Megakaryocyte-specific knockout of the Mir-99b/let7e/125a cluster lowers platelet count without altering platelet function.

The purpose of this research was to assess the effects of a microRNA (miRNA) cluster on platelet production. Human chromosome 19q13.41 harbors an evolutionarily conserved cluster of three miRNA genes (MIR99B, MIRLET7E, MIR125A) within 727 base-pairs. We now report that levels of miR-99b-5p, miR-let7e-5p and miR-125a-5p are strongly correlated in human platelets, and all are positively associated with platelet count, but not white blood count or hemoglobin level. Although the cluster regulates hematopoietic stem cell proliferation, the function of this genomic locus in megakaryocyte (MK) differentiation and platelet production is unknown. Furthermore, studies of individual miRNAs do not represent broader effects in the context of a cluster. To address this possibility, MK/platelet lineage-specific Mir-99b/let7e/125a knockout mice were generated. Compared to wild type littermates, cluster knockout mice had significantly lower platelet counts and reduced MK proplatelet formation, but no differences in MK numbers, ploidy, maturation or ultra-structural morphology, and no differences in platelet function. Compared to wild type littermates, knockout mice showed similar survival after pulmonary embolism. The major conclusions are that the effect of the Mir-99b/let7e/125a cluster is confined to a late stage of thrombopoiesis, and this effect on platelet number is uncoupled from platelet function.

CRISPR-edited megakaryocytes for rapid screening of platelet gene functions.

Human anucleate platelets cannot be directly modified using traditional genetic approaches. Instead, studies of platelet gene function depend on alternative models. Megakaryocytes (the nucleated precursor to platelets) are the nearest cell to platelets in origin, structure, and function. However, achieving consistent genetic modifications in primary megakaryocytes has been challenging, and the functional effects of induced gene deletions on human megakaryocytes for even well-characterized platelet genes (eg, ITGA2B) are unknown. Here we present a rapid and systematic approach to screen genes for platelet functions in CD34+ cell-derived megakaryocytes called CRIMSON (CRISPR-edited megakaryocytes for rapid screening of platelet gene functions). By using CRISPR/Cas9, we achieved efficient nonviral gene editing of a panel of platelet genes in megakaryocytes without compromising megakaryopoiesis. Gene editing induced loss of protein in up to 95% of cells for platelet function genes GP6, RASGRP2, and ITGA2B; for the immune receptor component B2M; and for COMMD7, which was previously associated with cardiovascular disease and platelet function. Gene deletions affected several select responses to platelet agonists in megakaryocytes in a manner largely consistent with those expected for platelets. Deletion of B2M did not significantly affect platelet-like responses, whereas deletion of ITGA2B abolished agonist-induced integrin activation and spreading on fibrinogen without affecting the translocation of P-selectin. Deletion of GP6 abrogated responses to collagen receptor agonists but not thrombin. Deletion of RASGRP2 impaired functional responses to adenosine 5'-diphosphate (ADP), thrombin, and collagen receptor agonists. Deletion of COMMD7 significantly impaired multiple responses to platelet agonists. Together, our data recommend CRIMSON for rapid evaluation of platelet gene phenotype associations.

Difficulty in distinguishing radiation-induced prostate sarcoma from radiation mucositis in a patient with persistent urinary retention and hematuria after prostate cancer radiotherapy.

