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Graphical abstract, Highlights • Radiation for prostate cancer is preferably provided with a full urinary bladder. • There are discrepancies how well current methods achieve consistent bladder filling. • A urinary catheter with a check-valve controlled by a float is under development., Radiation therapy for patients with prostate cancer is preferably provided with a full urinary bladder. Full bladder can potentially move the small intestine out of the radiation treatment regions, and results in decreased small bowel radiation dose and gastrointestinal toxicity. Maintaining consistent bladder filling during computerized tomography simulation scan used for treatment planning and at daily radiation treatments is challenging. Here we present an in-development urinary catheter with a floating balloon that drains the bladder only when urine reaches to a prespecified level, and review current methods used in clinic to ensure consistent bladder filling. These includes bladder filling protocols, ultrasound scanning and biofeedback techniques.

Background Traditionally, rectal cancer radiation therapy uses bony landmark fields to cover common lymphatic drainage sites, including the internal iliac, presacral, and perirectal lymph nodes. We aimed to investigate if bony landmark borders sufficiently cover the internal iliac nodes and to compare tumor volume and normal tissue avoidance using classic bony landmarks (c3DCRT), contoured elective clinical target volume (f3DCRT), and volumetric modulated arc therapy (VMAT) planning in locally advanced rectal cancer. Methods Computed tomography datasets of 11 patients with locally advanced rectal cancer who had completed treatment in the prone position on a bellyboard in c3DCRT technique. The elective clinical target volumes and organs at risk were contoured, and a f3DCRT VMAT plan generated for all patients. Planning target volume, gross tumor volume, and normal tissue dose limits were evaluated. Results The mean planning target volume 95% coverages were significantly lower for c3DCRT plans, and the lymph node coverage was better for f3DCRT. No differences were found in PTV coverages between f3DCRT and volumetric modulated arc therapy plans. No significant differences among all techniques were found for organs-at-risk constraints. The bladder dosage was higher in the VMAT plan. The c3DCRT technique missed coverage of the internal iliac lymph nodes and exposed smaller bowel, compared with the other methods. Discussion and Conclusion Tumor volume coverage was improved by f3DCRT planning, without significant differences in doses to critical structures compared with c3DCRT and was noninferior to VMAT planning. It is recommended that f3DCRT be used in routine clinical practice in radiotherapy treatments for locally advanced rectal cancer.

Incidence rates of Merkel cell carcinoma (MCC), an uncommon skin cancer with an aggressive disease course, have increased in recent decades. Limited treatment options are available for patients with metastatic MCC (mMCC). Avelumab, an anti-programmed cell death-ligand 1 monoclonal antibody, became the first approved treatment for mMCC after the results of the phase 2 JAVELIN Merkel 200 study. Prior to its regulatory approval, an expanded access program (EAP) enabled compassionate use of avelumab in patients with mMCC. Here we report findings from patients enrolled in the EAP in Europe and the Middle East. Efficacy and safety data were provided at the discretion of treating physicians. Between March 2, 2016, and December 22, 2018, 403 requests for avelumab were received from 21 countries, and avelumab was supplied to 335 patients. Most patients (96.7%) received avelumab as second-line or later treatment. In 150 patients for whom response data were available, the objective response rate was 48.0%, and in responding patients, median duration of treatment was 7.4 months (range, 1.0-41.7 months). The most common treatment-related adverse events were infusion-related reaction (2.4%) and pyrexia (2.1%), and no new safety signals were observed. Overall, results from European and Middle Eastern patients enrolled in this EAP confirm the efficacy and safety of avelumab treatment observed in previous studies in patients with mMCC. ispartof: INTERNATIONAL JOURNAL OF CANCER vol:149 issue:11 pages:1926-1934 ispartof: location:United States status: published

To establish a model to predict treatment outcome of periocular locally advanced basal cell carcinoma (POLA BCC) based on initial response to treatment with vismodegib (ErivedgeSubgroup analysis of data from the STEVIE study database.Analysis of medical history, treatment protocol, and treatment outcome of POLA BCC tumours in a STEVIE study population of 244 POLA BCC patients treated with ≥1 dose of vismodegib.A predictive model for complete response (CR) was established based on the initial treatment response. A cutoff value of 20% reduction in tumour size at 3 months of treatment identified the patients with a high probability (82.76%) to achieve CR. A second cutoff value of 67.7% reduction in tumour size at 6 months of treatment improved the prediction to a 95.42% probability of a CR outcome.A treatment model was constructed based on the prediction of a CR outcome and the initial response to vismodegib treatment at 3 and 6 months. The study result provide significant new insights can facilitate decision-making on treatment management according to tumour response in patients with POLA BCC.

Background: The best delivery modality of stereotactic body radiotherapy (SBRT) for hepatocellular carcinoma (HCC) from a technical point of view is still a matter of debate. The purpose of this study was to compare planning parameters with volumetric modulated arc therapy (VMAT) to static intensity modulated radiotherapy (IMRT) in treatment of HCC treated with SBRT. Methods: Twenty patients (pts) with localized HCC who were treated with SBRT were re-planned using two different radiation techniques: IMRT and VMAT. Patients with Child A cirrhosis received 45-54 Gy in 3 fractions and 5 pts with Child B cirrhosis received 30 Gy in 5 fractions. Planning was optimized to minimize doses to organs at risk (OAR) without compromising coverage of the planning treatment volume (PTV). VMAT and IMRT plans were compared using the conformity index (CI), homogeneity index of the PTV and monitor units (MUs) for time of treatment delivery, and other dose volume histogram (DVH) metrics.Results: The CI of VMAT plans were superior to those of IMRT(1.11±0.05 vs 1.18±0.06 (p Conclusion: PTV coverage was more conformal with VMAT planning, with lower MUs and shorter delivery time compared to IMRT in all pts. Moreover VMAT planning was more effective than IMRT planning in the sparing of normal liver and stomach.

