcomes of stereotactic body radiotherapy (SBRT) in metastatic castration-resistant prostate cancer (mCRPC) patients with oligoprogression (≤ 5 metastases) during first-line treatment with androgen receptor-targeted therapy (ARTT). PATIENTS AND METHODS: Retrospective multi-institutional analysis of mCRPC patients treated with SBRT to oligoprogressive lesions during ARTT. End-points were time to next-line systemic treatment (NEST), radiological progression-free survival (r-PFS) and overall survival (OS). Toxicity was registered according to Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Survival analysis was performed using the Kaplan-Meier method, univariate and multivariate analysis (MVA) were performed. RESULTS: Data from 34 patients were analyzed. Median NEST-free survival, r-PFS, and OS were 16.97, 13.47, and 38.3 months, respectively. At MVA, factors associated with worse NEST-free survival and r-PFS were polymetastatic burden at diagnosis of metastatic hormone-sensitive disease (hazard ratio [HR] 3.66, p = 0.009; HR 3.03, p = 0.034), PSA ≤ 7 ng/ml at mCRPC diagnosis (HR 0.23, p = 0.017; HR 0.19, p = 0.006) and PSADT ≤ 3 months at mCRPC diagnosis (HR 3.39, p = 0.026; HR 2.79, p = 0.037). Polymetastatic state at mHSPC diagnosis was associated with a decreased OS (HR 4.68, p = 0.029). No patient developed acute or late grade ≥ 2 toxicity. CONCLUSION: Our results suggest that SBRT in oligoprogressive mCPRC is safe, effective and seems to prolong the efficacy of the ongoing systemic treatment positively affecting disease progression. Prospective trials are needed.

Correction to: Vitamin D protects endothelial cells from irradiation-induced senescence and apoptosis by modulating MAPK/SirT1 axis.

Unfortunately, the 5th author name has been publisehd incorrectly in the original publication. The complete correct name is given below.

Decision tree algorithm in locally advanced rectal cancer: an example of over-interpretation and misuse of a machine learning approach.

PURPOSE: To analyse the classification performances of a decision tree method applied to predictor variables in survival outcome in patients with locally advanced rectal cancer (LARC). The aim was to offer a critical analysis to better apply tree-based approach in clinical practice and improve its interpretation. MATERIALS AND METHODS: Data concerning patients with histological proven LARC between 2007 and 2014 were reviewed. All patients were treated with trimodality approach with a curative intent. The Kaplan-Meier method was used to estimate overall survival (OS). Decision tree methods were was used to select important variables in outcome prediction. RESULTS: A total of 100 patients were included. The 5-year and 7-year OS rates were 76.4% and 71.3%, respectively. Age, co-morbidities, tumor size, clinical tumor classification (cT) and clinical nodes classification (cN) were the important predictor variables to the tree's construction. Overall, 13 distinct groups of patients were defined. Patients aged < 65 years with cT3 disease and elderly patients with a tumor size < 5 cm seemed to have highest rates of survival. But the process over-fitted the data, leading to poor algorithm performance. CONCLUSION: We proposed a decision tree algorithm to identify known and new pre-treatment clinical predictors of survival in LARC. Our analysis confirmed that tree-based machine learning method, especially classification trees, can be easily interpreted even by a non-expert in the field, but controlling cross validation errors is mandatory to capture its statistical power. However, it is necessary to carefully analyze the classification error trend to chose the important predictor variables, especially in little data. Machine learning approach should be considered the new unexplored frontier in LARC. Based on big datasets, decision trees represent an opportunity to improve decision-making process in clinical practice.

Implant placement in oral squamous cells carcinoma patients treated with chemoradiotherapy: "Sapienza Head and Neck Unit" clinical recommendations.