Urinary retention and hematuria owing to radiation-induced mucositis are occasional late adverse events in patients with prostate cancer. Moreover, radiation-induced secondary malignancies are late adverse events, although they are extremely rare. Herein, we describe a case of radiation-induced secondary malignancy of the prostate that was initially difficult to distinguish from radiation mucositis. A 74-year-old man with prostate cancer underwent brachytherapy and external beam radiotherapy 9 years ago. Twenty-eight months after irradiation, he presented with urinary retention and hematuria owing to radiation mucositis and underwent transurethral resection of the prostate. At 89 months after irradiation, the patient again showed urinary retention and hematuria. The cause of urinary retention and hematuria could not be identified on cystoscopy. Despite receiving medications, the patient's symptoms did not improve. Therefore, transurethral fulguration was performed, and prostate biopsy revealed spindle cell sarcoma. A diagnosis of radiation-induced undifferentiated pleomorphic/spindle cell sarcoma was made, and the patient underwent total cystectomy and construction of the ileal conduit. Two weeks after the surgery, computed tomography revealed peritoneal dissemination. The patient died 5 weeks after the surgery. The case findings indicate that clinicians should consider the possibility of radiation-induced secondary malignancy; moreover, thorough pathological examination of the prostate with CT and MRI is important to distinguish RISM from radiation mucositis even if no tumors are found on cystoscopy.

Organ-preserving approach via radiotherapy for small cell carcinoma of the bladder: an analysis based on the Japanese Radiation Oncology Study Group (JROSG) survey.

Small cell carcinoma of the bladder is extremely rare, accounting for <1% of all malignant tumours in the urinary tract. Thus, no standard therapy modality for this malignancy has been established. This study aimed to retrospectively analyse the clinical outcomes associated with definitive radiotherapy for small cell carcinoma of the bladder. A questionnaire-based survey of patients with pathologically proven small cell carcinoma of the bladder treated with definitive radiation therapy between 1990 and 2010 was conducted by the Japanese Radiation Oncology Study Group. The clinical records of 12 eligible patients were collected from nine institutions. The median age of the patients was 70.5 years (range: 44-87 years), and the median follow-up period was 27.3 months (range: 3.3-117.8 months). The median prescribed dose was 60 Gy (range: 50.0-61.0 Gy), and a median of 2.0 Gy (range: 1.2-2.0 Gy) was administered per fraction. Systemic chemotherapy combined with radiotherapy was performed in eight cases (66.7%). The 3- and 5-year overall survival rates were 50.0% and 33.3%, respectively. And the 3- and 5-year local control rates were 66.7% and 55.6%, respectively. Chemotherapy significantly improved overall survival and relapse-free survival (P = 0.006 and 0.001, respectively). No serious adverse events occurred in the observation period. All patients who achieved local control maintained functional bladders. In conclusion, radiotherapy is a potential local treatment option and has an important role in maintaining quality of life. Systemic chemotherapy combined with local radiotherapy seems to be effective in improving survival.

Human megakaryocytes possess intrinsic antiviral immunity through regulated induction of IFITM3.

Evolving evidence indicates that platelets and megakaryocytes (MKs) have unexpected activities in inflammation and infection; whether viral infections upregulate biologically active, antiviral immune genes in platelets and MKs is unknown, however. We examined antiviral immune genes in these cells in dengue and influenza infections, viruses that are global public health threats. Using complementary biochemical, pharmacological, and genetic approaches, we examined the regulation and function of interferon-induced transmembrane protein 3 (IFITM3), an antiviral immune effector gene not previously studied in human platelets and MKs. IFITM3 was markedly upregulated in platelets isolated from patients during clinical influenza and dengue virus (DENV) infections. Lower IFITM3 expression in platelets correlated with increased illness severity and mortality in patients. Administering a live, attenuated DENV vaccine to healthy subjects significantly increased platelet IFITM3 expression. Infecting human MKs with DENV selectively increased type I interferons and IFITM3. Overexpression of IFITM3 in MKs was sufficient to prevent DENV infection. In naturally occurring, genetic loss-of-function studies, MKs from healthy subjects harboring a homozygous mutation in IFITM3 (rs12252-C, a common single-nucleotide polymorphism in areas of the world where DENV is endemic) were significantly more susceptible to DENV infection. DENV-induced MK secretion of interferons prevented infection of bystander MKs and hematopoietic stem cells. Thus, viral infections upregulate IFITM3 in human platelets and MKs, and IFITM3 expression is associated with adverse clinical outcomes. These observations establish, for the first time, that human MKs possess antiviral functions, preventing DENV infection of MKs and hematopoietic stem cells after local immune signaling.