Importance The outcomes of vismodegib treatment in a relatively large cohort of study participants with periocular locally advanced basal cell carcinoma (POLA-BCC) may guide physicians when considering this treatment. Objective To report the outcomes of vismodegib treatment in patients with POLA-BCC in the Safety Events in Vismodegib (STEVIE) study. Design, Setting, and Participants This post hoc subgroup analysis from the STEVIE single-arm, multicenter, open-label cohort study screened all 1215 participants for ocular or periocular involvement and identified 244 participants with POLA-BCC or metastatic BCC. Data for the first STEVIE trial were collected from 167 treatment locations in 36 countries from June 30, 2011, to June 14, 2017. This post hoc analysis was performed from April 1 to August 31, 2019. Main Outcomes and Measures Response to treatment and adverse events. Results Ocular or periocular involvement was found in 244 of 1215 STEVIE participants (20.1%), who constituted the analytic sample. The median age of the study participants was 72.0 (interquartile range [IQR], 60.0-82.0]) years, and they included 143 men (58.6%). Locally advanced BCC was diagnosed in 238 of the 244 participants (97.5%) and metastatic BCC, in 6 (2.5%). The median duration of exposure to vismodegib was 40.0 (IQR, 20.0-78.0) weeks, specifically 39.7 (IQR, 19.9-76.0) weeks for POLA-BCC and 92.4 (IQR, 53.2-163.0) weeks for metastatic BCC. Sixty-nine participants (28.3%) sustained serious adverse events (alopecia, muscle spasms, dysgeusia, weight loss, decreased appetite, asthenia, ageusia, nausea, fatigue, and diarrhea). Two hundred thirty-two study participants (95.1%) sustained more than 1 adverse effect. The overall mean (SD) number of drug-related adverse effects per study participant by first adverse event, regardless of the severity, was 5.48 (3.84). Discontinuation of vismodegib treatment owing to an adverse event was recorded in 58 participants (23.8%). During the study, 22 participants (9.0%) died, 70 (28.7%) achieved complete response, and 94 (38.5%) achieved partial response. Conclusions and Relevance Vismodegib was well tolerated by the study participants with POLA-BCC. The safety of vismodegib treatment according to the STEVIE trial findings is consistent with that reported in previous studies. These data may be helpful when considering vismodegib for patients with POLA-BCC.

Medulloblastoma (MB) is an aggressive, primitive neuroectodermal tumor mainly affecting pediatric patients and with frequent involvement of the posterior fossa and extraneural metastasis. MB has a low incidence in adults (< 1% of adult brain tumors) and treatment protocols for adult patients have been adapted from pediatric oncology.1,2 PTCH13 tumor suppressor gene functions as an inhibitor of smoothened (SMO) and downstream sonic hedgehog (SHH) signaling. SHH ligand connects to the receptor on PTCH1, which results in SMO suppression (Fig 1). PTCH1 germline inactivating mutations are associated with Gorlin syndrome, which is associated with a high incidence of basal cell carcinoma (BCC) and predisposition to MB.4-6 This association is strengthened because somatic mutations that inactivate PTCH1 are frequently found in the sporadic forms of these types of cancers. Genomic analyses of MB have identified PTCH1 a mutation incidence of 3%-7% of MB cases. On the basis of gene expression profiling, four molecular subgroups of MB have been identified: WNT, SHH, group 3, and group 4.7 The prognosis for patients within the SHH subgroup MB differs greatly upon TP53 mutation status, wherein patients with wild-type TP53 have a significantly better 5-year overall survival rate (76%) compared with those with TP53 mutation (41%).8 Open in a separate window FIG 1. Graphic representation of sonic hedgehog (SHH) pathway. (1) HH ligand binding to PTCH1. (2) Binding of HH to PTCH1 releases SMO. (3) Showing the inhibition of SMO by vismodegib, which leads to inhibition of the whole pathway.

Purpose Limiting the heart dose in left sided breast cancer radiotherapy is critical. We sought to study the effect of using CPAP (continuous positive airway pressure) as an aid in reducing heart dose in breast cancer radiotherapy. Methods Patients with left sided breast cancer receiving adjuvant radiotherapy were enrolled on a prospective IRB (institutional review board) approved clinical trial utilizing CPAP during radiotherapy. Each patient was simulated and planned with and without CPAP and the best dosimetric results determined the patient’s treatment. Data on the differences in lung and heart volume and position as well as boost cavity position with and without CPAP were analyzed. Results Twenty-four women from 10/16 to 10/18 were enrolled. Seven patients were not treated on study; only two of these were due to treatment issues. Median age was 54 years. 70% had breast only radiation and 30% were treated to breast\CW (chest wall) and regional nodes. The median lung volume with CPAP was 60% larger than without CPAP. (1637 vs. 996 cc) p p = .0075) and V20 of the lungs from 17.1 to 13.8 with CPAP but this was not significant. Conclusion CPAP assisted radiotherapy was tolerable and produced superior treatment plans in left sided breast cancer. This method is worthy of further investigation as a method to normal tissue sparing treatment of left sided breast cancer patients.

