Carbon ion radiotherapy for 80 years or older patients with hepatocellular carcinoma.

BACKGROUND: To evaluate the safety and efficacy of carbon ion radiotherapy (C-ion RT) for 80 years or older patients with hepatocellular carcinoma (HCC). METHODS: Eligibility criteria of this retrospective study were: 1) HCC confirmed by histology or typical hallmarks of HCC by imaging techniques of four-phase multidetector-row computed tomography or dynamic contrast-enhanced magnetic resonance imaging; 2) no intrahepatic metastasis or distant metastasis; 3) no findings suggesting direct infiltration of the gastrointestinal tract; 4) performance status ≤2 by Eastern Cooperative Oncology Group classification; and 5) Child-Pugh classification A or B. Patients received C-ion RT with 52.8 Gy (RBE) or 60.0 Gy (RBE) in four fractions for usual cases and 60.0 Gy (RBE) in 12 fractions for close-to-gastrointestinal tract cases. Toxicities were classified using the National Cancer Institute's Common Terminology Criteria for Adverse Events (Version 4.0). RESULTS: Between March 2011 and November 2015, 31 patients were treated. The median follow-up period of all patients was 23.2 months (range: 8.4-55.3 months). Median age at the time of registration of C-ion RT was 83 years (range: 80-95 years). Child-Pugh grade A and B were 27 patients and 4 patients, respectively. The 2-year estimated overall survival, local control, and progression-free survival rates were 82.3%, 89.2%, and 51.3%, respectively. No patients had Grade 2 or higher acute toxicities (within 3 months after C-ion RT). One patient experienced progression in Child-Pugh classification from A to B within 3 months after C-ion RT. In late toxicities, Grade 3 encephalopathy was observed in 3 patients, and 2 improved with medication. CONCLUSIONS: C-ion RT was effective with minimal toxicities for 80 years or older patients with hepatocellular carcinoma. TRIAL REGISTRATION: UMIN000020571 : date of registration, 14 January 2016, retrospectively registered.

Transcatheter arterial embolization with N-butyl cyanoacrylate for arterial esophageal bleeding in esophageal cancer patients.

BACKGROUND: The aim of this study is to evaluate the clinical efficacy and safety of transcatheter arterial embolization (TAE) with N-butyl cyanoacrylate (NBCA) for the treatment of arterial esophageal bleeding in esophageal cancer patients. METHODS: Between November 2008 and December 2014, five esophageal cancer patients underwent TAE with NBCA for the treatment of arterial esophageal bleeding. We retrospectively evaluated the technical and clinical success, recurrent bleeding, and procedure-related complications. RESULTS: All of the patients had bleeding from the esophageal artery and were in shock at the beginning of TAE. Four patients had a coagulopathy at the time of TAE; however, the TAE could successfully arrest bleeding in all five patients. After TAE, they immediately recovered from the shock state. Two patients were discharged without event, one patient is currently hospitalized for another complication, and the other two patients died due to multiorgan failure. In addition, no procedure-related complications such as esophageal infarction and recurrence of arterial esophageal bleeding were observed during this study. CONCLUSIONS: TAE with NBCA can arrest bleeding in esophageal cancer patients with active arterial esophageal bleeding, even in those with a pre-existing coagulopathy.

A reporter gene system for the precise measurement of promoter activity in Thermus thermophilus HB27.

We developed a reporter gene system that enables precise analysis of promoter activity in Thermus thermophilus HB27. The reporter vector employs a promoterless ß-galactosidase gene of Thermus spp. strain T2. However, T. thermophilus HB27 strain has three genes (TTP0042, TTP0220 and TTP0222) whose products have ß-galactosidase activity, which would interfere with correct measurements of promoter activities. Thus, to eliminate this background activity, we disrupted all three of these genes to generate a host strain for measuring promoter expression as ß-galactosidase activity. In addition, T. thermophilus strains also produce carotenoids called thermoxanthins that are yellow pigments. To avoid the influence of these carotenoids on the ß-galactosidase assay, we also disrupted the phytoene synthase gene (crtB). The reporter gene system developed here is a powerful tool for studying transcriptional activity and the mechanisms that regulate gene expression in T. thermophilus HB27. We also showed that the crtB gene cassette could be used in repeated gene-disruption experiments to screen transformants by colony colour, thus eliminating the need for antibiotic resistance markers.

