Mutation of NIMA-related kinase 1 (NEK1) leads to chromosome instability.

BACKGROUND: NEK1, the first mammalian ortholog of the fungal protein kinase never-in-mitosis A (NIMA), is involved early in the DNA damage sensing/repair pathway. A defect in DNA repair in NEK1-deficient cells is suggested by persistence of DNA double strand breaks after low dose ionizing radiation (IR). NEK1-deficient cells also fail to activate the checkpoint kinases CHK1 and CHK2, and fail to arrest properly at G1/S or G2/M-phase checkpoints after DNA damage. RESULTS: We show here that NEK1-deficient cells suffer major errors in mitotic chromosome segregation and cytokinesis, and become aneuploid. These NEK1-deficient cells transform, acquire the ability to grow in anchorage-independent conditions, and form tumors when injected into syngeneic mice. Genomic instability is also manifest in NEK1 +/- mice, which late in life develop lymphomas with a much higher incidence than wild type littermates. CONCLUSION: NEK1 is required for the maintenance of genome stability by acting at multiple junctures, including control of chromosome stability.

Radiation oncology resident education in palliative care.

Palliative and supportive care education for radiation oncologists in training is essential to deliver comprehensive care to patients. Surveys on palliative care education among radiation oncology program directors and residents demonstrate a disparity in formal teaching and didactics. Integration of formal didactics, communications skills programs, and teaching modules are being piloted at academic centers. A dedicated palliative radiation oncology service has been implemented and the experience evaluated. Future directions to improve resident education in palliative care include improving access and time dedicated to formal didactics, online and interactive modules, rotation in a palliative care service, emphasis on board examinations, and consideration of an advanced palliative care fellowship for radiation oncologists. This is the first review of the available literature reviewing formal palliative education in radiation oncology training programs in the United States.

A targeted needs assessment to improve referral patterns for palliative radiation therapy.

Radiation therapy (RT) can effectively palliate a variety of symptoms in patients with metastatic cancer, using relatively low doses that infrequently cause major side effects. However, palliative radiation is often underutilized and sub-optimally implemented. In this study, we surveyed the Society of Palliative Radiation Oncology (SPRO) membership to identify barriers to appropriate referral for palliative RT that they encounter in their practice, and identify specific groups of physicians who radiation oncologists believed would benefit most from further education on when to refer patients. A total of 28 radiation oncologists responded to the survey with a response rate of 20.5%. On average, participants felt that referrals for palliative RT were inappropriately delayed 46.5% [standard deviation (STD) 20.2%] of the time. The most common barrier to referral for medical oncologists was thought to be potential interference with systemic therapy (33%); for primary care physicians and surgeons it was a lack of knowledge about the benefit (42%), and for palliative care physicians it was concern for patient convenience (25%). For brain metastases and spinal cord compression radiation oncology was felt to be part of the initial referral sequence more than 50% of the time, but less so for thoracic airway obstruction/bleeding (38%), esophageal obstruction (16%), or urinary obstruction/bleeding (8%), where another subspecialist was more often consulted first. Primary care, geriatric medicine, and emergency medicine were considered among the least knowledgeable specialties about palliative radiation. These hypothesis-generating findings can guide approaches to improve referral patterns for this important aspect of supportive care.

Palliative radiotherapy for skin malignancies.

Palliative radiotherapy (PRT) improves patient quality of life (QoL) through alleviating cancer-associated symptoms such as pain, bleeding, and ulceration. Palliative management of patients with skin malignancies requires consideration of cosmetic and psychosocial outcomes as QoL measures. In this review, we highlight the current literature and advances in the use of PRT for patients with the three most commonly encountered forms of skin malignancies: basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and melanoma. The disease course and sensitivity to radiation varies, thus dictating the palliative goal and scheduling for PRT.

Attitudes of radiation oncologists toward palliative and supportive care in the United States: Report on national membership survey by the American Society for Radiation Oncology (ASTRO).

