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Background: Radiation-induced angiosarcoma (RIA) is an uncommon but morbid complication after radiotherapy for breast cancer., Methods: Retrospective analysis of breast RIA patients at Cambridge University Hospital (CUH), a regional treatment centre in the East of England., Results: 22 patients were identified between 2010 and 2022. Median age of diagnosis was 65 years (range 41-78). Median time from breast radiotherapy to RIA diagnosis was 6.5 years (range 2.4-16.0)-this interval has decreased over the last 24 years (r 2  = 0.6601). 9% had metastasis at presentation. All patients underwent surgery (55% at CUH, 45% at local hospitals). 27% received peri-operative pegylated liposomal doxorubicin in the first-line setting. 62% relapsed following their primary curative-intent treatments after a median of 28 months. Metastases occurred in 36%, the commonest sites being lung (100%) and lymph node (50%). 2-year and 5-year overall survival (OS) rates for all patients were 73% and 60%, respectively. No correlation between progression-free survival (PFS) and OS was found with tumour size, margin, peri-operative chemotherapy, and whether surgery was performed at CUH. Patients with multifocal disease on their breasts had shorter PFS following surgery compared to single-lesion disease (median 10 vs 65 months; HR = 4.359 [95% CI 1.342-14.16]; P = 0.0143). Patients aged > 72 years had a median OS of 45 months vs 102 months for those ≤ 72 years (HR = 7.129 [95% CI 1.646-30.88]; P = 0.0086)., Conclusion: RIA has high rates of recurrence and mortality and appears to be occurring sooner after breast radiotherapy. Further studies on its pathogenesis and effective treatment are warranted., (© 2023. The Author(s), under exclusive licence to The Japanese Breast Cancer Society.)

Background: Angiosarcoma (AS) of the breast is very rare, accounting for 1% of all soft tissue breast tumors. AS may present as primary tumors of the breast or as secondary lesions usually associated with previous radiotherapy. Commonly, secondary AS affects older women (median age 67-71 years) with a clinical history of breast cancer. The preferred site of onset of RIAS is the edge of radiation fields, where radiation doses and tumor necrosis may be heterogeneous, resulting in a DNA damage and instability. Radical surgery is the treatment of choice, but no clear consensus exists on surgical management of breast AS., Case Report: We describe an atypical case of relapsed RIAS after radical mastectomy, treated with new surgery and, considering the higher risk of recurrence, subsequent adjuvant chemotherapy with weekly paclitaxel., Conclusions: The frequency of radiation-induced angiosarcomas (RIAS) after breast-conserving surgery and radiotherapy has been increased to 0.14-0.5% among long survivors. Nevertheless, even if RIAS continues to be prognostically an extremely unfavorable cancer due to a high rate of recurrence, distant spread, and median overall survival (OS) of about 60 months, the benefits of loco-regional breast radiotherapy are clearly higher than the risk in developing angiosarcoma.

Radiation-induced breast sarcomas (RIBS) are rare entities representing <1% of all primary breast malignancies, limiting most reports to small retrospective case series. They constitute a heterogeneous group of neoplasms, with high-grade angiosarcoma being the most common subtype. Other sarcoma histotypes, such as undifferentiated pleomorphic sarcoma and leiomyosarcoma, can also be identified. Radiation-induced breast angiosarcoma (RIBA) has an incidence of approximately 0.1% after breast-conserving therapy and arises mainly from the dermis of the irradiated breast. MYC gene amplification is highly indicative of secondary breast angiosarcomas. Their clinical presentation often mimics benign port-radiation lesions, leading to a delay in diagnosis and a lost window of opportunity for cure. Surgery with negative margins is the mainstay of treatment of localized RIBS. In the case of angiosarcoma, technical difficulties, including multifocality, infiltrative margins, and difficulty in assessing tumor margins, render surgical treatment quite challenging. A limited number of studies showed that adjuvant radiation therapy reduces local recurrences; therefore, it is proposed by many groups for large, high-grade tumors. Chemotherapy has been evaluated retrospectively in a small subset of patients, with some evidence supporting its use in angiosarcoma patients. Approximately half of patients with RIBA will show local recurrence. In the advanced setting, different therapeutic options are discussed in the review, including chemotherapy, antiangiogenic therapy, and immunotherapy, whereas the need for further research on molecular therapeutic targets is pointed out.

Background: Primary leiomyosarcoma (LMS) of the gastrointestinal (GI) tract is rare. Limited literature exists regarding the clinical characteristics and outcome for patients with localised and metastatic disease., Methods: A retrospective chart review was performed for patients greater than 18 years of age diagnosed with GI LMS at The Royal Marsden Hospital between 1 January 2000-1 May 2020. Descriptive statistics were performed. Patients were censored at data cut-off date of 27 June 2020., Results: Forty-six patients with a median age at diagnosis of 54 years (range 25-85) were identified. Fifteen percent (n = 7) of patients previously received abdominal radiation for an unrelated cancer. All patients with localised disease (n = 36) had resection with oncological margins. For patients who underwent potentially curative surgery, median recurrence-free survival (mRFS) was 13 months (0.4-183 months), and half of these patients (n = 18) developed recurrent disease post resection (distant n = 16, local n = 2). Median overall survival (mOS) was 27 months for patients with distant recurrence. Twenty-one percent (n = 10) of patients presented with synchronous metastatic disease and their mOS was 19 months. Median progression-free survival (mPFS) for patients treated with conventional chemotherapy ranged from 2.0 to 8.0 months., Conclusion: The risk of recurrence is significant, and recurrence-free survival was short even with complete oncologic resection. The relationship of prior abdominal radiotherapy to the development of GI LMS warrants further investigation. Outcomes with systemic therapy for metastatic disease were poor and there is a need for the development of more effective systemic therapies., Competing Interests: Declaration of competing interest RLJ is the recipient of grants/research support from MSD, GSK. AJH and MJS are the recipient of research support from Amgen. RLJ is the recipient of consultation fees from Adaptimmune, Athenex, Blueprint, Clinigen, Eisai, Epizyme, Daichii, Deciphera, Immunedesign, Lilly, Merck, Pharmamar, UptoDate. MJFS has been an advisory board member for Amgen. All other authors have no conflicts of interest to declare., (Crown Copyright © 2021. Published by Elsevier Ltd. All rights reserved.)