Alteration of PD-L1 expression and its prognostic impact after concurrent chemoradiation therapy in non-small cell lung cancer patients.

Concurrent chemoradiation therapy (CCRT) is the treatment of choice for locally advanced non-small cell lung cancer (LA-NSCLC). Several clinical trials that combine programmed cell death 1 (PD-1) axis inhibitors with radiotherapy are in development for patients with LA-NSCLC. However, the effect of CCRT on programmed cell death ligand-1 (PD-L1) expression on tumor cells is unknown. In this study, we analysed paired NSCLC specimens that had been obtained pre- and post-CCRT. PD-L1 expression on tumor cells was studied by immunohistochemistry. A total of 45 patients with LA-NSCLC were included, among which there were sufficient pre- and post-CCRT specimens in 35 patients. Overall, the percentage of tumor cells with PD-L1 expression significantly decreased between pre- and post-CCRT specimens (P = 0.024). Sixteen, 15, and 4 patients had decreased, unchanged, or increased PD-L1 expression after CCRT, respectively. Median OS of patients with decreased, unchanged, or increased PD-L1 expression was 85.1, 92.8, and 14.6 months, respectively (P < 0.001). In conclusion, the percentage of PD-L1-positive tumor cells significantly decreased after CCRT. Alteration of PD-L1 expression after neoadjuvant CCRT was associated with prognosis in patients with LA-NSCLC. These data should be considered when developing the optimal approach of integrating PD-1 axis inhibitors with CCRT.

Prevalence of hypothyroidism among patients with breast cancer treated with radiation to the supraclavicular field: a single-centre survey.

PURPOSE: We investigated the prevalence of hypothyroidism (HT) in patients with breast cancer who received radiation therapy to the supraclavicular (SC) field to evaluate the effect of radiation on thyroid. METHODS: Between April 2007 and May 2016, consecutive patients with invasive breast cancer who received SC radiation were recruited. Thyroid-stimulating hormone (TSH) and free thyroxine (fT4) were measured between April and August 2016. On the basis of the radiation-planning CT images, thyroid volume was calculated and dose-volume parameters were estimated. The endpoints were the prevalence of HT as determined by high levels of TSH and low levels of fT4 in serum, and the prevalence of subclinical HT, determined by high-serum TSH and normal fT4. RESULTS: Among the 68 consecutive patients, 26 were excluded from evaluation (10 patients died, 6 had a history of previous thyroid disease and 10 were lost to follow-up). One (2.4%) and six (14.3%) of these patients had HT and subclinical HT, respectively, with a mean TSH level of 8.27 µU/mL. By univariate analysis, a predictive factor of HT and subclinical HT was a thyroid volume <8 cm3 (OR 6.44, 95% CI 1.14 to 36.6; p=0.043). Multivariate analysis also showed an association between thyroid volume <8 cm3 and HT or subclinical HT (OR 18.48, 95% CI 1.48 to 230.86; p=0.024). CONCLUSIONS: The prevalence of HT in patients with breast cancer studied was relatively low. Although thyroid volume appeared to be a predictive marker of HT in this cohort, further prospective evaluation is needed.

Modifying the planning target volume to optimize the dose distribution in dynamic conformal arc therapy for large metastatic brain tumors.