OBJECTIVE: To date, the treatment of patients affected by head and neck squamous cell carcinoma (HNSCC) is highly challenging for clinicians. Possible therapies are surgical resection of the tumor mass, radiotherapy, chemotherapy or, more often, a combined treatment that inevitably affects both normal and tumor cells. Consequently, patients' anatomy and functions become reduced or altered. Nowadays the functional restoration is significantly improved thanks to the innovation in prosthetic rehabilitation and in radiotherapy. The current IMRT (Intensity Modulated Radiation Therapy) allows planning adequate treatments evaluating different tissues' involvement and radiation dosage. It is possible to define the most suitable sites for implant insertion, using data provided by dose-volume histogram (DVH). This study aims to illustrate the idea of obtaining a unique CT image by blending radiation-planning CT and Cone Beam CT. PATIENTS AND METHODS: Five patients among 54 candidates were selected for this study. Selection criteria were: good general health (PS0-1), age between 18 and 72 years, absence of metastatic disease or local recurrence, disease-free interval of at least 18 months. Radiation planning CT scan and maxillo-facial CT Cone Beam of every patient were overlapped and merged. Only one CT for every evaluated patient was obtained in order to plan the most suitable areas for implant placement. RESULTS: The placement of 10 implants in 5 patients was programmed using the explained method. Patients (all male) were aged between 48 and 72 years old, with a median age of 64.4 years. In every case of this study, a modification of the initial program of implant placement was necessary. The new imaging method we are proposing was able to provide information about radiation isodoses received in the planned osseointegrated implants' positions. CONCLUSIONS: This new method allows operators to correct their own therapy plans and choices, customizing the treatment plan on the actual condition of the patient. Moreover, it makes all the rehabilitation process safer and can reduce the risk of failure, side effects and inconveniences for the patients.

Immune check-point in glioblastoma multiforme.

Glioblastoma multiforme (GBM) represents one of the main frequent and aggressive primary brain neoplasms among adults worldwide. Despite a first-line multimodal treatment, including radical surgery and adjuvant radiation therapy with concomitant temozolomide-based chemotherapy, GBM prognosis continues to be unfavourable. During this decade, different research groups have explored immune check-point inhibitors role in order to improve response to therapy and subsequently prolong survival rate. The aim of this review was to analyze published literature to support immune check-point inhibitors use in the management of patients with GBM diagnosis. The hope was to help physicians for better decision-making.

Crestal bone loss around dental implants placed in head and neck cancer patients treated with different radiotherapy techniques: a prospective cohort study.

The aim of this prospective cohort study was to evaluate how the radiation technique can affect crestal bone loss and the implant survival rate in head and neck cancer patients treated with radiotherapy. In this study, the type of radiotherapy treatment, i.e. three-dimensional conformal radiotherapy (3D-CRT) or intensity modulated radiation therapy (IMRT), was the predictor variable. The primary outcome variable was crestal bone loss, recorded at implant placement and after 3, 6, 12, and 24 months. A descriptive analysis and ANOVA test were performed; significance was set at P<0.05. Thirty-two patients were enrolled and a total of 113 dental implants placed in irradiated residual bone. There was no statistically significant difference in crestal bone loss levels between the groups at any of the intervals (P>0.05), except after 6 months (P=0.028). The cumulative dental implant survival rate was 94.7%. After 24 months, the mean marginal bone loss was 0.83±0.12mm in the 3D-CRT group and 0.74±0.15mm in the IMRT group (P=0.179). The data suggest that the different radiation techniques did not affect the outcomes of implant-supported prosthetic rehabilitation, as related to crestal bone loss and implant survival. However, long-term follow-up studies are necessary to evaluate the real influence of the radiotherapy technique on dental implants.

Primary thyroid angiosarcoma: A systematic review.

Thyroid angiosarcoma (TAS) is rare and represents a very aggressive malignancy. Its rarity is principally linked to two major pitfalls. Firstly, TAS histopathology diagnosis can be difficult; second, the limited clinical experience with this condition can make its management complex. We conducted a detailed systematic review, focusing on the knowledge available regarding TAS etiopathogenesis, treatment options and prognosis. The aim is to present the main TAS characteristics and to summarize the clinical experiences described worldwide, in order to provide a useful clinical tool.

Excess of weight: is it a modifiable predictive and prognostic factor in locally advanced rectal cancer?