Objective: To characterize the presentation, patterns of care, and outcomes of radiation-associated muscle-invasive bladder cancer (RA-MIBC) compared to primary (non-radiation associated) MIBC. RA-MIBC has been suggested to represent a more aggressive disease variant and be more difficult to treat compared to primary (non-radiation associated) MIBC., Methods: We identified 60,090 patients diagnosed with MIBC between 1988-2015 using the Surveillance, Epidemiology, and End Results database and stratified patients based on whether radiation had been administered to a prior pelvic primary cancer. We used Fine-Gray competing risks regression to compare adjusted bladder cancer-specific mortality (BCSM) for RA-MIBC compared to primary MIBC., Results: There were 1,093 patients with RA-MIBC and 58,997 patients with primary MIBC. RA-MIBCs were more likely to be T4 at diagnosis (21.0% vs 17.3%, P < .001), and less likely to be node-positive (10.3% vs 17.1%, P < .001). The rate of 5-year BCSM was significantly higher for patients with RA-MIBC vs primary MIBC (56.1% vs 35.3%, AHR 1.24, P < .001), even after stratification by other tumor, treatment and patient-specific factors., Conclusion: RA-MIBCs tended to present with higher grade and T stage disease and were less likely to receive curative treatment. Even when accounting for stage, grade, and receipt of treatment, patients with RA-MIBC had worse survival compared to those with primary MIBC. These findings suggest that RA-MIBC present unique clinical challenges and may also represent a biologically more aggressive disease compared to primary MIBC. Future research is needed to better understand the biology of RA-MIBC and develop improved treatment approaches., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Mouse models of radiation-induced thymic lymphoma are commonly used to study the biological effects of total-body irradiation (TBI) on the formation of hematologic malignancies. It is well documented that radiation-induced thymic lymphoma can be inhibited by protecting the bone marrow (BM) from irradiation; however, the mechanisms underlying this phenomenon are poorly understood. Here, we aimed to address this question by performing transplantation of BM cells from genetically engineered mice that have defects in tumor immunosurveillance or occupying different thymic niches. We found that BM cells from mice that have impaired tumor immunosurveillance, by deleting tumor necrosis factor alpha (TNFα), interferon gamma (IFNγ) or perforin-1 (PRF1), remained sufficient to suppress the formation of radiation-induced thymic lymphoma. On the other hand, BM cells from Rag2-/-; γc-/- mice and Rag2-/- mice, which have defects in occupying thymic niches beyond double negative (DN2) and DN3, respectively, failed to inhibit radiation-induced lymphomagenesis in the thymus. Taken together, based on our findings, we propose a model where unirradiated BM cells suppress radiation-induced lymphomagenesis in the thymus by competing with tumor-initiating cells for thymic niches beyond the DN3 stage., (©2021 by Radiation Research Society. All rights of reproduction in any form reserved.)

Ionising radiation-induced normal tissue damage is a major concern in clinic and public health. It is the most limiting factor in radiotherapy treatment of malignant diseases. It can also cause a serious harm to populations exposed to accidental radiation exposure or nuclear warfare. With regard to the clinical use of radiation, there has been a number of modalities used in the field of radiotherapy. These includes physical modalities such modified collimators or fractionation schedules in radiotherapy. In addition, there are a number of pharmacological agents such as essential fatty acids, vasoactive drugs, enzyme inhibitors, antioxidants, and growth factors for the prevention or treatment of radiation lesions in general. However, at present, there is no standard procedure for the treatment of radiation-induced normal tissue lesions. Stem cells and their role in tissue regeneration have been known to biologists, in particular to radiobiologists, for many years. It was only recently that the potential of stem cells was studied in the treatment of radiation lesions. Stem cells, immediately after their successful isolation from a variety of animal and human tissues, demonstrated their likely application in the treatment of various diseases. This paper describes the types and origin of stem cells, their characteristics, current research, and reviews their potential in the treatment and regeneration of radiation induced normal tissue lesions. Adult stem cells, among those mesenchymal stem cells (MSCs), are the most extensively studied of stem cells. This review focuses on the effects of MSCs in the treatment of radiation lesions.

Background: Cancer survivors have a 14% increased risk of developing a malignancy compared with the general population. Second radiation-induced malignancies with different histologies have been described in different organs. Based on individual observations, we hypothesized that neuroendocrine carcinoma (NEC) could arise in irradiated organs., Methods: In a retrospective analysis of Gustave Roussy database of NEC patients (small cell lung cancer excluded) diagnosed as a second cancer, we looked for the frequency of grade 3 NEC that arose in patients who had received previous radiation therapy for a first cancer. Radiation therapy for the first cancer, dose, location of radiation therapy, pathological characteristics, overall survival, and response to treatment of secondary NEC were analyzed., Results: From January 1995 to December 2017, 847 cases of NEC were seen at Gustave Roussy. Among them, 95 (11.2%) patients had a history of previous malignancy of which 36 (4%) had been treated with radiation therapy. Out of these 36 patients, 12 (1.4% of all NEC patients) developed a NEC within the previous irradiated organ (median dose of 50 Gy, range 36-67.5). Most frequent first cancers were breast cancer (n = 4) and Hodgkin lymphoma (n = 3). NEC arose within a median time of 21.7 years (range 5.1-36.4) from radiation in the thorax (n = 5), digestive tract (n = 3), and other sites. Five large cell NEC, 3 small cell NEC, 1 mixed neuroendocrine neoplasm and 3 not otherwise specified NEC were diagnosed. Ten patients had stage IV disease at diagnosis; median overall survival was 37.8 months (95% CI [17.6 to NA]). Three patients (25%) achieved complete response with multimodal treatment., Conclusions: NEC can arise from previously irradiated organs and may have a better outcome in this setting. Other risk factors should be investigated to explain the high rate of previous cancer in this population of neuroendocrine neoplasm., (© 2019 S. Karger AG, Basel.)