This study explores the perspectives of doctors, nurses, and technicians on the medical clown. A total of 35 subjects were interviewed one on one. Interviews were transcribed and analyzed for common themes. Medical staff outlined novel limitations and views of future directions for the field of medical clowning. Most importantly, many previously unpublished benefits of medical clowns were described. These reported benefits included cost-saving measures for the hospital, increases in staff efficiency, better patient outcomes, and lower stress in medical staff. Given that most of the limitations on medical clowning are financial in nature, these findings have substantial implications for the future of the field. As medical clowning continues to grow, this study outlines the potential for various future research projects within this field of study.

BackgroundAvelumab, a human anti–programmed death-ligand 1 immunoglobulin G1 monoclonal antibody, showed favorable efficacy and safety in patients with metastatic Merkel cell carcinoma (mMCC) in the phase II JAVELIN Merkel 200 trial, leading to approval in multiple countries. We describe real-world experience with avelumab in patients with mMCC from an expanded access program.MethodsEligible patients had mMCC and progressive disease during or after chemotherapy or were ineligible for chemotherapy or clinical trial participation. Patients received an initial 3-month supply of avelumab (administered as 10 mg/kg intravenously every 2 weeks until progressive disease or unacceptable toxicity); resupply was allowed following complete response, partial response, stable disease, or clinical benefit per physician assessment.ResultsBetween December 15, 2015, and March 4, 2019, 558 of 620 requests from 38 countries were medically approved, and 494 patients received avelumab. Among 240 evaluable patients, the objective response rate was 46.7% (complete response in 22.9%, including 3 of 16 potentially immunocompromised patients), and the disease control rate was 71.2%. The median duration of treatment in evaluable patients with response was 7.9 months (range, 1.0–41.7) overall and 5.2 months (range, 3.0–13.9) in immunocompromised patients. No new safety signals were identified. The expanded access program closed for new requests on December 31, 2018, as required after regulatory approval; benefitting patients continued to receive avelumab.ConclusionsThe avelumab expanded access program for patients with mMCC demonstrated efficacy and safety in a real-world setting, consistent with the results from JAVELIN Merkel 200, and provided a treatment for patients with limited options.

To determine whether the expression of specific molecular markers in the rectal cancer biopsies prior to treatment, can correlate with complete tumor response to chemoradiotherapy (CRT) as determined by the pathology of the surgical specimen.We retrospectively examined pretreatment rectal biopsies of patients aged 18 years or older with locally advanced rectal cancer who had been treated with neoadjuvant CRT and surgical resection in our tertiary-care, university-affiliated medical center, between January 2001 and December 2011. Samples were analyzed for expression of B-cell lymphoma 2, P53, Ki67, epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptor, and the tumor regression grade after CRT and radical surgery.Forty-seven patients were included in the final analysis. Main outcome measures were the correlation between the expression of the molecular markers tested in the pretreatment biopsy, and complete tumor response. Complete pathologic response after CRT was attained in 27% of the patients. Percentage of cells expressing EGFR in the pretreated biopsies of patients having complete pathologic response after CRT and surgery was 33.08±7.87% compared to 19±15.36% (P=0.38), 6.66±2.83% (P0.003), and 12.5±4.93% (P=0.033) in patients with partial response and tumor regression grades of 2, 3, and 4, respectively. The other molecular markers tested in the pretreatment biopsy did not corresponded with complete pathologic response.EGFR expression pattern in the pretreatment biopsies of rectal tumors can assist in identifying patients who will benefit from neoadjuvant CRT.

Background SBRT is standard therapy for early stage lung cancer. Toxicity in central tumors has been a concern. RTOG 0813 showed that central SBRT is safe and effective. We report our experience with central SBRT. Methods We reviewed the records of patients treated with SBRT for central lung tumors (

SummaryBackground Primary cutaneous marginal zone B-cell lymphoma (PCMZL) has rarely been reported in patients younger than 20 years. Objectives To report our experience with PCMZL in the paediatric/adolescent age group. Methods Medical records of patients diagnosed with PCMZL before age 20 years and managed at two cutaneous lymphoma clinics in the United States and Israel in 1992-2015 were reviewed. Results The study group included 11 patients (6 girls) of median age 16 years (range 6–19.5); 10 had generalized/multifocal (T3) and 1 had regional/localized (T2) disease. Lesions were located on the limbs in all patients and the trunk in 6; 2 had facial lesions. Staging in all but one was based on whole-body computed tomography or positron emission tomography. Initial management in most patients included non-radiation modalities: 1 patient with localized disease received intralesional steroids; 6 patients with multifocal disease received the following: 3 - topical/intralesional steroids, 2 - excision, 1 - “watch and wait”. No extracutaneous progression was noted during a median follow-up of 5.5 years (mean 7.5, range 0.5-14). At present, 5/11 patients are in complete remission. Conclusions Based on our data (largest series in the literature with the longest follow up); the clinico-pathological presentation and course of PCMZL in the paediatric/adolescent age group are similar to adults. Given the indolent course and the long life expectancy of these young patients, the cumulative risk of imaging studies and the age-related potential toxicity of treatment, especially radiation, should be taken into consideration. This article is protected by copyright. All rights reserved.