OBJECTIVE: To evaluate the relationship between body mass index (BMI) and rates of treatment tolerance and clinical outcomes in patients with locally advanced rectal cancer treated with a multimodality approach. PATIENTS AND METHODS: This study was conducted on 56 patients with histologically proven rectal adenocarcinoma, staged T3-4, and/or node-positive tumor, which underwent intensified radiochemotherapy (RT-CHT) treatment before surgery. We calculated adiposity indices and analyzed their influence on treatment tolerance and clinical outcomes. RESULTS: Distribution of the 56 patients according to BMI was BMI < 25 kg/m2 (n = 19; 33.9%), BMI 25-29 kg/m2 (n = 29; 51.8%) and BMI ≥ 30 kg/m2 (n = 8; 14.3%). BMI had no significant influence on neo-adjuvant treatment-related toxicity. With a median follow-up of 23 months (range 11-47), the 2-year survival was 85.7%. We did not observe any significant difference among the three BMI categories for any of the outcomes. CONCLUSIONS: This study suggested no evident links between overweight and survival in patients with locally advanced rectal carcinoma treated with neo-adjuvant RT-CHT. Overweight patients tolerate treatment as normal-weight patients.

Diffusion-weighted magnetic resonance imaging in locally advanced rectal cancer treated with neoadjuvant chemoradiotherapy.

PURPOSE: To analyze diffusion-weighted magnetic resonance imaging (DW-MRI) for treatment response assessment in locally advanced rectal cancer (LARC). PATIENTS AND METHODS: Patients with histologically proven rectal adenocarcinoma, stage II-III disease, were enrolled and underwent surgery following neoadjuvant chemoradiotherapy (nCRT). All patients were referred for a DW-MRI protocol on a 3 Tesla MR-system, consisting of axial T2-weighted and DWI sequences prior (I), during (II) and after (III) nCRT. Corresponding apparent diffusion coefficient (ADC) values were calculated. RESULTS: Between February 2011 and June 2015, 37 patients participated in the study. All patients completed programmed treatment. Overall, 11 patients (29.7%) had pathologic complete response (pCR). No correlation between the mean pre- (ADC-I), during (ADC-II), post- (ADC-III) ADC and the reduction in tumor size after nCRT was recorded. No substantial difference in the ADC distribution was found between pCR and no-pCR patients. The ADC-II level significantly increased in the pCR cases (T = 1.675; p < 0.05). CONCLUSION: ADC value could be useful for discriminating between the pCR patients and the no-pCR patients. Further studies are necessary to identify the optimal MRI parameters combination to predict tumor response to nCRT. It is hoped that these data will provide the basis for a more solid scientific evidence.

Unenhanced whole-body MRI versus PET-CT for the detection of prostate cancer metastases after primary treatment.

OBJECTIVE: The aim of this study was to evaluate the accuracy of unenhanced whole-body MRI, including whole-body Diffusion Weighted Imaging (DWI), used as a diagnostic modality to detect  pathologic lymph nodes and skeletal metastases in patients with prostate cancer (PCa) undergoing restaging after primary treatment. PATIENTS AND METHODS: 152 male patients with biochemical recurrence after radical prostatectomy (RP) or external beam radiation therapy (EBRT) underwent MRI at a 1.5 Tesla magnet with whole spinal sagittal T2-weighted, sagittal T1-weighted, sagittal STIR images, axial T1 and T2-weighted and STIR images of the pelvis and whole-body. 18Fcholine-PET/CT exam was used as the reference standard. RESULTS: MRI protocol including whole-body combined T1-weighted+T2-weighted+STIR+DWI showed a sensitivity (Se) of 99%, a specificity (Spe) of 98%, a positive predictive value (PPV) of 98%, a negative predictive value (NPV) of 96%, an accuracy of 98% and an area under the receiver operating characteristic curve (AUC) of 0.971 for identification of bone metastatic lesion. The same protocol, displayed a Se of 98%, a Spe of 99%, a PPV of 97%, a NPV of 98%, an accuracy of 98 % and an AUC of 0.960 in the detection of pathologic lymph nodes. CONCLUSIONS: Unenhanced whole-body MRI, including whole-body-DWI, is an accurate and cost-effective diagnostic tool which is able to detect lymph node involvement and bone metastases in patients with biochemically recurrent PCa after RP or EBRT. Thanks to its lack of ionizing radiation, excellent soft tissue contrast, high spatial resolution, no need of contrast agent, high Se and Spe, it could play a role in the restaging procedure of such patients.

c-Myc Sustains Transformed Phenotype and Promotes Radioresistance of Embryonal Rhabdomyosarcoma Cell Lines.