PURPOSE: When treating large metastatic brain tumors with stereotactic radiotherapy (SRT), high dose conformity to target is difficult to achieve. Employing a modified planning target volume (mPTV) instead of the original PTV may be one way to improve the dose distribution in linear accelerator-based SRT using a dynamic conformal technique. In this study, we quantitatively analyzed the impact of a mPTV on dose distribution. MATERIALS AND METHODS: Twenty-four tumors with a maximum diameter of >2 cm were collected. For each tumor, two plans were created: one used a mPTV and the other did not. The mPTV was produced by shrinking or enlarging the original PTV according to the dose distribution in the original plan. The dose conformity was evaluated and compared between the plans using a two-sided paired t test. RESULTS: The conformity index defined by the Radiation Therapy Oncology Group was 1.34 ± 0.10 and 1.41 ± 0.13, and Paddick's conformity index was 0.75 ± 0.05 and 0.71 ± 0.06, for the plans with and without a mPTV, respectively. All of these improvements were statistically significant (P < 0.05). CONCLUSION: The use of a mPTV can improve target conformity when planning SRT for large metastatic brain tumors.

Treatment of malignant melanoma with nivolumab and vemurafenib combined with hypofractionated radiation therapy.

Management of metastatic malignant melanoma is challenging. Although several new systemic therapies for metastatic malignant melanoma have recently been developed, some patients still also require radiation therapy (RT) for palliative care. However, the safety and efficacy of combining use of novel drugs with RT remain unclear. Here, we report treating a patient with rapidly growing malignant melanoma with a programmed cell death protein 1 (PD-1) inhibitor and a BRAF inhibitor together with 60 Gy of hypofractionated RT without severe adverse effects. The tumor within the radiation field exhibited a more marked response than that outside it. A combination of RT with an anti-PD-1 antibody or a BRAF inhibitor may, therefore, be a useful and tolerable approach to treating metastatic BRAF-mutant melanoma.

Postoperative External Irradiation of Patients with Primary Biliary Tract Cancer: A Multicenter Retrospective Study.

BACKGROUND/AIM: The aim of the present study was to assess clinical outcomes of postoperative radiotherapy for biliary tract cancer patients. PATIENTS AND METHODS: Clinical results of 187 patients treated with external irradiation in 31 Japanese Institutions between 2000 and 2011 were retrospectively analyzed. The median radiation dose was 50.4 Gy in fractions of 1.8-2 Gy. RESULTS: Two-year actuarial overall survival and locoregional control (LCs) rates were 56% and 68%, respectively. In multivariate analysis, macroscopic residual tumor (R2) and irradiated doses <54 Gy were significant indicators of poor LC prognosis. For patients with complete resection (R0) or microscopic residual tumor (R1), 2-year LCs were 71% for <54 Gy and 83% for ≥54 Gy; doses ≥54 Gy were associated with high long-term LCs. There was no significant difference in acute adverse event rates between <54 Gy and ≥54 Gy. CONCLUSION: Postoperative irradiation doses of approximately 54 Gy are safe and effective for R0 or R1 resection patients.

Mixed large cell neuroendocrine carcinoma and mucosa-associated lymphoid tissue lymphoma of the lung: A case report.

In the present study, a 79-year-old male was referred to Kobe City Medical Center General Hospital due to an abnormal shadow that was revealed on a chest X-ray. The patient possessed a five-year history of consolidation in the right lower lobe, which was diagnosed as chronic aspiration pneumonia and followed up. However, the abnormal shadow adjacent to the pleura gradually increased in size and a novel mass appeared in the right lower lobe that rapidly increased in size. A repeat biopsy revealed a combination of large cell neuroendocrine carcinoma with a clinical tumor-node-metastasis (cTNM) stage of cT2bN2M0 (stage 3A) and mucosa-associated lymphoid tissue lymphoma at Ann Arbor stage 1E. Chemoradiotherapy markedly affected the lesion and the size of the mass was significantly reduced subsequent to four cycles of chemotherapy, which was considered to be a near complete response. The present study reports an extremely rare combination of tumors. The disease course was followed over a period of six years, which included the onset of disease, and the present case may therefore be valuable in clarifying the mechanism of lung cancer development.

Stereotactic Body Radiotherapy for Synchronous Primary Lung Cancer: Clinical Outcome of 18 Cases.