There is growing evidence that intraoperative radiation therapy (IORT) may be a viable option in selected patients with early breast cancer. This study reports our 4-year experience with IORT. The perioperative outcome and imaging data of all patients who underwent IORT for early breast cancer at a tertiary medical center in 2014-2018 were retrospectively retrieved. The cohort included 158 patients aged 52-84 years (mean 68) with stage I (n = 137) or II (n = 21) breast cancer. Mean applicator size was 4.13 cm; IORT added a mean of 29 minutes to the operative time. Minor wound infections (n = 18, 11.4%) requiring antibiotics and drainage were the only postoperative complication. In 25 patients (15%), postoperative mammography demonstrated a seroma (n = 22) or fat necrosis (n = 3). The risk of wound infection or a new postoperative imaging finding was unrelated to patient age, operative time, tumor size, or comorbid diabetes or obesity. After a mean of 30 months' follow-up, none of the patients who met the institutional criteria for IORT had local recurrence, regardless of age, histology, tumor grade, KI67 proliferation index, pathologic stage, Recurrence Score, or additional whole-breast irradiation or adjuvant treatment. Patients for whom a Recurrence Score was determined (n = 55, 35%) had a significantly higher tumor grade, pathologic stage, and whole-breast irradiation/adjuvant chemotherapy rate than the remaining patients. IORT may be a safe alternative to traditional external beam radiation in well-selected patients with early breast cancer, with few minor complications and good 30-month outcome.

We report the unexpected absence of early relapse (before 30 months) in 24 consecutive patients with isolated limb primary Ewing sarcoma treated with an intensified pilot protocol, SCMCIE94. Clinical data for the study were collected retrospectively from the patient files. The protocol included 6 courses of chemotherapy, split radiation, and limb salvage surgery. This SCMCIE94 protocol had been used in almost all the patients described in an earlier report, in whom those with non-pelvic isolated tumors and low/absent CD56 expression in Ewing sarcoma tumor cells were all long-term survivors. The 5-year (10-year) event-free survival rate for the patients with isolated limb primary Ewing sarcoma was 78.95 ± 8.3% (68.6 ± 10.0%) and the overall survival rate was 90.7 ± 6.2% (71.1 ± 11.2%). There were no relapses before 30 months in any of these patients. The intensified SCMCIE94 pilot protocol has been shown previously to cure patients with localized CD56-negative non-pelvic Ewing sarcoma. The present study shows that among all patients with localized extremity disease who were treated with this protocol, there were no cases of early relapse. Although our cohort was small, the difference in results from studies using other protocols is so striking, that it would seem reasonable to assume it is attributable to the changes made in the protocol itself rather than risk factors. Late relapses of isolated limb CD56-positive Ewing sarcoma suggest minimal residual disease warranting additional therapeutic approaches such as autologous stem cell rescue after Busulfan Melfelan.

This study evaluated the effect of an intensified pilot protocol, SCMCIE 94, on the outcome of Ewing sarcoma (EWS). The cohort included 121 patients with local or metastatic EWS treated at a tertiary pediatric medical center with the SCMCIE 94 (protocol 3, 1994 to 2011) or an earlier protocol (protocol 2, 1988 to 1994; protocol 1, 1985 to 1988). All protocols included 4 to 6 courses of chemotherapy, radiation, and surgery. Clinical data were collected retrospectively by chart review. Survival rates for protocol 3 were as follows: all patients-5-year event-free survival (EFS): 52.5%±5.6%, 10-year EFS: 49.3%±5.8%, 5-year overall survival (OS): 68.8%±5.3%, and 10-year OS: 51.1%±6.3%; patients with localized disease (any site)-5-year EFS: 63.5%±6.0% and 5-year OS: 77.2%±5.3%; patients with localized extremity disease-5-year EFS: 78.95%±8.3%, 10-year EFS: 68.6%±10.0%, 5-year OS: 90.7%±6.2%, and 10-year OS: 71.1%±11.2%. Protocol 3 was associated with an increase in 10-year EFS of 16% overall and 33% in patients with localized extremity disease compared with protocols 1+2, and a significant improvement in 5-year EFS and OS in patients with any localized disease (P=0.001). No survival benefit was found for metastatic disease. On multivariate analysis, protocol and metastatic disease were significantly independent prognostic factors. The intensified SCMCIE 94 protocol seems to increase survival in patients with localized but not metastatic EWS.