We have previously reported that the MEK/ERK pathway sustains in vitro and in vivo transformed phenotype and radioresistance of embryonal rhabdomyosarcoma (ERMS) cell lines. Furthermore, we found that aberrant MEK/ERK signaling activation promotes c-Myc oncoprotein accumulation. In this study, the role of c-Myc in sustaining the ERMS transformed and radioresistant phenotype is characterized. RD and TE671 cell lines conditionally expressing MadMyc chimera protein, c-Myc-dominant negative and shRNA directed to c-Myc were used. Targeting c-Myc counteracted in vitro ERMS adherence and in suspension, growth motility and the expression of pro-angiogenic factors. c-Myc depletion decreased MMP-9, MMP-2, u-PA gelatinolytic activity, neural cell adhesion molecule sialylation status, HIF-1α, VEGF and increased TSP-1 protein expression levels. Rapid but not sustained targeting c-Myc radiosensitized ERMS cells by radiation-induced apoptosis, DNA damage and impairing the expression of DNA repair proteins RAD51 and DNA-PKcs, thereby silencing affected ERMS radioresistance. c-Myc sustains ERMS transformed phenotype and radioresistance by protecting cancer cells from radiation-induced apoptosis and DNA damage, while promoting radiation-induced DNA repair. This data suggest that c-Myc targeting can be tested as a promising treatment in cancer therapy.

Erythropoiesis-stimulating agents in gynecological malignancies: A study-level meta-analysis.

This meta-analysis was planned to define the role of erythropoiesis-stimulating agents (ESAs) in gynecological cancer patients, receiving myelosuppressive treatment. Pubmed, Medline and Scopus were searched to select English-language articles. Only randomized controlled trials (RCTs) were included. Endpoints were incidence of transfusions, thrombotic events (TE), deaths, and failures. Odd ratio (OR) with 95% confidence interval (CI) was calculated using fixed or random effects model. In seven RCTs ESAs studies of 892 patients under treatment, use of ESAs correlates with a significant reduction of transfusions rate (OR=0.35; 95% CI: 0.19-0.65; p=0.008). OR for overall mortality was 1.10 (95% CI 0.82-1.49; p=0.53). ESAs OR for disease failure in 5 studies was 1.71 (95% CI: 0.90-3.24; p=0.1). This meta-analysis, even if limited by few RCTs, suggests that ESAs reduce transfusions without increasing mortality or disease progression in gynecological cancer patients receiving treatment.

Tyrosine-kinases inhibitors in recurrent platinum-resistant ovarian cancer patients.

For many decades, ovarian cancer (OC) has been one of the most common gynecological cancer. Despite advances in OC diagnosis and treatment, the risk of recurrence is ever present and approximately 85% of patients will experience relapse. Recurrent OC after first-line therapy is almost always incurable. Multiple novel therapies, including tyrosine-kinases inhibitors (TKI), have shown promising results, but their role needs to be clarified. In this review we describe the rationale and the clinical evidence regarding the use of TKI for the treatment of recurrent platinum-resistant OC patients.

Vitamin D protects endothelial cells from irradiation-induced senescence and apoptosis by modulating MAPK/SirT1 axis.

PURPOSE: Radiotherapy toxicity is related to oxidative stress-mediated endothelial dysfunction. Here, we investigated on radioprotective properties of Vitamin D (Vit.D) on human endothelial cells (HUVEC). METHODS: HUVEC, pre-treated with Vit.D, were exposed to ionizing radiation (IR): ROS production, cellular viability, apoptosis, senescence and western blot for protein detection were performed. The role of MAPKs pathway was investigated by using U0126 (10 µM) MEKs/ERKs-, SB203580 (2.5 µM) p38-inhibitor or by over/expressing MKK6 p38-upstream activator. RESULTS: Vit.D reduced IR-induced ROS production protecting proliferating and quiescent HUVEC from cellular apoptosis or senescence, respectively, by regulating MAPKs pathways. In proliferating HUVEC, Vit.D prevented IR-induced apoptosis by activating ERKs while in quiescent HUVEC counteracted IR-induced senescence by inhibiting the p38-IR-induced activation. MEKs&ERKs inhibition in proliferating or MKK6/mediated p38 activation in quiescent HUVEC, respectively, reverted anti-apoptotic or anti-senescent Vit.D properties. SirT1 protein expression levels were up-regulated by Vit.D. ERKs inhibition blocked Vit.D-induced SirT1 protein up-regulation in proliferating cells. In quiescent HUVEC cells, p38 inhibition counteracted the IR-induced SirT1 protein down-regulation, while MKK6 transfection abrogated the Vit.D positive effects on SirT1 protein levels after irradiation. SirT1 inhibition by sirtinol blocked the Vit.D radioprotective effects. CONCLUSION: Vit.D protects HUVEC from IR induced/oxidative stress by positively regulating the MAPKs/SirT1 axis.