BACKGROUND: Previous reports have shown that curative surgical approaches for synchronous primary lung cancer (SPLC) yielded excellent treatment outcomes. However, patients with SPLC are often unsuitable for such surgery as a result of poor general condition or other medical comorbidities. The effectiveness and feasibility of stereotactic body radiotherapy (SBRT) as a definitive treatment for SPLC are not well understood. PATIENTS AND METHODS: We retrospectively reviewed the records of the patients who received lung SBRT between July 2007 and December 2012 at our institution and identified patients with SPLC. The clinical outcome was analyzed for each patient. The first progression site was classified as local, regional, distant, or new primary lung cancer. RESULTS: A total of 18 patients were eligible. Fifteen patients received SBRT for both lesions, and 3 patients received surgery for one tumor and SBRT for the other. The median follow-up time was 34.3 months (range, 12.2-64.7 months). The median overall and progression-free survival was 45.6 months (95% confidence interval [CI] 21.0-60.6) and 25.3 months (95% CI, 13.1-50.6 months), respectively. The 3-year overall survival and progression-free survival rates were 69.1% (95% CI, 40.7-85.9) and 43.2% (95% CI, 20.2-64.4), respectively. Eleven patients (61%) experienced disease progression. The first progression site was local in 4 (22%), regional in 5 (28%), distant in 3 (17%), and new primary lung cancer in 2 patients (11%). Grade 3 radiation pneumonitis was observed in 2 patients (11%). CONCLUSION: SBRT for SPLC is a highly effective local treatment with limited toxicity, although the progression rate seems relatively high.

Impact of intraluminal brachytherapy on survival outcome for radiation therapy for unresectable biliary tract cancer: a propensity-score matched-pair analysis.

PURPOSE: To determine whether adding intraluminal brachytherapy (ILBT) to definitive radiation therapy (RT) for unresectable biliary tract cancer has a positive impact on survival outcome. METHODS AND MATERIALS: The original cohort comprised 209 patients, including 153 who underwent external beam RT (EBRT) alone and 56 who received both ILBT and EBRT. By matching propensity scores, 56 pairs (112 patients) consisting of 1 patient with and 1 patient without ILBT were selected. They were well balanced in terms of sex, age, performance status, clinical stage, jaundice, and addition of chemotherapy. The impact of ILBT on overall survival (OS), disease-specific survival (DSS), and local control (LC) was investigated. RESULTS: The 2-year OS rates were 31% for the ILBT+ group and 40% for theILBT- group (P=.862). The 2-year DSS rates were 42% for the ILBT+ group and 41% for the ILBT- group (P=.288). The 2-year LC rates were 65% for the ILBT+ group and 35% for the ILBT- group (P=.094). Three of the 4 sensitivity analyses showed a significantly better LC for the ILBT+ group (P=.010, .025, .049), and another showed a marginally better LC (P=.068), and none of the sensitivity analyses showed any statistically significant differences in OS or DSS. CONCLUSIONS: In the treatment for unresectable biliary tract cancer, the addition of ILBT to RT has no impact on OS or DSS but is associated with better LC. Therefore, the role of ILBT should be addressed by other measures than survival benefit, for example, by less toxicity, prolonged biliary tract patency decreasing the need for further palliative interventions, or patient quality of life.

14-3-3ε plays a role in cardiac ventricular compaction by regulating the cardiomyocyte cell cycle.