11518 Background: CKS is a mesenchymal neoplasm associated with HHV8 infection. Though recombinant INFa is approved for treatment of AIDS-related KS, data is limited regarding the role of immune modulation in CKS therapy. Based on favorable responses in viral-induced cancers, we hypothesized that CTLA-4 and PD-1 blockade can induce tumor regression in CKS. We present pre-planned interim analysis of a phase II study of Nivo/Ipi in previously treated progressive CKS. Methods: CKS pts with progressive disease after > 1 line of systemic therapy and measurable disease received nivolumab 240mg d1,15,28 and ipilimumab 1mg/kg d1 q42 days until progression or toxicity. The primary endpoint was overall response rate (ORR) evaluated clinically, radiologically (RECIST) and metabolically (FDG-PET). Secondary endpoints include 6-months progression free survival rate (PFS) and safety. Exploratory endpoints included PD-L1/MMR by IHC, DNAseq (596 genes)/RNAseq (whole transcriptome) of tumor and matched blood specimens to explore CKS genomic traits and IO correlates: TMB and MSI status, MMR and PD-L1 protein expression, and immune gene transcript expression (PD-1, PD-L1, CTLA-4, and others) (Tempus Labs, Chicago, IL, USA). Results: Fifteen patients were enrolled and evaluable (Apr18-Jan20). Median age 72.5 (61-81), all male. At a median FU of 15.7 mo ORR as per RECIST was 66% (9 pts PR, 1 pt CR, 2 pts SD, 3 pts NE). Clinical ORR was 87% and metabolic ORR was 60%. Median PFS was not reached, 6mo PFS rate was 85% and 1y PFS rate was 75%. The safety profile was as expected with all pts experiencing G1 toxicity, 3 pts with G2 toxicity (1 hepatic, 2 asymptomatic lipase increase) and 2 pts with G3 toxicity (1 colitis, 1 asymptomatic lipase increase). One SAE was reported (TIA considered not related to therapy) and treatment was discontinued in 3 pts. Correlative results are available for 8 pts showing a trend for copy number loss in genes with tumor-suppressive activity (FOXA1, ELF3), no PDL1 expression, low TMB, microsatellite stability, but marked overexpression of CTLA-4, PD-1, PDL-1, CD40, OX40 and LAG3 RNA immune transcripts. Conclusions: The interim analysis of this prospective phase II study of nivolumab and low-dose ipilimumab demonstrates promising activity in progressive CKS, with 66% ORR and a 6mo PFS rate of 85%. Toxicity profile is as expected in this class of drugs. Correlative studies are preliminary, but warrant further investigation into genomic traits and immune gene expression profiles. Clinical trial information: NCT03219671. Clinical trial information: NCT03219671 .

AIM This phase IB/II study evaluated the safety and efficacy of the addition of cetuximab to standard preoperative chemoradiotherapy (CRT) in locally advanced esophageal cancer (LAEC). METHODS Patients (pts) with resectable LAEC (T2-3N0-1M0, T1-3N1M0 or T1-3N0-1M1A) received an induction cycle of cisplatin 100 mg/m2, day 1, and 5-fluorouracil (5-FU) 1000 mg/m2/day, days 1-5, followed 4 weeks later by radiotherapy, 50.4 Gy, given with 2 cycles of cisplatin 75 mg/m2 and escalating doses of 5-FU, days 1-4 and 29-32. Pts received 10 weekly infusions of cetuximab, 250 mg/m2, with a loading dose, 400 mg/m2. Surgery was planned 6-8 weeks after CRT. RESULTS 64 pts were treated and 60 completed CRT. Median age was 65 years and 66% were males. Adenocarcinoma/squamous ratio was 61%/39%. Tumors were advanced: 95% T3 and 67% N1. Grade ≥3 toxicities occurred in 72%, with two (3%) toxic deaths. The 5-FU maximal tolerated dose (MTD) was 1000 mg/m2/day. Clinical complete response rate was 33%. Of the 55 operated pts, R0 resection was achieved in 51 (93%) and pathological complete response (pCR) in 18 (33%), with 8 (14%) postoperative deaths. The 5-year survival rate for all pts was 38%. Pts with squamous histology had higher pCR (55% vs 20%, p = 0.015), local control (96% vs. 74%, p

Background: Trimodality therapy (chemoradiation followed by surgery) provides a benefit in progression-free survival but not overall survival. We sought to determine if a high dose of radiation could be delivered safely and provide a clinical benefit. Methods: Consecutive patients with stage IIIA or IIIB non-small-cell lung cancer (NSCLC) treated with concurrent chemoradiotherapy followed by surgery were reviewed with IRB approval. Results: A total of 48 patients were treated from November 2007 to May 2014. Of these, 64% had stage IIIA disease while 36% had stage IIIB; 46% had adenocarcinoma, 34% squamous, and 23% NSCLC not otherwise specified. The median dose of chemoradiotherapy was 72 Gy (60–72). Overall, 86% of patients received cisplatin (50 mg/m2) and etoposide (50 mg/m2) concurrently with radiotherapy; 72% of patients underwent lobectomy following chemoradiotherapy and 28% underwent pneumonectomy. The 30- and 90-day mortality rates were 0%. The nodal downstaging rate was 82% and there was a 64% rate of pathologic complete response. The overall survival was 29.9 months (95% CI, 19–86 months). The median time to locoregional progression was 35.1 months and the median time to distant progression was 39.3 months. Locoregional failure was 8% and distant failure was 44%. Conclusion: High-dose preoperative chemoradiotherapy was safe and effective. This combination should be further considered.