Synchronous ipsilateral carcinoma of the accessory mammary gland and primary lymphoma of the breast with subsequent rectal carcinoma: report of a case.

A case of synchronous carcinoma of the accessory mammary gland and primary breast lymphoma with subsequent rectal carcinoma has not been reported previously. We present a very rare case of primary non-Hodgkin lymphoma of the left breast diagnosed simultaneously with invasive lobular carcinoma of the left axillary accessory mammary gland and rectal adenocarcinoma. An 82-year-old Japanese woman presented with two palpable masses on the left chest wall. She was given a diagnosis of suspected breast malignant tumor and axillary accessory mammary gland. She underwent excision of the axillary accessory mammary gland and left mastectomy with axillary lymph node dissection. Histopathological examination revealed diffuse large B-cell lymphoma of the breast and invasive lobular carcinoma of the axillary accessory mammary gland with lymph nodes metastasis. Three months after the surgery, primary rectal adenocarcinoma was also detected by F-18 fluorodeoxyglucose positron emission tomography. Hartmann's operation was performed, since which time the patient has been doing well.

Two cases of gastric cancer with elevated serum levels of KL-6.

BACKGROUND: The serum level of Krebs von den Lungen-6 (sKL-6) is a biomarker of interstitial pneumonia and has been reported to be elevated in patients with cancers. However, there have been few cases of gastric cancer (GC) with elevated sKL-6 that were treated by chemotherapy. We herein report two cases of GC with elevated sKL-6 that were treated with oxaliplatin plus S-1 (SOX) chemotherapy and discussed the resulting changes in sKL-6. CASE PRESENTATION: The first patient was a 79-year-old woman complaining of loss of appetite. Esophagogastroduodenoscopy (EGD) showed a type-3 tumor in the gastric antrum and biopsy specimens showed adenocarcinoma. Computed tomography (CT) showed multiple liver metastases. sKL-6 was elevated to 1,292 U/ml, but a CT revealed no obvious lesions of the lungs, including interstitial pneumonia. The tumor was diagnosed as GC with liver metastases and elevated sKL-6. Respiratory function data were normal. SOX therapy using oxaliplatin and S-1 was performed. After 3 courses of SOX therapy, CT showed reductions of the liver metastases as well as the primary tumor, and sKL-6 was decreased to 201 U/ml. After the 44 courses, sKL-6 was slightly elevated. Chest CT showed interstitial pneumonia and chemotherapy was stopped. The patient is still alive without any metastasis 72 months later. The second patient was a 69-year-old woman complaining of upper abdominal pain. EGD revealed a type-3 tumor in the gastric antrum showing adenocarcinoma with HER2-positive pathology. CT showed multiple node metastases around the abdominal aorta. sKL-6 was elevated to 2,239 U/ml, but a respiratory function test showed no abnormalities, and CT of the lungs showed no obvious lesions. The tumor was diagnosed as GC with distant node metastases and elevated sKL-6. The patient received SOX therapy combined with trastuzumab. After 6 courses, the size of the primary tumor and multiple node metastases were reduced, and sKL-6 was decreased to 284 U/ml. CONCLUSIONS: These two cases suggest that sKL-6 may be important not only as an indicator of interstitial pneumonia in chemotherapeutic courses, but also as a tumor marker in GC patients with multiple metastases.

Two versatile shuttle vectors for Thermus thermophilus-Escherichia coli containing multiple cloning sites, lacZα gene and kanamycin or hygromycin resistance marker.

Two versatile shuttle vectors for Thermus thermophilus and Escherichia coli were developed on the basis of the T. thermophilus cryptic plasmid pTT8 and E. coli vector pUC13. These shuttle vectors, pTRK1T and pTRH1T, carry a gene encoding a protein homologous to replication protein derived from pTT8, a replicon for E. coli, new multiple cloning sites and a lacZα gene from E. coli vector pUC13, and also have a gene encoding a thermostable protein that confers resistance to kanamycin or hygromycin, which can be used as a selection marker in T. thermophilus. These shuttle vectors are useful to develop enzymes and proteins of biotechnological interest. We also constructed a plasmid, pUC13T, which carries the same multiple cloning sites of pTRK1T and pTRH1T. These vectors should facilitate cloning procedures both in E. coli and T. thermophilus.