Purpose: Meningiomas are common brain tumors, the majority of which are considered benign. Despite surgery and/or radiation therapy, recurrence rates are approximately 8-10%. One likely cause is the dysregulation of cyclin D-cyclin-dependent kinases 4 and 6 (CDK4/6)-retinoblastoma (Rb) pathway, which controls the cell cycle restriction point. This pathway is commonly dysregulated in anaplastic meningioma cell lines (AM) and radiation-induced meningioma cells (RIM), making it a rational target for anti-meningioma therapy. In this study, we investigate the effect of a CDK4/6 inhibitor, palbociclib, with radiation in relevant pre-clinical models., Methods: In vitro cell culture, ex vivo slice culture and in vivo cell line-derived orthotopic xenograft animal models of AM/RIM were utilized to assess treatment efficacy with palbociclib plus radiation. Treatment effects were examined by immunoblot, cell viability, apoptosis, and cell cycle progression., Results: The in vitro and ex vivo studies demonstrate that palbociclib plus radiation treatment reduced proliferation and has additional effects on cell cycling, including induction of an RB-associated G (1) arrest in Rb+ AM and RIM cells, but not in Rb- cells. Our results also demonstrated reduced CDK4 and CDK6 expression as well as reduced E2F target gene expression (CCNA2 and CCNE2) with the combination therapy. MRI results in vivo demonstrated reduced tumor size at 5 weeks when treated with 14 days palbociclib (10 mg/kg) plus 6 Gy radiation compared to saline-treated tumors. Finally, no hepatic toxicity was found after treatments., Conclusion: A pre-clinical murine model provides preclinical evidence for use of palbociclib plus radiation as a therapeutic agent for Rb+ meningiomas.

Background and Aims: Compared to the general population, the incidence of thyroid cancer in childhood and adolescent and young adult malignancy survivors is increased 14.0-18.0 times (CI 11.7-23.8). The cumulative incidence is variably reported as 0.5% by age 45 with 30-year incidence of 1.3% in women and 0.6% in men. This study aims to evaluate the incidence of radiation-associated thyroid cancer amongst patients treated with prior radiation to the thyroid followed up in a late effects service. A secondary aim was to assess screening compliance in this cohort., Methods: The medical records of all patients attending the late effects service from 1 January 2000 to 20 February 2013 were interrogated to identify patients exposed to thyroid irradiation. The screening compliance and incidence of thyroid cancer were assessed for the duration whilst under the guidance of the late effect service. Mode of diagnosis, all imaging and cytology were retrieved from the institutional electronic record. Cytology was categorized according to Bethesda., Results: Four hundred and sixty-five patients were exposed to direct or scatter neck irradiation. Compliance with thyroid surveillance was observed in 76.9%. Ultrasound features of microcalcification and increased internal vascularity had a low sensitivity (62.5%) for predicting a malignant nodule, which improved when used in conjunction with a Bethesda IV-VI result (91.7%). However, cytological assessment was not performed in 45.6% of operative cases. Thirty-three patients had thyroid carcinoma of which 45.4% (n = 15) were incidental. The majority were papillary thyroid cancers (88.9%); of which 12.5% were node positive and 34.4% were multifocal. The incidence of thyroid cancer was elevated 57.6 times compared to the Australian general population (p < 0.001)., Conclusion: Due to the high incidence of thyroid cancer, this study supports screening in this cohort. However, due to the risk of overtreatment, we endorse further investigation of thyroid nodules with ultrasound-guided fine-needle aspiration cytology based on sonographic criteria as for the general population and American Thyroid Association guidelines.

Background: Despite improved survival, many pediatric brain tumor survivors receiving radiation therapy (RT) experience late effects., Procedure: To study calvarial lesions in this population, we retrospectively reviewed records of patients undergoing neurosurgical evaluation for calvarial bone lesions detected in posttreatment follow-up imaging at St. Jude Children's Research Hospital. Primary tumor diagnosis, treatment, imaging, surgical intervention, and histopathology from patients with radiographic evidence of lesions followed for ≥2 years post-RT were studied., Results: For 17 patients with 18 index lesions, median time to lesion manifestation was 2.34 years. Medulloblastoma patients developed lesions at a shorter interval from RT than ependymoma patients (P = .05). Twelve of 14 lesions requiring surgery were benign fibro-osseous or sclerotic. Two malignant lesions distinct from the primary tumor had genetic predisposition to malignancy., Conclusion: Most calvarial lesions arising post-RT are benign and fibro-osseous. Serial imaging is recommended, and high index of suspicion for malignant lesions is warranted for patients genetically predisposed to cancer., (© 2020 Wiley Periodicals, Inc.)

Secondary carcinogenesis within the irradiation range is one of the most severe problems in cancer survivors. A 60-year-old woman developed hypopharyngeal carcinoma, and she received radical surgery and postoperative radiotherapy. Eight years later, brown pigmentation and induration were observed in the left subaural region. Fine-needle aspiration biopsy revealed malignancy and the parotid tumor was diagnosed as recurrence of hypopharyngeal carcinoma. Neoadjuvant chemotherapy followed by radical parotidectomy was performed. The pathological diagnosis was angiosarcoma, which was most likely induced by past irradiation. About two months after surgery, lung metastases were detected. Docetaxel did not affect to lung metastases, but paclitaxel therapy was partially effective. The lung tumors increased in size, and brain metastases developed, resulting in death. Both neoadjuvant chemotherapy and radical surgery played important roles in the local disease control. Administration of newer agents as adjuvant chemotherapeutic agent should also be considered for improving the prognosis., (Copyright © 2019. Published by Elsevier B.V.)

