Carbon-ion radiotherapy for inoperable upper tract ureteral cancer.

AIM: This study aimed to report initial results of hypofractionated carbon-ion radiotherapy (C-ion RT) for inoperable upper tract ureteral cancer. METHODS: Retrospective chart review was performed for five consecutive patients with medically inoperable ureter cancer that was treated with radical C-ion RT between December 2013 and December 2014. The median age of the patients was 80 years (range, 68-84 years). The reasons for inoperability were advanced age, post-contralateral nephrectomy, alcoholic cirrhosis, both advanced age and contralateral renal function degeneracy, and pneumonia. The median size of tumor was 2.8 cm (range, 2.2-4.0 cm). Diagnostic imaging did not identify lymph node metastases or distant metastases in any case. All patients underwent C-ion RT (52.8 Gy relative biological effectiveness; 12 fractions in 3 weeks). The clinical target volume encompassed the growth tumor volume with a 5-mm margin bilaterally; there was a 40-mm margin craniocaudally but the clinical target volume did not encompass the whole ureter. RESULTS: Within a median follow-up time of 32.9 months (range, 24-36 months), two patients died and three remained alive. Neither local recurrence nor regional lymph node metastases were observed. Secondary bladder tumor was observed in four patients, and one patient had a liver metastasis. Grade 1 hematuria was observed in two patients, and Grade 3 pyelonephritis was observed in one patient as acute toxicity. Ureteral obstruction was observed in two patients. CONCLUSION: C-ion RT might be a useful treatment option for inoperable ureter cancer.

Efficacy of immune checkpoint inhibitor treatment for head and neck mucosal melanoma recurrence in patients treated with carbon-ion radiotherapy.

BACKGROUND: Carbon-ion radiotherapy (C-ion RT) is effective for head and neck mucosal melanoma (HN-MM), including radioresistant mucosal melanoma. Melanoma also responds effectively to immune checkpoint inhibitors (ICIs). Data on the efficacy and safety of ICIs for HN-MM are insufficient. AIMS: To analyze the efficacy and safety of ICI salvage therapy in patients with HN-MM recurrence after C-ion RT. METHODS AND RESULTS: This retrospective study analyzed the medical records of 52 patients with HN-MM treated with C-ion RT between 2012 and 2020. A dose of 57.6 or 64.0 Gy (relative biological effectiveness) was provided in 16 fractions. The primary endpoint was 3-year overall survival (OS) rate. The median follow-up time was 26.8 months for all patients. A total of 29 patients had local recurrence or distant metastasis, and 16 patients who received ICI therapy. The 3-year OS rate in the ICI group (n = 16) and best supportive care group (n = 13) were 53.8% and 0.0%, respectively (p = 0.837); the difference was not statistically significant. There were no deaths after 1 year among patients who underwent ICI therapy. No adverse events associated with C-ion RT were related to or exacerbated by ICI. CONCLUSION: ICI salvage therapy is effective and safe for patients with HN-MM recurrence after C-ion RT.

A long-term survival case of histiocytic sarcoma by surgery alone in a Japanese elderly breast tumor patient.

INTRODUCTION: Histiocytic sarcoma (HS) is a rare hematologic malignancy. HS of the breast is extremely rare, and we present a case of an elderly patient with breast HS. CASE PRESENTATION: An 81-year-old woman with unremarkable past medical and family histories presented to our hospital with a palpable mass in her right upper breast. She had noticed a mass in her right breast 3 months before her first visit. Physical examination revealed a mass measuring approximately 30 mm in the right upper quadrant of the breast; there were no cervical or axillary lymphadenopathies. Mammography revealed a high-concentration mass with unclear margins in the upper and outer breast. Ultrasound and magnetic resonance imaging (MRI) revealed a 31 × 23-mm nodule with a relatively clear margin and necrotic sign on the T2-intensified image. A mastectomy was performed upon the patient's request, and the surgical specimen revealed a 35-mm hemorrhagic mass. The lesion was estrogen receptor-, progesterone receptor-, and HER2/neu-negative. The Ki-67 labeling index was approximately 30%. The immunohistochemical panel showed immune reactivity for the histiocytic markers CD68, CD163, and CD206 and was immune-negative for B lineage, T lineage, Langerhans cells, and keratins. The diagnosis of HS was based on the morphological and immunophenotypic characteristics of the mass. The patient received no systemic therapy and survived for 50 months without recurrence. CONCLUSIONS: Here, we report the case of an elderly patient with rare breast HS. Although the prognosis of HS seems poor, the breast HS was not as poor as expected, since it might have been discovered in the local region before it metastasized.