Radiation dermatitis occurs frequently during adjuvant radiation therapy for breast cancer. Prevention of radiation dermatitis by applying various creams and ointments has a limited success, and Aqua cream which has urea as one of its active ingredients is used in many institutions as a preventive treatment. The primary goal of this study is to assess the effect of vitamin D (calcipotriol) ointment in prevention of radiodermatitis in breast cancer patients compared to Aqua cream. Twenty-three women with localized breast cancer who underwent breast-conserving surgery and opted to receive adjuvant radiotherapy to breast only were enrolled in this study. A cream containing an active vitamin D analog, calcipotriol (Daivonex), was randomly applied either to the medial or to the lateral half of the irradiated breast, while Aqua cream was applied to the complimentary half of the same breast along the whole treatment days, each day, after the delivery of radiation. Skin reaction was recorded and compared between the two halves of the breast. Vitamin D was well tolerated by patients with no local or systemic allergic reactions. Radiation dermatitis was not significantly different between both treatment arms. Topical vitamin D ointment is not superior to Aqua cream for prevention of radiation-induced dermatitis in women treated with adjuvant radiation for breast cancer., Radiation: Vitamin D not great for skin protection Vitamin D ointment is no better than urea cream at preventing radiation-induced skin damage in breast cancer patients. Researchers in Israel led by Eyal Fenig from the Rabin Medical Center in Petah Tikva studied 23 women with localized breast cancer who underwent breast-conserving surgery and received adjuvant radiation to destroy any tumor cells left behind. Each day after their radiation therapy, the women applied an active vitamin D analog called calcipotriol (Daivonex) to half of their irradiated breast and a skin-hydrating, urea-containing ointment called Aqua cream to the other half of the same breast. The topical vitamin D ointment was well tolerated by the study participants. However, there was no noticeable difference in the effect of calcipotriol or Aqua cream for the vast majority of the women.

Background Unilesional folliculotropic mycosis fungoides (UFMF) has been rarely reported. Objective The aim of this study was to describe our experience with UFMF. Methods Data were collected on all patients with clinicopathological UFMF who attended the Department of Dermatology of a tertiary university-affiliated medical centre in 1996–2013 and were followed prospectively. Results The sample included seven patients (five male, two female) of mean age 38 years at diagnosis; two were aged

In recent years some interrelationships between time of birth and longevity were published. Concomitant publications appeared demonstrating links between Space Weather and the timing of medical events; in part of both these studies it was shown that Space Weather indices are stronger connected with the time of conception as with the birth time. The aim of these study was to consider birth and conception month of patients suffering from a number of “big killer” pathologies, affecting human longevity and comparing with published data on centenarians—100 - 112 years old persons in the USA. Patients and Methods: We included monthly births distribution of our four papers including patients with Acute Myocardial Infarction undergoing Percutaneous Coronary Intervention (PCI)—n-3765, and admitted in another tertiary medical facility for AMI—n-22,047, and, also patients suffering Rapid—n-1239 and Sudden Cardiac Death—n-327 and, also, patients with oncologic malignancies—n-44587. At all in this group 71,965 patients were included. Their birth and conception months were compared with analogical data of 1574 people of 100 - 112 years old using data of L.A. and N.S. Gavrilov for USA centenarians. Results: The birth months of the cardiovascular and oncology patients were maximal in January, March and April (above 10% at each of these months); their conception was maximal in April, June and July. The monthly distribution of conception and birth of the studied population is presented in Tables 1-3. The maximal birth months of the centenarians were November, September, and October; the maximal conception months were December, January, and February. Conclusion: People suffering Myocardial Infarction, Sudden Cardiac Death and Oncologic Malignancies are in higher numbers born in the first four months of the year and conception in April, June and July. The maximal birth months of the very old people were November, September and October and conception were December, January and February.

Background CKS is an angioproliferative mesenchymal neoplasm causatively associated with human herpes virus 8 infection. Though recombinant IFNa is approved for treatment of AIDS-related KS, data is limited regarding the role of immune modulation. Based on favorable responses in viral-induced cancers, we hypothesized that CTLA-4 and PD-1 blockade can induce tumor regression in CKS. We present pre-planned interim analysis of a phase II study of Nivo/Ipi in previously treated (tx) progressive CKS. Methods CKS pts with progressive disease after > 1 line of systemic tx and measurable disease by PET/CT and/or physical exam received nivolumab 240mg d1,15,28 and ipilimumab 1mg/kg d1 q42 days until progression or toxicity. The primary endpoint (EP) was overall response rate (ORR), secondary EP include 6-months progression free survival rate (PFS) and safety. Exploratory EP included PD-L1/MMR IHC, DNAseq (596 genes)/RNAseq (whole transcriptome) of tissue and matched blood to explore CKS genomic traits and IO correlates: TMB, MSI, dMMR, PD-L1, immune gene expression (PD1, CTLA4, etc) (Tempus Labs, Chicago, IL, USA). Results Twelve patients were enrolled and evaluable between Apr2018-Jun2019 and 11 were evaluable for response. Median age 72 (61-81). At a mFU of 6 months ORR was 45% (4 pts PR, 1 pt CR, 6 pts SD). mPFS was not reached, 6-mo PFS rate was 91% (1 out of 11 patients had PD). The safety profile was as expected with three patients with G2 toxicity (1 ALT/AST increase, 1 asymptomatic lipase increase) and two patients with G3 toxicity (1 colitis, 1 asymptomatic lipase increase). One SAE was reported (TIA considered not related to therapy) and treatment was discontinued in one pt (G2 LFT increase. maintaining CR 4 months after treatment discontinuation). Correlative results are available for four patients showing negative PDL1 IHC in all, low TMB, MS-S, but marked overexpression of CTLA4, PD1 and PDL1. Conclusions The interim analysis in this prospectively designed phase II study of nivo/ipi demonstrate promising activity in progressive CKS, with 45% ORR and a 6mo PFS rate of 91%. Toxicity profile as expected in this class of drugs. Correlative studies are preliminary but warrants further investigation into immune gene expression profiles. Clinical trial identification NCT03219671. Legal entity responsible for the study The authors. Funding BMS Rabin Medical Center. Disclosure A. Zer: Honoraria (self), Research grant / Funding (institution): BMS; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: AZ. All other authors have declared no conflicts of interest.