The therapies used to treat Ewing sarcoma are associated with a risk of second malignant neoplasm (SMN). We conducted a systematic review to pool available evidence on the risks, types, and outcomes after SMN. We obtained 52 articles that met inclusion criteria. Cumulative incidence rates of SMN ranged from 0.9 to 8.4% and 10.1 to 20.5% at 5 and 30 years after initial diagnosis. Of the 327 reported SMNs, 63.6% were solid tumors, although acute myeloid leukemia /myelodysplastic syndrome was the single most commonly diagnosed SMN, with generally poor outcomes. Patients treated for Ewing sarcoma are at substantial risk of SMN, with a broad range of reported secondary cancers., (© 2019 Wiley Periodicals, Inc.)

Background: Undifferentiated pleomorphic sarcoma (UPS) of the breast is an extremely rare, but aggressive subtype of sarcoma that can develop in radiotherapy (RT)-treated breast cancer patients. Due to the low incidence, there are many uncertainties regarding the adequate management of these tumors. We present a rare case of radiation-induced UPS in a 63-year-old woman who had undergone breast conserving therapy for invasive ductal carcinoma of the left breast, six years prior to presentation., Case Presentation: A 63-year-old woman presented with a rapidly growing left breast mass. She had been diagnosed with invasive ductal carcinoma of the left breast for which she underwent a left upper outer quadrantectomy and ipsilateral axillary dissection followed by RT, six years previously. During her routine oncologic follow-up, the mammography revealed a dense, nodular opacity with microcalcifications. The breast ultrasound (US) confirmed the presence of the nodule. US-guided fine needle aspiration biopsy was performed and the diagnosis of UPS was made, the reason for which the patient underwent wide local excision of the left breast., Conclusion: The diagnosis of RT-induced UPS is challenging and often missed due to the low incidence, long latency period, unspecific imaging findings, and difficulties in clinical and histological detection of these lesions. These tumors should be considered in differential diagnoses of rapidly-growing breast masses in previously RT-treated breast cancer patients, as they can mimic the local recurrence of the primary tumor. Since the prevalence of breast-conserving surgery followed by RT has been increasing, the careful monitoring of at risk patients is of utmost importance, as UPSs are highly aggressive tumors associated with very poor outcomes.

Childhood cancer survivors are at risk for ongoing health risks related to their initial treatment. One potential long-term complication following radiation is the development of secondary tumors, including peripheral nerve tumors, such as schwannomas. We present three adolescent and young adult (AYA)-aged survivors of pediatric cancer (22-40 years), followed in our AYA survivorship clinic. Each was found to have a schwannoma many years following total body irradiation for a childhood primary malignancy. We highlight a late effect of low-dose total body irradiation as well as the importance of long-term monitoring in this population.

Background: Radiation-induced bilateral external auditory canal cancer is an extremely rare disease that has yet to be fully characterized in the clinical literature., Methods: Herein, we present a case study of a 75-year-old man with radiation-induced bilateral external auditory canal cancer. The patient's medical history included left maxillary cancer that had been treated with chemoradiation 19 years earlier and local recurrence with total maxillectomy 10 years earlier. Intracavitary radiation was delivered to the site of postoperative recurrence 8 years before the current presentation. The patient declined radical surgery for the external auditory canal cancer at this time, and a customized combined modality regimen was thus administered., Results: There was no recurrence of cancer for 22 months, to date, after completing chemoradiotherapy., Conclusions: Our finding that radiotherapy can be successfully used for radiation-induced cancer indicates that chemoradiotherapy may be a useful strategy for treating this type of malignancy., (© 2019 Wiley Periodicals, Inc.)

Introduction: Osteosarcoma, a primary malignant bone tumor, has a well-recognised double peak of incidence in early adolescence and after 50 years. This study investigates the clinical features and prognostic factors of patients older than 50 years with osteosarcoma., Materiel and Methods: From January 2000 to December 2012, in one bone tumor reference center, 32 patients aged more than 50 years at the diagnosis (mean age: 62.4 years (50-85), sex ratio: 13 males, 19 females) diagnosed with osteosarcoma were included. Patients younger than 50 years at diagnosis or with a non-histologically proved osteosarcoma were excluded. For each patient, we registered medical history, tumor location, systemic and local extension, treatment, and survival., Results: 62% were located in the extremities and 28% in the axial skeleton. 6 were secondary sarcomas. Mean delay between first symptoms and biopsy was 7.4 months (range from 0 to 28 months). Ten patients had a systemic osteosarcoma with one or more pulmonary metastases. Six patients were treated with palliative care (18.8%). Eighteen patients received neodajuvant chemotherapy, sixteen of them received postoperative chemotherapy. Twenty-five patients had surgery. Postoperative complications were reported in eight cases (25%). Overall survival for all 31 patients was 25% at 5 years and 6.2% at 10 years. Survival without metastases was 15.6% at 5 years and nil at 10 years. Median survival time for the 22 localised osteosarcoma patients was 4 years (0.9-12.6) versus 1.2 years (0.3-12.3) for the 10 systemic osteosarcoma patients (p = 0.01)., Conclusion: Metastases at diagnosis, age, axial location are worse prognostic for survival., (Copyright © 2019 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Purpose: Radiation-associated sarcomas (RAS) are considered to have a poor prognosis. Although the incidence is anticipated to rise, contemporary data regarding predictors of outcomes are few. We performed a retrospective analysis to identify RAS prognostic factors and subset analyses for radiation-associated angiosarcoma arising after treatment for breast cancer (RAAB) and other RAS subtypes (other-RAS)., Methods and Materials: Patients with localized RAS evaluated at an institutional multidisciplinary sarcoma clinic were identified. Clinical and histologic review was performed, and outcomes were assessed to identify prognostic features. A subset of cases underwent molecular analysis by next-generation sequencing., Results: Among 176 patients, histologic subtypes of RAS included angiosarcoma (41%), undifferentiated/unclassified sarcoma (40%), leiomyosarcoma (8%), malignant peripheral nerve sheath tumor (6%), and osteosarcoma (2%). Sixty-seven patients (38%) had RAAB, and 109 (62%) had other-RAS. RAAB had significantly shorter latency from time of initial radiation compared with other-RAS (8 vs. 15 years; P < .001). Treatment approaches included surgery (91%), chemotherapy (44%), and radiation therapy (27%). Median follow-up was 3.2 years; 3-year overall survival (OS) was 74%. On multivariate analysis, positive margins (P < .0001), deep tumor location (intrathoracic/intra-abdominal, P = .002), and high grade (P < .0001) were associated with worse OS. In particular, 3-year OS with negative versus positive margins was 90% versus 66%. Patients with RAAB versus other-RAS showed a trend for higher 3-year OS (84% vs 68%; P = .09), significantly higher 3-year metastasis-free survival (82% vs 67%; P = .001), but similar 3-year local recurrence-free survival (54% vs 61%; P = .28). Next-generation sequencing identified overall low tumor mutational burden, recurrent MYC amplification in RAAB, and few clinically actionable mutations., Conclusions: Margin negative excision, superficial tumor location, and low tumor grade are determinants of improved OS for RAS, suggesting that complete surgical excision, when possible, is an optimal component of treatment. RAAB is a clinicopathologically distinct type of RAS with shorter latency from initial RT, different recurrence patterns, and when aggressively managed has potentially better outcomes compared with other-RAS., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Cutaneous epithelioid angiosarcoma is a rare neoplasm of vascular endothelial cell origin that can mimic a cutaneous lymphoma, metastatic carcinoma, or Kaposi sarcoma. It is one of the most malignant cutaneous tumors and early diagnosis is essential, as the tumor metastasizes quickly. We describe a 75-year-old man who presented with three tender, indurated violaceous plaques on his scalp. Biopsy revealed a poorly circumscribed infiltrate extending into the subcutaneous fat, composed of atypical epithelioid cells lining vascular spaces. We provide a brief review of the clinical presentation, histopathologic features, differential diagnosis, and management of this rare tumor.