Squamous cell carcinoma of the rectum: The treatment paradigm.

PURPOSE: This study was planned to clarify the optimal treatment for squamous cell carcinoma of the rectum, an histological entity extremely rare. METHODS: Ten patients with histologically proven squamous cell carcinoma of the rectum were treated with concomitant radiochemotherapy. Radiation therapy was delivered with a 3Dconformational multiple field technique to a dose ranging from 45 to 76.5 Gy, with 6-15 MV energy photons. Chemotherapy consisted of an antimetabolite drug in association with mitomycin C or oxaliplatin. Overall survival and disease free survival were considered in months from the end of the concomitant treatment. RESULTS: All patients completed programmed radiochemotherapy treatment but two patients were excluded to the analysis. Six patients (75%) presented negative biopsy 6 months after the end of radiochemotherapy. Seven patients (87.5%) showed a tumour regression after initial treatment. Only 1 patient underwent salvage surgery. Considering a mean follow-up of 41.75 months, 7 patients are still disease free survivors. Only 1 patient developed local recurrence at 6 months and he died 14 months after abdomino-perineal resection. CONCLUSION: Primary radio chemotherapy, with a curative intent, could be considered the treatment modality of choice for squamous carcinoma of the rectum.

Early and long-term outcomes after open or endovascular repair for abdominal aortic aneurysms in high-risk patients.

AIM: The aim of our study was to evaluate the earlier and long term survival as well the postoperative complications in high-risk patients who received endovascular aortic repair (EVAR) as first choice, or open repair when anatomical requirements for EVAR were not met. METHODS: Between January 2005 and January 2010, 593 patients underwent procedures for elective abdominal aortic aneurysm (AAA) repair; 172 of these were considered at high risk according to the American Society of Anesthesiology (ASA) score (ASA III and IV): 150 high-risk patients were males (mean age 72.7, range 53-93 years) and 22 females (mean age 72.9 years, range 60-90 years). The median AAA diameter was 64 (53-75) mm in the open repair group and 62 (55-70) mm in the EVAR group. 121 patients underwent open repair and 51 EVAR, respectively. RESULTS: The 30-day mortality rate was 0% in the EVAR group and 2.4% (3/121) in the open repair group (P=0.26). Long-term results showed: no EVAR-related mortality, no late conversion to open repair in the EVAR group was required during follow-up. No aneurysmal expansion was observed. In the open repair group, no graft-related events were observed during follow-up. The mean follow-up for survival analysis was 1542 days. Overall 5-year survival was 71.7% (SE=4.2%). Survival during follow-up was 92.2%, 86.1%, 76.2%, 65.9% and 61.8% at 12, 24,36,48,60 months respectively in EVAR Group. Open Group present long term survival of 95%, 88.9%, 83.9%, 79.7%, 76% at 12, 24, 36, 48, 60 months respectively. CONCLUSION: Our results in open repair surgery show a perioperative low mortality rate with high survival rate in long term. This result could be successfully achieved even in high-risk patients unsuitable for EVAR.

Therapeutic options for breast cancer treatment in patients previously irradiated for Hodgkin's disease: radical mastectomy or conservative surgery followed by reirradiation?

Patients undergoing radiotherapy for the treatment of Hodgkin' disease (HD) occurred at young age present a higher risk to develop second cancer compared to general population. Among the possible second tumours, breast cancer is the most frequent and the age at presentation is younger than the "classic" form. Patients at risk for second cancer undergo a strict follow-up permitting often to diagnose breast cancer at early stages (I-II).The aim of this work is to review the various therapeutic options for the treatment of breast cancer in patients previously irradiated for HD, with particular attention to the possibility of reirradiation of mammary tissue thanks to the new radiotherapy techniques developed in the last years.