Palliative radiation therapy for bleeding from gastric cancer: A case series of seven patients.

The hemostatic effect of palliative radiation therapy (RT) for unresectable gastric cancer is unclear. We performed palliative RT (20 Gy in 5 fractions or 30 Gy in 10 fractions) in 7 consecutive patients with bleeding. The number of blood transfusions decreased significantly post-RT, supporting the hemostatic effect of palliative RT.

Successful surgical treatment of epithelioid hemangioendothelioma involving multiple liver lesions and bilateral lung nodules.

Epithelioid hemangioendothelioma (EHE) affects many organs, particularly lung and liver, and typically presents as multiple lesions. Treatment for EHE is not yet standardized, but surgery is appropriate when lesions are resectable. In our patient, radiography revealed multiple bilateral pulmonary nodules, and CT showed several liver tumors. The liver masses and those in the right lung were removed during the initial surgery; pathology of hepatic specimens confirmed the diagnosis of EHE. During the second operation, the left lung nodules were excised, and all were EHEs. Surgical removal of multiorgan multinodular EHE is a viable treatment option, especially for young patients.

Radiotherapy With Hydrogen Peroxide-Soaked Gauze for Preauricular Sebaceous Carcinoma.

Sebaceous carcinoma is a rare and aggressive malignant tumor deriving from the adnexal epithelium of the sebaceous glands. The case of inoperable preauricular sebaceous carcinoma treated with definitive radiotherapy is first reported herein. Radiotherapy of 60 Gy in 30 fractions was combined with a hydrogen peroxide-soaked gauze bolus aiming at potential radiosensitization. Macroscopic complete remission was achieved eight months after radiotherapy with tolerable adverse effects. Although further clinical studies are needed, radiotherapy with a hydrogen peroxide-soaked gauze bolus can be an effective and tolerable treatment for inoperable patients with extraocular sebaceous carcinoma.

Radiosensitization by the Selective Pan-FGFR Inhibitor LY2874455.

Ionizing radiation activates cytoprotective pathways in cancer cells. Fibroblast growth factor receptor (FGFR) is a key player in these pathways. Thus, FGFR signaling is a potential target to induce radiosensitization. LY2874455 is an orally administrable selective pan-FGFR inhibitor. However, the radiosensitizing effects of LY2874455 remain unclear. In this study, we addressed this issue by using radioresistant human cancer cell lines H1703 (FGFR1 mutant), A549 (FGFR1-4 wild-type), and H1299 (FGFR1-4 wild-type). At an X-ray dose corresponding to 50%-clonogenic survival as the endpoint, 100 nM LY2874455 increased the sensitivity of H1703, A549, and H1299 cells by 31%, 62%, and 53%, respectively. The combination of X-rays and LY2874455 led to a marked induction of mitotic catastrophe, a hallmark of radiation-induced cell death. Furthermore, combination treatment suppressed the growth of A549 xenografts to a significantly greater extent than either X-rays or the drug alone without noticeable toxicity. This is the first report to show the radiosensitizing effect of a selective pan-FGFR inhibitor. These data suggest the potential efficacy of LY2874455 as a radiosensitizer, warranting clinical validation.

Dosimetric analysis of intraocular hemorrhage in nonsquamous head and neck cancers treated with carbon-ion radiotherapy.

BACKGROUND AND PURPOSE: Carbon-ion radiotherapy is an attractive treatment option for unresectable/inoperable, nonsquamous cancers of the head and neck. Intraocular hemorrhage associated with carbon-ion radiotherapy for head and neck cancer is largely an unresearched area; hence, we investigated its incidence and predictive factors. MATERIAL AND METHODS: We evaluated 79 patients (i.e., 158 eyes) with nonsquamous cancers of the head and neck treated by carbon-ion radiotherapy with a follow-up period of ≥12 months. Dosimetric parameters such as Dmax, Dmean and Vd [volume irradiated with "d" Gy (RBE)] and age, gender, primary site, histology and comorbidities were analyzed as predictors of intraocular hemorrhage. RESULTS: Seven (8.9%) of 79 patients (158 eyes) developed intraocular hemorrhage with a median latent period of 24 months (range, 15-47 months). The 5-year cumulative incidence of intraocular hemorrhage was 6%. Dmax and V10-60 for eyeballs, retina and optic nerves were significantly higher in intraocular hemorrhage group than the rest (p <0.001 for Dmax and V10-60). On univariate analysis, V40 ≥0.83 cm3 and ≥0.66 cm3 (p = 0.001) and Dmax ≥54.75 Gy (RBE) and ≥54.58 Gy (RBE) (p = 0.002) for eyeball and retina, respectively, were predictors of intraocular hemorrhage. Additionally, maxillary primary (p = 0.025) and younger age (age <60 years, p = 0.048) were significant risk factors for intraocular hemorrhage. CONCLUSIONS: Dosimetric parameters such as V40 and Dmax for the eyeball, retina and maxillary sinus primary and younger age were significant predictors of intraocular hemorrhage following carbon-ion radiotherapy.