Purpose of Review: To present the current status of knowledge regarding radiation-induced papillary thyroid cancer (RIPTC), defining its epidemiologic, pathologic, and clinical characteristics, with ensuing possible therapeutic and prognostic consequences., Recent Findings: Cumulative evidence shows that RIPTC resembles sporadic papillary thyroid cancer (PTC) of comparable age, both in terms of clinical-pathological features and prognosis. Therefore, more aggressive treatment does not seem to be required when managing RIPTC as its prognosis is comparable to that of never-irradiated patients., Summary: Radiation exposure in childhood is a well-documented risk factor for development of PTC. Therefore, increased exposure to medical or environmental radiation may be in part responsible, along with increased screening, of the recent burgeoning incidence of PTC. A specific morphological and molecular portrait of RIPTC is unlikely to exist. The more aggressive histologic and clinical features initially reported in radiation-induced cases are consistent with the expectations in nonradiation-related PTC of a comparable age. Aggressive histology, nodal, and distant metastases correlate with early age at onset rather than with radiation exposure. Although relapses are frequent in children, long-term cancer-specific mortality is approximately 1%, lower than that observed for adults and comparable between irradiated and nonirradiated cohorts. RIPTC does not require more aggressive surgery or more adjuvant treatments, as prognosis is as good as that of sporadic PTC when matched for stage and treatment received.

DSBs are harmful lesions produced through endogenous metabolism or by exogenous agents such as ionizing radiation, that can trigger genomic rearrangements. We have recently shown that exposure to 2 Gy of X-rays has opposite effects on the induction of Shh-dependent MB in NHEJ- and HR-deficient Ptch1 +/- mice. In the current study we provide a comprehensive link on the role of HR/NHEJ at low doses (0.042 and 0.25 Gy) from the early molecular changes through DNA damage processing, up to the late consequences of their inactivation on tumorigenesis. Our data indicate a prominent role for HR in genome stability, by preventing spontaneous and radiation-induced oncogenic damage in neural precursors of the cerebellum, the cell of origin of MB. Instead, loss of DNA-PKcs function increased DSBs and apoptosis in neural precursors of the developing cerebellum, leading to killing of tumor initiating cells, and suppression of MB tumorigenesis in DNA-PKcs -/- /Ptch1 +/- mice. Pathway analysis demonstrates that DNA-PKcs genetic inactivation confers a remarkable radiation hypersensitivity, as even extremely low radiation doses may deregulate many DDR genes, also triggering p53 pathway activation and cell cycle arrest. Finally, by showing that DNA-PKcs inhibition by NU7441 radiosensitizes human MB cells, our in vitro findings suggest the inclusion of MB in the list of tumors beneficiating from the combination of radiotherapy and DNA-PKcs targeting, holding promise for clinical translation., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Xeroderma pigmentosum (XP) is a form of general dermatosis characterised by photo-induced cutaneous-ocular impairment and by skin cancers. In addition to these signs, there may also be neurological involvement. This disease is related to a defect in genes within the nucleotide excision repair system for the first seven genetic groups (A-G), and to an abnormality in transcription groups for the eighth group (xeroderma pigmentosum variant - XPV). Cutaneous carcinomas are the most common types of cancer seen. They may begin in childhood. Multiple melanoma commonly occurs during the course of XP but given the frequency of spontaneous regression, the incidence is underestimated. The clinical appearance is characterised by polymorphous lesions with characteristic dyschromia and in most cases it is sufficient to establish the diagnosis. Investigation of unscheduled DNA synthesis (UDS) and cell survival following ultraviolet (UV) radiation were formerly considered the reference examination for laboratory diagnosis. However, these tests are now being replaced by new molecular biology techniques to screen for the genetic mutations characteristic of the disease. These techniques have proved extremely useful in identifying heterozygous patients and in antenatal diagnosis. Photoprotection is the key preventive measure: patients must avoid all exposure to the sun and to artificial sources of UV radiation. The therapeutic arsenal has recently been enriched by several modern therapeutic methods used to destroy cutaneous tumours such as imiquimod and photodynamic therapy (PDT). These approaches are valuable since they eliminate incipient tumours while sparing healthy skin. Surgery and cryosurgery are the most suitable methods for treating cutaneous tumours in children. Chemotherapy may be considered an alternative for the treatment of keratoacanthomas and squamous cell carcinomas (SCC). Cryosurgery may be combined with other therapeutic approaches to eliminate SCC of the lip. Management of these patients in reference centres, coupled with assistance from associations providing support for patients' families, has resulted in improved quality of therapy while slowing down disease progression., (Copyright © 2018. Published by Elsevier Masson SAS.)