PURPOSE: Radiation oncologists are frequently involved in providing palliative and supportive care (PSC) for patients with advanced cancers through delivery of palliative radiation. Whether they are confident in their ability to assess and initiate treatments for pain, nonpain, and psychosocial distress is unknown. The American Society for Radiation Oncology surveyed its practicing members in the United States on self-assessment of their primary PSC skills and access to continuing medical education on PSC. METHODS: We electronically surveyed 4093 practicing radiation oncologists in the United States. The survey consisted of 16-questions in 5 sections1: demographics,2 PSC training,3 domains of PSC,4 perceived barriers as a radiation oncologist to initiate advanced care planning, and5 discussion of prognosis. RESULTS: The survey was e-mailed to 4093 American Society for Radiation Oncology members, and 649 responses were received (response rate 16%). The majority (91%) of radiation oncologists surveyed believe PSC is an important competency for radiation oncologists. Most radiation oncologists reported that they are moderately confident in their ability to assess and manage pain and gastrointestinal symptoms, but less confident in their ability to manage anorexia, anxiety, and depression. Despite areas of decreased confidence, a large number (42%) of radiation oncologists do not receive any additional PSC education beyond their residency training. Lastly, a perceived fear of upsetting referring medical oncologists and lack of clinic time are concerns for radiation oncologists who may want to initiate goals of care/advance care planning discussions with patients and their families. CONCLUSION: Radiation oncologists are more confident in their ability to assess and manage pain than in their ability to manage depression, anxiety, anorexia, and fatigue. There is a need for increasing continuing medical educational efforts in PSC for practicing radiation oncologists, and strengthening PSC training in residency programs.

Palliative care and palliative radiation therapy education in radiation oncology: A survey of US radiation oncology program directors.

PURPOSE: The purpose of this study was to assess the state of palliative and supportive care (PSC) and palliative radiation therapy (RT) educational curricula in radiation oncology residency programs in the United States. METHODS AND MATERIALS: We surveyed 87 program directors of radiation oncology residency programs in the United States between September 2015 and November 2015. An electronic survey on PSC and palliative RT education during residency was sent to all program directors. The survey consisted of questions on (1) perceived relevance of PSC and palliative RT to radiation oncology training, (2) formal didactic sessions on domains of PSC and palliative RT, (3) effective teaching formats for PSC and palliative RT education, and (4) perceived barriers for integrating PSC and palliative RT into the residency curriculum. RESULTS: A total of 57 responses (63%) was received. Most program directors agreed or strongly agreed that PSC (93%) and palliative radiation therapy (99%) are important competencies for radiation oncology residents and fellows; however, only 67% of residency programs had formal educational activities in principles and practice of PSC. Most programs had 1 or more hours of formal didactics on management of pain (67%), management of neuropathic pain (65%), and management of nausea and vomiting (63%); however, only 35%, 33%, and 30% had dedicated lectures on initial management of fatigue, assessing role of spirituality, and discussing advance care directives, respectively. Last, 85% of programs reported having a formal curriculum on palliative RT. Programs were most likely to have education on palliative radiation to brain, bone, and spine, but less likely on visceral, or skin, metastasis. CONCLUSIONS: Residency program directors believe that PSC and palliative RT are important competencies for their trainees and support increasing education in these 2 educational domains. Many residency programs have structured curricula on PSC and palliative radiation education, but room for improvement exists in management of fatigue, assessing role of spirituality, and discussion regarding advance care planning.

Radiation dermatitis caused by a bolus effect from an abdominal compression device.

American Association of Physicists in Medicine (AAPM) Task Group 176 evaluated the dosimetric effects caused by couch tops and immobilization devices. The report analyzed the extensive physics-based literature on couch tops, stereotactic body radiation therapy (SBRT) frames, and body immobilization bags, while noting the scarcity of clinical reports of skin toxicity because of external devices. Here, we present a clinical case report of grade 1 abdominal skin toxicity owing to an abdominal compression device. We discuss the dosimetric implications of the utilized treatment plan as well as post hoc alternative plans and quantify differences in attenuation and skin dose/build-up between the device, a lower-density alternative device, and an open field. The description of the case includes a 66-year-old male with HER2 amplified poorly differentiated distal esophageal adenocarcinoma treated with neoadjuvant chemo-radiation and the use of an abdominal compression device. Radiation was delivered using volumetric modulated arc therapy (VMAT) with 2 arcs using abdominal compression and image guidance. The total dose was 50.4Gy delivered over 40 elapsed days. With 2 fractions remaining, the patient developed dermatitis in the area of the compression device. The original treatment plan did not include a contour of the device. Alternative post hoc treatment plans were generated, one to contour the device and a second with anterior avoidance. In conclusion, replanning with the device contoured revealed the bolus effect. The skin dose increased from 27 to 36Gy. planned target volume (PTV) coverage at 45Gy was reduced to 76.5% from 95.8%. The second VMAT treatment plan with an anterior avoidance sector and more oblique beam angles maintained PTV coverage and spared the anterior wall, however at the expense of substantially increased dose to lung. This case report provides an important reminder of the bolus effect from external devices such as abdominal compression. Special consideration must be given to contour and/or avoiding beam entrance to the device, and to the use of such devices in patients who may have heightened radiosensitivity, such as those who are human immunodeficiency virus (HIV)-positive.