A retrospective study of small-pelvis radiotherapy plus image-guided brachytherapy in stage I-II non-bulky cervical squamous cell carcinoma.

We herein report a retrospective analysis of the efficacy of a combination therapy of pelvic irradiation that excluded the common iliac lymph nodes region and image-guided brachytherapy (IGBT) for non-bulky (≤4 cm) cervical cancer. Thirty-three patients with stage I-II cervical squamous cell carcinoma (≤4 cm) and without pelvic/para-aortic lymphadenopathy who were treated with definitive radiotherapy alone between February 2009 and September 2016 were included. The radiotherapy consisted of CT-based small-pelvis irradiation (whole pelvis minus common iliac lymph node area) of 20 Gy/10 fractions followed by pelvic irradiation with a midline block of 30 Gy/15 fractions and IGBT of 24 Gy/4 fractions (6 Gy/fraction for high-risk [HR] clinical target volume [CTV] D90%). In-room computed tomography (CT) imaging with applicator insertion was used for brachytherapy planning, with physical examinations and diagnostic magnetic resonance imaging (MRI) also being referred to for determination of HR CTV. Over a median follow-up of 60.5 months (range, 7-89), two patients developed distant recurrence and one developed local and distant recurrence. Two patients died from cervical cancer, one from hepatocellular carcinoma and one from non-cancerous disease. The 2/5-year local control (LC), progression-free survival (PFS) and overall survival (OS) rates were 100%/96.7%, 93.8%/90.6% and 93.9%/93.9%, respectively. No pelvic/para-aortic lymph node recurrence was observed. There were no late complications of grade 3 or higher in the small bowel, large bowel/rectum, or bladder. Our results suggest that a combination therapy of IGBT plus small-pelvis irradiation excluding common iliac lymph nodes provides reasonable clinical outcomes and can be a treatment option in non-bulky (≤4 cm) cervical squamous cell carcinoma.

Carbon-ion Radiotherapy for Inoperable Head and Neck Bone and Soft-tissue Sarcoma: Prospective Observational Study.

BACKGROUND/AIM: Bone and soft-tissue sarcomas of the head and neck have very poor prognoses. This prospective study aimed to investigate the efficacy and safety of carbon-ion radiotherapy (C-ion RT) for bone and soft-tissue sarcoma of the head and neck. PATIENTS AND METHODS: The present study was a prospective clinical study that included 10 consecutive patients diagnosed with bone and soft-tissue sarcoma of the head and neck who were treated with C-ion RT between 2012 and 2018 at our institution. C-Ion RT consisted of 70.4 Gy (relative biological effectiveness) in 16 fractions. RESULTS: The 3-year local control, overall survival, and progression-free survival rates for patients overall were 72.9%, 77.8%, and 36%, respectively. CONCLUSION: The present study demonstrated the efficacy of C-ion RT for bone and soft-tissue sarcoma of the head and neck; adverse events were within the expected range.

Relationship between oral mucositis and the oral bacterial count in patients with head and neck cancer undergoing carbon ion radiotherapy: A prospective study.

BACKGROUND AND PURPOSE: Acute adverse events, such as oral mucositis, can affect treatment success in patients undergoing head and neck radiotherapy. In this study, we aimed to identify the relationship between oral mucositis and oral bacterial counts during carbon ion radiotherapy (C-ion RT) in patients with head and neck cancer. MATERIALS AND METHODS: This prospective study included patients with head and neck tumors treated with C-ion RT between 2017 and 2019. C-ion RT consisted of treatment at 57.6, 64.0, or 70.4 Gy (relative biological effectiveness) in 16 fractions. Bacterial counts in the saliva and the back of the tongue were measured using a rapid oral bacteria quantification system. The relationship between the oral bacterial count and oral mucositis was subsequently analyzed. RESULTS: In total, 46 patients were included in the analysis. The bacterial count in the saliva gradually increased from the commencement of C-ion RT and peaked at 16 fractions. Bacterial counts at the back of the tongue were already high at the beginning of C-ion RT; however, they decreased with continued treatment, peaked at 16 fractions, and subsequently decreased again. Patients with bacterial counts exceeding the mean before C-ion RT (high-count group) did not experience more severe mucositis than those with counts below the mean (low-count group). However, patients in the high-count group tended to experience faster-onset mucositis and slower healing than those in the low-count group. CONCLUSION: Bacterial counts may aid in the development of clinical strategies for C-ion RT-induced oral mucositis.