We describe a gentleman diagnosed with a posterior fossa medulloblastoma in 1998, successfully treated with craniospinal radiation therapy (RT) and posterior fossa RT boost, followed by 12 months of adjuvant chemotherapy. Nineteen years later, at the age of 28, the patient presented with multiple cranial neuropathies and was found to have disseminated high-grade glioma with leptomeningeal dissemination. In addition to the salient features of this case, we provide a brief review of RT-induced malignancies and the need for further research regarding surveillance and prevention strategies.

Radiation-associated sarcoma (RAS) is a rare complication of radiation therapy (RT) to breast cancer (BC). This study explored RAS after RT to BC in a nationwide population-based material. The Finnish Cancer Registry was queried for patients with BC treated during 1953-2014 who were later diagnosed with a secondary sarcoma in 1953-2014. Registry data, patient files, and sarcoma specimens were  analyzed to confirm diagnosis and location of RAS at or close to the RT target volume. A total of 132 512 patients were diagnosed with invasive BC during the study period. A subsequent sarcoma was diagnosed in 355 patients. After exclusion, 96 RAS were identified. Angiosarcoma (AS) was the most prevalent histology in 50 (52%) of 96 patients. However, the first radiation-associated AS was diagnosed in a patient treated for BC with breast-conserving surgery in 1984, and thereafter, the proportion of AS continuously increased. The 5-year sarcoma-specific survival was 75.1% for RAS treated with a curative intent. The distribution of histologic subtypes of RAS has changed during the 60 years of this registry study. The first radiation-associated AS was diagnosed in 1989, and presently, AS is the most common histologic subtype of RAS. It is possible that changes in BC treatment strategies are influencing the characteristics of RAS., (© 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Purpose: Complications can occur following a prolonged latency period after radiation therapy for cancer, and this is a growing concern because secondary tumors are potentially fatal. Few studies have examined secondary tumors in patients who received radiation therapy as children., Methods and Materials: This retrospective study examined 1697 pediatric patients with central nervous system tumors who received treatment at Taipei Veterans General Hospital from January 1, 1975, to December 31, 2013. Secondary tumors developed in 27 of 681 patients who received cranial irradiation. Overall survival was estimated using the Kaplan-Meier method, and the significance of differences was determined by the log-rank test., Results: The overall cumulative incidence of secondary tumors at 25 years was 3.96%, and there were similar numbers of male patients (n = 16) and female patients (n = 11). The mean age at diagnosis was 8.8 years (range, 3-16.5 years), the median dose of cranial irradiation was 52.5 Gy (mean, 53.4 Gy), the mean latency period was 14.6 years (range, 2-33 years), and the mean age at diagnosis of a secondary tumor was 23.1 years. The secondary tumors were mainly meningiomas (n = 13), sarcomas (n = 7), and high-grade gliomas (n = 6), and the mean latency periods were 19.66, 8.00, and 10.83 years, respectively. The overall survival rate from these secondary tumors was significantly different (P < .05). Age at irradiation of <7 years and craniospinal irradiation significantly increased the risk of a secondary tumor (P < .05). Secondary tumors developed in 11 of 128 patients (8.6%) with primary medulloblastomas, which was higher than the overall cumulative incidence., Conclusions: Clinicians should consider the increased risk of secondary tumors in long-term cancer survivors who received craniospinal irradiation as children. Using a selective dose de-escalation strategy or deferring radiation therapy for young patients at highest risk of secondary cancers should be studied., (Copyright © 2018 Elsevier Inc. All rights reserved.)

By conducting a systemic search of the PubMed database, we performed a comprehensive literature review to characterize secondary gliomas following radiotherapy treatment and to determine the most appropriate treatment strategy. Our analysis included 296 cases of radiation-induced gliomas. The primary lesion was characterized as a hematological malignancy in 104 cases (35.1 %), pituitary adenoma in 35 (11.8 %), craniopharyngioma in 19 (6.4 %), medulloblastoma in 38 (12.8 %), germ cell tumor in 13 (4.3 %), low-grade glioma in 28 (9.4 %), cancer/sarcoma in 12 (4.0 %), scalp region disease in 15 (5.0 %), meningioma/schwannoma in 13 (4.3 %), metastatic brain tumor in 5 (1.6 %), and other types (e.g., arteriovenous malformations and angiomas) in 14 (4.7 %). The average age of onset for primary lesions was 16.0 ± 15.8 years, and the average radiation dose delivered to the primary lesion was 37.6 ± 20.0 Gy. Secondary gliomas could be divided into grade I (1), grade II (32), grade III (88), and grade IV (173) tumors. The median overall survival for all glioma cases was 11 months (95 % confidence interval [CI], 9-12), with a 2-year survival rate of 20.2 %. On multivariate analysis, combined modality treatment and the latency period from the radiotherapy treatment to the glioma diagnosis were variables associated with the overall survival of patients with grade III/IV secondary gliomas. For patients treated with cranial radiotherapy, the risk of secondary glioma incidence warrants a longer follow-up period beyond the standard time frame typically designated for determining the risk of primary tumor relapse. Moreover, combination therapy is a potential treatment option for radiation-induced gliomas.