Trabecular myocardium accounts for the majority of the ventricles during early cardiogenesis, but compact myocardium is the primary component at later developmental stages. Elucidation of the genes regulating compact myocardium development is essential to increase our understanding of left ventricular noncompaction (LVNC), a cardiomyopathy characterized by increased ratios of trabecular to compact myocardium. 14-3-3ε is an adapter protein expressed in the lateral plate mesoderm, but its in vivo cardiac functions remain to be defined. Here we show that 14-3-3ε is expressed in the developing mouse heart as well as in cardiomyocytes. 14-3-3ε deletion did not appear to induce compensation by other 14-3-3 isoforms but led to ventricular noncompaction, with features similar to LVNC, resulting from a selective reduction in compact myocardium thickness. Abnormal compaction derived from a 50% decrease in cardiac proliferation as a result of a reduced number of cardiomyocytes in G(2)/M and the accumulation of cardiomyocytes in the G(0)/G(1) phase of the cell cycle. These defects originated from downregulation of cyclin E1 and upregulation of p27(Kip1), possibly through both transcriptional and posttranslational mechanisms. Our work shows that 14-3-3ε regulates cardiogenesis and growth of the compact ventricular myocardium by modulating the cardiomyocyte cell cycle via both cyclin E1 and p27(Kip1). These data are consistent with the long-held view that human LVNC may result from compaction arrest, and they implicate 14-3-3ε as a new candidate gene in congenital human cardiomyopathies.

Convergence of the insulin and serotonin programs in the pancreatic ß-cell.

OBJECTIVE: Despite their origins in different germ layers, pancreatic islet cells share many common developmental features with neurons, especially serotonin-producing neurons in the hindbrain. Therefore, we tested whether these developmental parallels have functional consequences. RESEARCH DESIGN AND METHODS: We used transcriptional profiling, immunohistochemistry, DNA-binding analyses, and mouse genetic models to assess the expression and function of key serotonergic genes in the pancreas. RESULTS: We found that islet cells expressed the genes encoding all of the products necessary for synthesizing, packaging, and secreting serotonin, including both isoforms of the serotonin synthetic enzyme tryptophan hydroxylase and the archetypal serotonergic transcription factor Pet1. As in serotonergic neurons, Pet1 expression in islets required homeodomain transcription factor Nkx2.2 but not Nkx6.1. In ß-cells, Pet1 bound to the serotonergic genes but also to a conserved insulin gene regulatory element. Mice lacking Pet1 displayed reduced insulin production and secretion and impaired glucose tolerance. CONCLUSIONS: These studies demonstrate that a common transcriptional cascade drives the differentiation of ß-cells and serotonergic neurons and imparts the shared ability to produce serotonin. The interrelated biology of these two cell types has important implications for the pathology and treatment of diabetes.

Osteoradionecrosis of the cervical vertebrae in patients irradiated for head and neck cancers.

Osteoradionecrosis (ORN) is one of the common late adverse effects that follow radiation therapy for head and neck cancers. ORN usually develops on the mandible and less frequently on the maxilla. We present three cases of ORN of the cervical vertebrae, which is rarely reported. Two patients suffered from secondary osteomyelitis after neoadjuvant chemotherapy followed by definitive concurrent chemoradiation therapy with a hyperfractionated and an accelerated hyperfractionated regimen, respectively. For these patients, the high intensity of treatment was considered the cause of ORN. The third patient underwent concurrent chemoradiation therapy for upper thoracic esophageal cancer and subsequently underwent endoscopic laser resection and radiation therapy for hypopharyngeal cancer. ORN developed in the area of reirradiation. In this case, an excessive radiation dose was considered the cause. ORN of cervical vertebrae, different from that of the mandible and maxilla, has a risk of radiculopathy and myelopathy. In the future, ORN of cervical vertebrae will increase because metachronous double cancers will increase and opportunities for reirradiation, in turn, will increase. To prevent this, it is necessary to optimize the treatment schedule for radiation therapy, including the total dose, fractionation, and concurrent chemotherapy, and to decrease the volume of cervical vertebrae within the irradiation field.

The ETS oncogene family transcription factor FEV identifies serotonin-producing cells in normal and neoplastic small intestine.