Radiotherapy With Hydrogen Peroxide-Soaked Gauze for Unresectable Breast Cancer.

A hydrogen peroxide (H2O2)-soaked gauze has been used in combination with radiotherapy in anticipation of sensitizing tumors exposed to the skin surface. Although used empirically in the clinic, the method is rarely reported in the literature, making its efficacy and tolerability unclear. Here, we report a case of primary metastatic breast cancer whose primary tumor was treated with palliative radiotherapy using an H2O2-soaked gauze. The primary tumor in the right breast regrew after treatment with palbociclib plus letrozole followed by fulvestrant and denosumab. The tumor was exposed to the skin surface, causing exudation, bleeding, pain, and difficulty in raising the right upper limb. Radiotherapy (51 Gy in 17 fractions) using the H2O2-soaked gauze resolved the patient's symptoms and the tumor showed macroscopic complete remission at three months post-treatment. This case indicates that radiotherapy with an H2O2-soaked gauze is an effective and tolerable palliative treatment for superficially exposed tumors. This non-invasive and inexpensive method of radiosensitization warrants validation and optimization in a prospective setting.

Myocardial ultrastructure can augment genetic testing for sporadic dilated cardiomyopathy with initial heart failure.

AIMS: The aim of the present study was to consider whether the ultrastructural features of cardiomyocytes in dilated cardiomyopathy can be used to guide genetic testing. METHODS AND RESULTS: Endomyocardial biopsy and whole-exome sequencing were performed in 32 consecutive sporadic dilated cardiomyopathy patients [51.0 (40.0-64.0) years, 75% men] in initial phases of decompensated heart failure. The predicted pathogenicity of ultrarare (minor allele frequency ≤0.0005), non-synonymous variants was determined using the American College of Medical Genetics guidelines. Focusing on 75 cardiomyopathy-susceptibility and 41 arrhythmia-susceptibility genes, we identified 404 gene variants, of which 15 were considered pathogenic or likely pathogenic in 14 patients (44% of 32). There were five sarcomeric gene variants (29% of 17 variants) found in five patients (16% of 32), involving a variant of MYBPC3 and four variants of TTN. A patient with an MYBPC3 variant showed disorganized sarcomeres, three patients with TTN variants located in the region encoding the A-band domain showed sparse sarcomeres, and a patient with a TTN variant in encoding the I-band domain showed disrupted sarcomeres. The distribution of diffuse myofilament lysis depended on the causal genes; three patients with the same TMEM43 variant had diffuse myofilament lysis near nuclei (P = 0.011), while two patients with different DSP variants had lysis in the peripheral areas of cardiomyocytes (P = 0.033). CONCLUSIONS: Derangement patterns of myofilament and subcellular distribution of myofilament lysis might implicate causal genes. Large-scale studies are required to confirm whether these ultrastructural findings are related to the causative genes.

Colorectal Cancer Screening Outcomes of 2412 Prostate Cancer Patients Considered for Carbon Ion Radiotherapy.

Colorectal cancer (CRC) screening is effective for detecting cancer in average-risk adults. For prostate cancer (PCa) patients considered for carbon ion radiotherapy (CIRT), pre-treatment CRC screening is performed empirically to avoid post-treatment colonoscopic manipulation. However, the outcomes of screening this population remain unclear. Here, we compared the outcomes of routine pre-CIRT CRC screening of 2412 PCa patients at average risk for CRC with data from two published datasets: the Japan National Cancer Registry (JNCR) and a series of 17 large-scale screening studies analyzing average-risk adults. The estimated prevalence rate was calculated using the pooled sensitivity elucidated by a previous meta-analysis. Consequently, 28 patients (1.16%) were diagnosed with CRC. CRC morbidity was significantly associated with high pre-treatment levels of prostate-specific antigen (p = 0.023). The screening positivity rate in this study cohort exceeded the annual incidence reported in the JNCR for most age brackets. Furthermore, the estimated prevalence rate in this study cohort (1.46%) exceeded that reported in all 17 large-scale studies, making the result an outlier (p = 0.005). These data indicate the possibility that the prevalence of CRC in PCa patients is greater than that in general average-risk adults, warranting further research in a prospective setting.