Purpose Early assessment of tumor response to therapy is vital for treatment optimization for the individual cancer patient. Induction of apoptosis is an early and nearly universal effect of anticancer therapies. The purpose of this study was to assess the performance of 18F-ML-10, a novel PET radiotracer for apoptosis, as a tool for the early detection of response of brain metastases to whole-brain radiation therapy (WBRT).

Background and Aims: Management of bulky cervical tumours is controversial. We describe the addition of high dose rate brachytherapy with concomitant chemotherapy to an attenuated protocol of radiation followed by simple hysterectomy in the management of bulky cervical tumours. Methods: Between January, 2003 and December, 2006, 23 patients diagnosed with bulky cervical tumours underwent a fixed chemo-radiation protocol followed by simple hysterectomy. Fractionated external beam pelvic radiation (4500 cGy) followed by two high-dose rate applications of brachytherapy (700 cGy – prescription dose to point A) was given with weekly concomitant cisplatin (35 mg/m2). Patients then underwent simple hysterectomy. Clinical information was prospectively collected and patient charts were then further reviewed. Results: Twenty patients had stage IB2 and three bulky IIA. Median tumour size was 5 cm. Sixteen patients (70%) achieved a clinical complete and seven (30%) a clinical partial response. All patients had a total abdominal hysterectomy and bilateral salpingo-oophorectomy (TAH BSO). On final pathology, 12 patients (52%) had a pathological complete response, whereas 11 patients (48%) had residual carcinoma in the cervix. Surgical margins were not involved. With a median follow-up time of 20 months (range 10–50 months), four patients (17.4%), all from the pathological partial response group, have suffered a pelvic recurrence, within 6 months from therapy; nineteen patients (82.6%) remain free of disease. Conclusions: This attenuated protocol of chemo-radiation using HDR brachytherapy followed by simple hysterectomy is a viable option in the treatment of bulky cervical carcinomas. The rate of residual cervical disease after chemo-radiation is substantial, but simple hysterectomy achieved negative surgical margins in all cases.

Summary Background Radiotherapy can induce severe skin responses that may limit the clinically acceptable radiation dose. The responses include erythema, dry and moist desquamation, erosions and dermal–epidermal blister formation. These effects reflect injury to, and reproductive failure of, epidermal cells and may also be due to dysregulation of the tissue remodelling process caused by excessive proteolytic activity. Calcitriol, the hormonally active vitamin D metabolite, protects keratinocytes from programmed cell death induced by various noxious stimuli. Objective To examine whether calcitriol protects proliferating keratinocytes from the damage inflicted by ionizing radiation under conditions similar to those employed during radiotherapy. Methods Autonomously proliferating HaCaT keratinocytes, used as a model for basal layer keratinocytes, were irradiated using a linear accelerator. Cell death was monitored by vital staining, executioner caspase activation, lactic dehydrogenase release and colony formation assay. Induction of matrix metalloproteinase-9 was assessed by gelatinase activity assay and mRNA determination. Levels of specific proteins were determined by immunoblotting. Results Treatment with calcitriol inhibited both caspase-dependent and -independent programmed cell death occurring within 48 h of irradiation and increased the colony formation capacity of irradiated cells. These effects may be attributable to inhibition of the c-Jun NH2-terminal kinase cascade and to upregulation of the truncated antiapoptotic isoform of p63. Treatment with the hormone also attenuated radiation-induced increase in matrix metalloproteinase-9 protein and mRNA levels. Conclusions The results of this study suggest that active vitamin D derivatives may attenuate cell death and excessive proteolytic activity in the epidermis due to exposure to ionizing radiation in the course of radiotherapy.

Metronomic low-dose chemotherapy regimen was found to have an antiangiogenic effect in tumors. However, its effect on levels of circulating pro-angiogenic and anti-angiogenic factors is not fully explored.The levels of both VEGF and PDGF-BB were measured in three time points, in the serum of 32 rectal carcinoma patients receiving daily reduced-dose/continuous capecitabine in combination with preoperative pelvic irradiation.We found a significant decrease in VEGF and PDGF-BB serum levels during the combination treatment (p0.0001), followed by an increase in the successive rest-period (p0.0001). In addition, substantial changes in platelets counts were observed during treatment in correlation with the changes of VEGF and PDGF-BB serum levels.These results suggest that combined chemo-irradiation affect levels of pro-angiogenic factors during treatment, and may reflect an anti-angiogenic window induced during this treatment. The potential implications of this inducible phenomenon, including a possible clinical benefit from the administration of long lasting metronomic chemotherapy immediately following combined chemo-irradiation, would warrant further investigation.

Vismodegib, a hedgehog pathway inhibitor has been recently introduced as an oral therapy for locally advanced and metastatic basal cell carcinoma. Although treatment of patients with basal cell carcinoma with vismodegib has been associated with partial or complete clinical response, it is still unclear if it is also associated with histological cure.Two patients with 3 large and aggressive basal cell carcinomas were treated with Vismodegib for 6 months. The treatment was followed by Mohs micrographic surgery.Two tumors disappeared clinically and one was reduced dramatically in its size following treatment with vismodegib. Mohs surgery in all three tumors revealed residual islands of BCC although margins were cleared at the end of surgery.Neoadjuvant therapy with vismodegib for 6 months prior to Mohs surgery was effective in reducing the size of primary and recurrent aggressive basal cell carcinoma. However, residual tumor nests were found during surgery. Further larger studies are needed to evaluate the efficacy of Vismodegib as a neoadjuvant treatment prior to Mohs surgery.