Purpose: Many cases of postirradiation oral carcinoma have been reported, but its prognosis and optimal treatment modalities are not clear. Thus, the clinicopathologic characteristics and prognosis between postirradiation tongue squamous cell carcinoma (PTSCC) and primary tongue squamous cell carcinoma (TSCC) were compared., Patients and Methods: A retrospective cohort study was conducted to assess patients with PTSCC or TSCC. The primary predictor variable was tumor type. The primary outcome variable was prognosis, and the additional outcome variables were clinicopathologic characteristics. Survival analysis was performed, and Kaplan-Meier analysis was conducted to compare the effects of clinicopathologic factors on survival using SPSS 18.0. Moreover, the Cox model was applied in multivariate analysis., Results: The sample was composed of 449 patients with PTSCC (n = 68; 47 men and 21 women; age range, 31 to 72 yr) and TSCC (n = 381; 247 men and 134 women; age range, 20 to 86 yr). Patients with PTSCC were found to have a substantially poorer prognosis and several specific clinicopathologic characteristics compared with patients with TSCC., Conclusion: Patients with PTSCC had several unique biological tumor characteristics and a poorer prognosis than patients with TSCC. Thus, different surgical strategies should be used to treat patients with PTSCC., (Copyright © 2017 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)

Introduction and Objectives: Primary cutaneous angiosarcoma is one of the most aggressive skin tumors and carries a very poor prognosis. Its initially indolent clinical presentation explains the frequently late diagnosis that, together with its typically multifocal pattern and poor delimitation, often makes surgery difficult. The low incidence of primary cutaneous angiosarcoma means that few large single-center series have been published. We review the clinical and pathologic characteristics of cutaneous angiosarcomas treated in our hospital, looking for prognostic factors and for possible diagnostic traits that could facilitate early diagnosis., Material and Methods: This was a retrospective observational study including all patients diagnosed with cutaneous angiosarcoma in Instituto Valenciano de Oncología in Valencia, Spain between January 2000 and December 2015. We recorded 16 clinical parameters, including age, sex, type of angiosarcoma, site, size, and time since diagnosis, and 8 histopathologic parameters., Results: We identified 16 patients (11 women and 5 men) with cutaneous angiosarcoma. Their mean age was 67 years (median, 71 years). The most common site was the trunk (10 cases), followed by the head and neck (5 cases). The mean size of the tumor was 10cm (median, 6.5cm). Fourteen patients underwent surgical excision. Six of the 16 patients were alive at the end of the study, after a mean follow-up period of 42.5 months., Conclusions: The major determinants of survival among patients with cutaneous angiosarcoma are tumor size and patient age. Other characteristics associated with a poor prognosis were infiltration of deep planes (muscle), a predominantly solid histologic pattern, and a larger number of mitoses., (Copyright © 2017 AEDV. Publicado por Elsevier España, S.L.U. All rights reserved.)

Background: Worldwide, the incidence of cancer in young adults (20-39 years) is increasing, and represents an important cause of mortality in this age group. A retrospective study was undertaken to provide information that may lead to improved treatment outcomes., Methods: Epidemiological, clinicopathological, treatment, and survival information were retrieved from the electronic database registry of a tertiary referral hospital in São Paulo, Brazil for patients 19-29 years of age diagnosed with cancer between January 2007 and December 2012., Results: There were 960 patients with a median age at diagnosis of 26 years; female patients comprised 59.2%. A previous diagnosis of malignancy was present in 2.3%; 0.4% had malignant tumors that were radiation-associated; regular alcohol use was present in 10.4%; 9% of patients reported tobacco use; a family history of cancer was present in 41.7%. Malignant tumors included carcinomas (45.7%), germ cell and trophoblastic neoplasms (12.3%), and lymphomas (12.1%). Median follow-up was 47.7 months (range: 0.62-100.9 months) during which time 111 patients (13.5%) died. Carcinomas (n = 43, 38.7%), soft tissue sarcomas (n = 18, 16.2%), and leukemias (n = 10, 9.0%) were the most common causes of death., Conclusions: This study has shown that carcinomas represent the most common malignancy in adolescents and young adults referred to a tertiary cancer center in Brazil and are the most common cause of mortality. Because clinical outcome may be affected by multiple factors in this patient population, further global studies are needed to characterize this population and improve clinical care.

Thyroid cancers have long been considered to arise in middle age and, after their repeated proliferation, resulting in further damage to the genome, they progress to more aggressive and lethal cancers. However, in 2014, some studies were reported that might lead to a marked change in our understanding of the natural history of thyroid cancer. A high prevalence of papillary carcinoma in the young suggested that the first initiation of thyroid cancer is likely to occur in the infantile period. Such a conclusion was also supported by a very slow growth rate of papillary microcarcinomas (PMCs) in an observation trial. The proliferation rate of PMCs was negatively correlated with the age, and surgery to remove PMCs did not contribute to reduce mortality from thyroid cancer. These findings strongly suggested the existence of self-limiting cancers, which are truly malignant but do not progress to lethal cancers, for the first time in human history. The early detection of self-limiting cancers results in overdiagnosis. Ultrasonographic screening of the thyroid in the young should be avoided. Lethal thyroid cancers, whose origin is still unknown, appear suddenly after middle age. In the elderly, thyroid cancers are a mixture of self-limiting and lethal cancers; thus, when thyroid cancer is detected, careful follow-up with examination of its growth rate is required.

Background: Burkitt lymphoma is a high-grade B cell lymphoma which accounts for less than 1% of all adult cases of non-Hodgkin lymphoma. Rare instances of Burkitt lymphoma developing secondary to prior irradiation have been described in the literature., Case Presentation: We report a case of a 90-year-old white woman with a recent history of irradiation for Hodgkin lymphoma, who presented with primary Burkitt lymphoma of the supraglottic larynx. She underwent emergency awake tracheostomy with biopsy. A histopathological examination confirmed non-Hodgkin, B cell lymphoma of Burkitt type. Given her age and poor functional status, she underwent treatment with palliative radiotherapy., Conclusions: A literature review was performed to clarify the clinical characteristics of radiation-induced Burkitt lymphoma in the head and neck, as well as its diagnosis and management. The present case represents the second case of radiation-induced Burkitt lymphoma in the head and neck in the reported literature, and the first in the supraglottic larynx. It highlights the need to maintain a broad differential in the assessment of malignancies of the larynx, particularly in patients with a prior history of radiation treatment.