Bone mineral density loss in thoracic and lumbar vertebrae following radiation for abdominal cancers.

PURPOSE: To investigate the relationship between abdominal chemoradiation (CRT) for locally advanced cancers and bone mineral density (BMD) reduction in the vertebral spine. MATERIALS AND METHODS: Data from 272 patients who underwent abdominal radiation therapy from January 1997 to May 2015 were retrospectively reviewed. Forty-two patients received computed tomography (CT) scans of the abdomen prior to initiation and at least twice after radiation therapy. Bone attenuation (in Hounsfield unit) (HU) measurements were collected for each vertebral level from T7 to L5 using sagittal CT images. Radiation point dose was obtained at each mid-vertebral body from the radiation treatment plan. Percent change in bone attenuation (Δ%HU) between baseline and post-radiation therapy were computed for each vertebral body. The Δ%HU was compared against radiation dose using Pearson's linear correlation. RESULTS: Abdominal radiotherapy caused significant reduction in vertebral BMD as measured by HU. Patients who received only chemotherapy did not show changes in their BMD in this study. The Δ%HU was significantly correlated with the radiation point dose to the vertebral body (R=-0.472, P<0.001) within 4-8 months following RT. The same relationship persisted in subsequent follow up scans 9 months following RT (R=-0.578, P<0.001). Based on the result of linear regression, 5 Gy, 15 Gy, 25 Gy, 35 Gy, and 45 Gy caused 21.7%, 31.1%, 40.5%, 49.9%, and 59.3% decrease in HU following RT, respectively. Our generalized linear model showed that pre-RT HU had a positive effect (ß=0.830) on determining post-RT HU, while number of months post RT (ß=-0.213) and radiation point dose (ß=-1.475) had a negative effect. A comparison of the predicted versus actual HU showed significant correlation (R=0.883, P<0.001) with the slope of the best linear fit=0.81. Our model's predicted HU were within ±20 HU of the actual value in 53% of cases, 70% of the predictions were within ±30 HU, 81% were within ±40 HU, and 90% were within ±50 HU of the actual post-RT HU. Four of 42 patients were found to have vertebral body compression fractures in the field of radiation. CONCLUSIONS: Patients who receive abdominal chemoradiation develop significant BMD loss in the thoracic and lumbar vertebrae. Treatment-related BMD loss may contribute to the development of vertebral compression fractures. A predictive model for post-CRT BMD changes may inform bone protective strategies in patients planned for abdominal CRT.

Salvage craniospinal irradiation with an intensity modulated radiotherapy technique for patients with disseminated neuraxis disease.

PURPOSE: To report the use and results of a novel intensity modulated radiotherapy (IMRT)-based technique used for salvage craniospinal irradiation (CSI) in 6 patients who developed neuraxis disease after initial high-dose conformal radiotherapy (RT) to the brain. METHODS AND MATERIALS: After Institutional Review Board approval, all patients treated for disseminated leptomeningeal disease with salvage CSI using IMRT with conventional external beam radiotherapy were identified. The medical records and radiotherapy dosimetry were reviewed. Tolerance, morbidity, tumor control, and overall survival were evaluated. RESULTS: Six patients who received IMRT-based salvage CSI were identified. The median age was 6.5 years (range 2- 34 years) at initial RT and 7.7 years (range, 3-35 years) at salvage CSI. Disease progression necessitating salvage CSI was noted at a median of 10 months (range, 1-26 months) from the initial RT. The original disease site remained well controlled in all 6 patients. The median dose of the initial RT treatment was 52 Gy (range, 30.6-60 Gy). Salvage CSI dose was 36 Gy in 20 fractions in all 6 patients. IMRT was used to treat the cranial contents excluding the previously treated area. Five pediatric patients received electron beams to spine and 1 adult patient received photon beams to spine. IMRT allowed a conformal and uniform dose distribution to the target tissue while excluding previously treated areas. Salvage CSI dose of 36 Gy, delivered using IMRT and 36 Gy using electrons or photons to the spine, proved effective in providing good control of the disease. CONCLUSIONS: This technique of salvage CSI was effective in this patient cohort for leptomeningeal dissemination occurring outside of an area of focal irradiation. The technique was well tolerated and thus far has not been associated with any significant toxicity. Salvage therapy has been effective in 4 of the 6 patients thus far.