Background: Pontine tumors carry the worst prognosis of all brain tumors. In most cases, the diagnosis is based solely on MR imaging, without biopsy. Objective: To describe the MR findings of pontine tumors at diagnosis and during follow-up and correlate those with prognosis and to assess the value of MR imaging in patient management compared to clinical evaluation. Materials and methods: Ninety-one MR scans of 15 children with diffuse pontine tumors were reviewed at diagnosis and during follow-up. The parameters analyzed were as follows: tumor extent, area, and volume; encasement of the basilar artery; presence of exophytic component; necrosis; cysts; hydrocephalus; and intensity and enhancement. Findings were correlated to length of progression-free and overall survival. Trends of amelioration or worsening on imaging were compared with the clinical findings. Results: Median length of progression-free survival was 10 months, and median survival was 20 months. Only hydrocephalus at presentation was associated with shorter progression-free survival (P=0.02). On the last examination of each patient, the craniocaudal diameter was significantly greater than at diagnosis (P=0.03). The concordance between the imaging and the clinical findings was good.Conclusion: MR is the mainstay for the diagnosis and management of pontine tumors. Cranial growth seems to be an ominous sign. However, the prognostic value of MR is limited. MR findings correlate well with the clinical examination.

Imatinib mesylate (IM) is a tyrosine kinase inhibitor, which inhibits phosphorylation of downstream proteins involved in BCR-ABL signal transduction. It has proved beneficial in treating patients with chronic myeloid leukaemia (CML). In addition, IM demonstrates activity against malignant cells expressing c-kit and platelet-derived growth factor receptor (PDGF-R). The activity of IM in the blastic crisis of CML and against various myeloma cell lines suggests that this drug may also target other cellular components. In the light of the important role of telomerase in malignant transformation, we evaluated the effect of IM on telomerase activity (TA) and regulation in various malignant cell lines. Imatinib mesylate caused a dose-dependent inhibition of TA (up to 90% at a concentration of 15 microM IM) in c-kit-expressing SK-N-MC (Ewing sarcoma), SK-MEL-28 (melanoma), RPMI 8226 (myeloma), MCF-7 (breast cancer) and HSC 536/N (Fanconi anaemia) cells as well as in ba/F3 (murine pro-B cells), which do not express c-kit, BCR-ABL or PDGF-R. Imatinib mesylate did not affect the activity of other DNA polymerases. Inhibition of TA was associated with 50% inhibition of proliferation. The inhibition of proliferation was associated with a decrease in the S-phase of the cell cycle and an accumulation of cells in the G2/M phase. No apoptosis was observed. Inhibition of TA was caused mainly by post-translational modifications: dephosphorylation of AKT and, to a smaller extent, by early downregulation of hTERT (the catalytic subunit of the enzyme) transcription. Other steps of telomerase regulation were not affected by IM. This study demonstrates an additional cellular target of IM, not necessarily mediated via known tyrosine kinases, that causes inhibition of TA and cell proliferation.

To test the benefit of hydroxyurea in the treatment of recurrent and non-resectable slow-growing meningiomas.Twelve patients with regrowing non-malignant meningiomas, were enrolled for a protocol of 2 years with continuous chemotherapy with hydroxyurea, 20 mg/kg/day. Response to treatment was evaluated both clinically and by diagnostic imaging using computed tomography (CT) and 201-Thallium single photon emission CT. One minimal response was documented by CT, accompanied by clinical stabilization. Nine patients showed progressive disease, at least by one imaging procedure, with a median time to progression of 13 months (range 4-24). Two other patients were not available for response due to early removal from the study, following abrupt manifestation of grades 3-4 hematological toxicity.In this series hydroxyurea has not shown effectiveness in the treatment of non-resectable slow-growing meningiomas: neither for achieving response, nor for arresting disease progression.

Study objectives High dose rate (HDR) endobronchial brachytherapy is widely used as a palliative treatment for symptomatic airway obstruction by primary or secondary malignant tumors. We report on a successful use of HDR brachytherapy in patients with nonmalignant airway obstruction. Design Case series Patients Six patients received HDR brachytherapy for airway obstruction caused by granulation tissue around a metal stent placed for restoration of the airway patency for nonmalignant causes. In four patients, brachytherapy was performed following recurrent occlusion of the airway by granulation tissue formation; in two patients, it was done as a prophylactic procedure. Intervention HDR brachytherapy catheters were passed through the metal stents under direct fluoroscopic guidance. Simulation and computerized treatment planning were done, and a single dose of 10 Gy was administered using a brachytherapy remote afterloader with a 192 Ir source. The dose was prescribed to a distance of 1 cm from the center of the source, with a margin of 1 cm from the proximal and distal ends of the stent. Results At a median follow-up of 15 months, moderate granulation tissue formation was observed in only one patient; in four others, it was categorized as minimal, 5 to 30 months from the procedure. Restoration of the lumen was complete in four patients, near complete in one patient, and partial in one patient. In one patient, previously treated by external radiotherapy, local tissue necrosis was evident. Conclusion HDR brachytherapy can be used safely for nonmalignant airway obstruction. Further studies including more patients and longer follow-up are needed.