Merkel cell carcinoma, though rare, is one of the most aggressive tumors a dermatologist faces. More than a third of patients with this diagnosis die from the disease. Numerous researchers have attempted to identify clinical and pathologic predictors to guide prognosis, but their studies have produced inconsistent results. Because the incidence of Merkel cell carcinoma is low and it appears in patients of advanced age, prospective studies have not been done and no clear treatment algorithm has been developed. This review aims to provide an exhaustive, up-to-date account of Merkel cell carcinoma for the dermatologist. We describe prognostic factors and the imaging techniques that are most appropriate for evaluating disease spread. We also discuss current debates on treating Merkel cell carcinoma., (Copyright © 2016 AEDV. Publicado por Elsevier España, S.L.U. All rights reserved.)

Objective: Radiation-induced sarcomas (RISs) of the central nervous system are an uncommon late risk of irradiation. We conducted a systematic review of individual patient data to characterize RISs., Methods: We conducted a systemic search of the PubMed databases and compiled a comprehensive literature review. Student t tests were used to evaluate differences between variables. Kaplan-Meier analysis was used to estimate survival. Statistical significance was assessed using a log-rank test., Results: We analyzed 180 cases of RISs, including 59 osteosarcomas, 50 fibrosarcomas, and 16 malignant fibrous histiocytomas. The average age of onset for primary lesions was 28.8 ± 17.9 years, and the average dose of radiation delivered to the primary lesion was 51.4 ± 18.6 Gy. The latency period between radiotherapy and the onset of sarcomas was 12.4 ± 8.6 years. The median overall survival time for all sarcoma patients was 11 months, with a 5-year survival rate of 14.3%. The median survival in patients who received chemotherapy was 18 months, with a 2-year survival rate of 39.4%, whereas patients who did not receive chemotherapy had a median survival of 5 months and a 2-year survival rate of 13.7% (P < 0.0001)., Conclusions: The risk of secondary sarcomas in patients treated with cranial radiotherapy warrants longer follow-up periods beyond the standard time frame typically designated for determining the risk of primary tumor relapse. Moreover, chemotherapy should be considered a potential treatment option for RISs., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Introduction: Patients treated with radiotherapy are under increased long-term risk of developing radiation-induced tumors. In this report we present an exceptionally rare case of a patient who, following radiotherapy for cervical cancer, developed 3 radiation-induced metachronous pelvic tumors., Case Presentation: In 1997, a 37-year-old patient with cervical adenocarcinoma (FIGO stage IB2) was subjected to adjuvant conventionally fractionated external-beam radiation therapy and brachytherapy following surgical treatment. Eleven, 14 and 15 years later, 3 radiation-induced malignant tumors developed: a leiomyosarcoma of the gluteus and 2 separate carcinomas of the rectum., Discussion and Conclusion: Radiotherapy for cervical carcinoma increases the standardized incidence ratios for rectal cancer and soft tissue sarcoma. Unfortunately, the current guidelines on contraindications to radiotherapy appear insufficient as they take into account a very limited number of clinical states and associated conditions, which is in disproportion to the rather high risk of radiation-induced malignancies of 0.45%. Information on the molecular characteristics of human radiation-induced tumors is still of no relevance for everyday clinical practice. Although radiotherapy is one of the most important modalities of oncological treatment, it should be judiciously used in cases where the benefits clearly outweigh the risk of serious untoward effects. In the case of patients undergoing pelvic irradiation, careful follow-up is needed for years.

Radiotherapy and surgery are the two main pillars of the locoregional treatment of cancer. The risk of second malignancy is better evaluated and constitutes a major issue regarding radioprotection of the patients. Among malignant disease observed in the surviving irradiated patients, the occurrence of sarcoma is a rare event but associated with a poor outcome since the 5 year overall survival is estimated at 10 to 35 %. The SARI protocol, written in 2011, included 120 patients and 240 controlled patients, irradiated in the same conditions but without sarcoma observed during the follow up. The main objective was to identify the clinical and biological factors associated with the occurrence of such a complication. The secondary objective was to identify the dosimetric characteristics of the treatment of the primary. Preliminary results will be presented during the 2016 meeting of the French radiation oncology society., (Copyright © 2016 Société française de radiothérapie oncologique (SFRO). Published by Elsevier SAS. All rights reserved.)

The authors herein summarize six presentations dedicated to the key session "molecular radiation epidemiology" of the ConRad meeting 2015. These presentations were chosen in order to highlight the promise when combining conventional radiation epidemiology with molecular biology. Conventional radiation epidemiology uses dose estimates for risk predictions on health. However, combined with molecular biology, dose-dependent bioindicators of effect hold the promise to improve clinical diagnostics and to provide target molecules for potential therapeutic intervention. One out of the six presentations exemplified the use of radiation-induced molecular changes as biomarkers of exposure by measuring stabile chromosomal translocations. The remaining five presentations focused on molecular changes used as bioindicators of the effect. These bioindicators of the effect could be used for diagnostic purposes on colon cancers (genomic instability), thyroid cancer (CLIP2), or head and neck squamous cell cancers. Therapeutic implications of gene expression changes were examined in Chernobyl thyroid cancer victims and Mayak workers.

Radiation-induced sarcoma (RIS) is a rare complication following therapeutic external irradiation for lung cancer patients. Patients with RIS may develop recurrence or metastasis of the previous disease and also at high risk for early chest wall complications following operation, which requires close follow-up and multidisciplinary approach. We present a challenging case of RIS with a multidisciplinary teamwork in the decision-making and successful management., Competing Interests: Dr. D’Amico is a consultant for Scanlan International. All the other authors have declared no competing interest.