Clinical features and dosimetric evaluation of carbon ion radiation-induced osteoradionecrosis of mandible in head and neck tumors.

BACKGROUND AND PURPOSE: Osteoradionecrosis (ORN) affects the patient's quality of life by making eating and maintaining oral hygiene painful. This study aimed to analyze carbon ion radiotherapy (C-ion RT)-induced ORN of the mandible. MATERIALS AND METHODS: A retrospective study of 199 patients with head and neck tumors treated with C-ion RT was performed from 2010 to 2019. Only 11 patients with tumors located in the oropharynx and floor of the mouth were analyzed. C-ion RT consisted of 57.6 Gy or 64.0 Gy (relative biological effectiveness) in 16 fractions. The mandible was analyzed for magnetic resonance imaging (MRI) changes and bone exposure. The relationship between the radiation dose and ORN of the mandible was analyzed. RESULTS: Five patients (45.5%) had ORN of the mandible. The median follow-up time was 68 months. The median onset times based on MRI changes and bone exposure were 9 and 15 months, respectively. Doses of 30 Gy (relative biological effectiveness) to the mandible and teeth showed the most significant effect, causing ORN at 29.5 ± 6.7 cc and 3.9 ± 1.8 cc, respectively, with cut-off values at 16.5 cc (p = 0.002) and 1.8 cc (p = 0.0059), respectively. CONCLUSION: This is the first study reporting the incidence, onset time, and risk-predictive dosimetry parameters of C-ion RT-induced ORN of the mandible. Our study will be useful for establishing clinical strategies for C-ion RT to the head and neck near the mandible.

Unresectable cutaneous metastatic tumor in the arm that underwent complete remission after radiotherapy.

Cutaneous metastasis of solid malignancies can cause severe disfigurement, which reduces quality of life (QOL). This case indicates potential utility of photon radiotherapy for this disease, leading to recovery of QOL.

Decreased MYC-associated factor X (MAX) expression is a new potential biomarker for adverse prognosis in anaplastic large cell lymphoma.

MYC-associated factor X (MAX) is a protein in the basic helix-loop-helix leucine zipper family, which is ubiquitously and constitutively expressed in various normal tissues and tumors. MAX protein mediates various cellular functions such as proliferation, differentiation, and apoptosis through the MYC-MAX protein complex. Recently, it has been reported that MYC regulates the proliferation of anaplastic large cell lymphoma. However, the expression and function of MAX in anaplastic large cell lymphoma remain to be elucidated. We herein investigated MAX expression in anaplastic large cell lymphoma (ALCL) and peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) and found 11 of 37 patients (30%) with ALCL lacked MAX expression, whereas 15 of 15 patients (100%) with PTCL-NOS expressed MAX protein. ALCL patients lacking MAX expression had a significantly inferior prognosis compared with patients having MAX expression. Moreover, patients without MAX expression significantly had histological non-common variants, which were mainly detected in aggressive ALCL cases. Immunohistochemical analysis showed that MAX expression was related to the expression of MYC and cytotoxic molecules. These findings demonstrate that lack of MAX expression is a potential poor prognostic biomarker in ALCL and a candidate marker for differential diagnosis of ALCL and PTCL-NOS.

Whole-bladder Radiation Therapy for Lymph Node-negative Bladder Cancer With Muscle Invasion in Elderly Patients.

BACKGROUND: The Japanese bladder cancer treatment guidelines recommend concurrent chemoradiotherapy, including wide pelvic irradiation. Many elderly patients, however, cannot tolerate standard treatment because of low performance status. Therefore, to reduce complications, elderly patients sometimes receive radiation therapy without elective nodal irradiation or chemotherapy. PATIENTS AND METHODS: Outcomes were retrospectively analyzed in 19 elderly patients with N0 muscle-invasive bladder cancer treated with whole-bladder irradiation without chemotherapy. RESULTS: The 3- and 5-year overall survival rates were 30.7% and 12.2%, respectively. No patient experienced severe late complications (grade 3 or higher). Recurrence was observed in 11 patients (57.9%). The initial location of recurrence was within the bladder. CONCLUSION: Whole-bladder irradiation alone did not increase lymph node metastases or severe complications in elderly patients. Whole-bladder radiation therapy without chemotherapy or wide pelvic irradiation may be a promising treatment method for patients who are not candidates for standardized treatment.