Neuroendocrine (NE) or carcinoid tumors of the small intestine (SI) frequently metastasize and produce the hormone serotonin, causing significant morbidity and mortality. A member of the ETS oncogene family of transcription factors, Fev, acts with the homeodomain transcription factor Nkx2.2 in the development of serotonin neurons in mice. In this study, we investigated the role of Fev in normal and neoplastic SI. In NE tumors (NETs) of the SI, serotonin stimulates tumor growth and causes debilitating symptoms, such as diarrhea, flushing, wheezing, and right-sided valvular heart disease (i.e. carcinoid syndrome). Compared with those in the matched normal human SI, FEV expression levels were significantly elevated in primary NETs (20-fold, P<0.0001), lymph node metastases (35-fold, P=0.004), and NET liver metastases (22-fold, P<0.0001) resected from patients with serotonin excess. Fev is expressed in the wild type but not in Nkx2.2 (-/-) mouse SI, in which cells producing serotonin are absent. Using recombination-based cell lineage tracing, we found that FEV-positive cells give rise to serotonin-producing cells in the SI. In Fev (-/-) mouse SI, we observed no difference in the number of cells producing serotonin or other hormones. We conclude that FEV expression identifies serotonin-producing cells in normal and neoplastic SI and is a novel target for diagnosis of patients with NETs of the SI.

Feasibility of accelerated partial breast irradiation using three-dimensional conformal radiation therapy for Japanese women: a theoretical plan using six patients' CT data.

BACKGROUND: Several methods have been reported for accelerated partial breast irradiation (APBI), but in Japan, there are few facilities where brachytherapy or intra-operative radiotherapy is available. Japanese women have smaller physiques than American women in general. Thus, we developed external beam plans for APBI using computed tomography (CT) data of Japanese patients, to investigate whether APBI using three-dimensional conformal radiation therapy is safely applicable for Japanese women, while verifying the dose distributions. METHODS: We used CT data from six Japanese patients with early breast cancer, which were obtained in routine clinical practice during whole breast irradiation (WBI) after wide excision, and made 32 APBI plans according to the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-39 and the Radiation Therapy Oncology Group (RTOG) 0413 protocol, which compared APBI with WBI. We then investigated the compliance to the dose constraints of the protocol. RESULTS: None of 16 plans for the medial regions met the dose constraints regardless of laterality of the breast. The major reason was overdosage to the contralateral breast. Thirteen of 16 plans (81%) for the lateral regions met the dose constraints. The remaining three plans (19%) did not meet the dose limitation of the uninvolved normal breast, suggesting that a large ratio of the target to the breast was problematic. CONCLUSIONS: In Japanese women, patients with a laterally located small tumor can be candidates for APBI using three-dimensional conformal radiation therapy.

Avascular necrosis of bilateral femoral head as a result of long-term steroid administration for radiation pneumonitis after tangential irradiation of the breast.

We report a patient with avascular necrosis of the bilateral femoral head resulting from long-term steroid administration for radiation pneumonitis that occurred after tangential irradiation of the breast. The patient was a 50-year-old postmenopausal woman with breast cancer, stage IIIB (T4bN0M0) in the right C area. Following wide excision of right breast carcinoma and level III axillary lymph node dissection, whole-breast X-ray irradiation was given, at a dose of 2 Gy per fraction; the total dose was 50 Gy. On day 84 after the initiation of radiation therapy, she developed radiation pneumonitis. As the lung shadow expanded to the contralateral lung, she received steroid medication. Despite the steroid medication, the symptoms were exacerbated; therefore, she underwent steroid pulse administration with subsequent oral steroid medication. She improved immediately, but subsequently the radiation pneumonitis relapsed three times when the steroid medication was stopped. The period of medication was 423 days and the cumulative amount of steroids was 7365 mg before complete resolution occurred. In the 19 months after she stopped the steroid administration, she developed avascular necrosis (AVN) of the bilateral femoral head. This was regarded as a complication of the steroid treatment. Patients treated with long-term or high-dose steroid administration have been suggested to be at great risk of developing AVN, but this hypothesis remains controversial. The probability of AVN occurrence may be very small, but it should be considered as one of the complications of steroids, which are often used to treat radiation pneumonitis.