Location of major vessels in prone-positioned patients undergoing percutaneous lumbar sympathectomy.

INTRODUCTION: The topographic relationship between major vessels and the sympathectomy target is not identical across patients and may not be clear, especially in patients in the prone position. The aim of this study was to provide anatomic data regarding the location of the major vessels (i.e., vena cava and aorta) based on computed tomography (CT) images obtained during lumbar sympathectomy under CT fluoroscopic guidance. METHODS: Thirty-six patients with peripheral arterial occlusive disease or chronic pain syndrome were treated using fluoroscopic CT-guided percutaneous lumbar sympathectomy between April 2006 and March 2010. We analyzed the shortest distances between the sympathectomy target and the major vessels, and the relationship between the location of the major vessels and the vertebral anterior line using CT images obtained during the procedure. RESULTS: At the L3 level, the shortest distances from the right side target to the inferior vena cava were significantly shorter than the other distances (P < 0.05). In 11 of 36 patients (30.6%), the IVC was located dorsal to the vertebral anterior line at the L3 level. CONCLUSION: Needle insertion for right side sympathectomy at the L3 level may present a higher risk of major vessel puncture than sympathectomy at other sites. CT guidance is recommended for lumbar sympathectomy to reduce the risk of vascular puncture.

A case report of adenosquamous carcinoma of the esophagogastric junction.

BACKGROUND: Many types of tumors can arise in the esophagogastric junction (EGJ). Squamous cell carcinoma (SCC) arising from the esophageal epithelia, adenocarcinoma arising from the gastric mucosa, or Barrett's esophageal mucosa are frequently observed in the EGJ. However, adenosquamous carcinoma (ASC) has been rarely observed in this area. We herein report a rare case of ASC of the EGJ. CASE PRESENTATION: An 81-year-old man visited our hospital complaining of dysphagia. Esophagogastroduodenoscopy detected an elevated tumor in the gastric cardia. Biopsy specimens taken from the tumor showed SCC. Computed tomography revealed a tumor located in the EGJ and node metastases surrounding the EGJ. The tumor was diagnosed as SCC, overhanging in the stomach, of the EGJ. The patient underwent a proximal gastrectomy with a lower esophagectomy and node dissection for the metastases surrounding the EGJ, and esophagogastrostomy in the lower mediastinum. Histopathologic examination showed the tumor consisted of SCC and adenocarcinoma. The adenocarcinoma consisted of nests scattered in the SCC. We observed adenocarcinoma component in 35% of the tumor and epithelial spread of SCC in the lower esophagus. Thus, we diagnosed the tumor as ASC of the EGJ. Eight metastatic nodes were dissected; both SCC and adenocarcinoma were observed in seven. CONCLUSIONS: In the present case, SCC may be originated from the squamous epithelia of the lower esophagus and grew into the stomach, and the adenocarcinoma may have differentiated from SCC through the infiltration.

Efficacy and Safety of 4 Fractions of Carbon-Ion Radiation Therapy for Hepatocellular Carcinoma: A Prospective Study.

INTRODUCTION: Prospective evidence supporting the safety and efficacy of carbon-ion radiotherapy (C-ion RT) for hepatocellular carcinoma (HCC) remains lacking. This prospective study aimed to evaluate the safety and efficacy of hypofractionated C-ion RT in patients with HCC. METHODS: The inclusion criteria were as follows: (1) pathologically or clinically diagnosed HCC; (2) measurable tumor and tumor size ≤10 cm; (3) absence of major vascular invasion; (4) no extrahepatic metastasis; (5) the alimentary tract was not adjacent to the target lesion (>1 cm); (6) not suitable for or refusal to undergo surgery or local ablative therapies; (7) an interval ≥4 weeks from previous therapy; (8) no other intrahepatic lesion or at least 2 years after the previous curative therapy; (9) performance status score, 0-2; and (10) Child-Pugh score, 5-9. The prescribed C-ion RT dose was 52.8 Gy (relative biological effectiveness [RBE]) or 60.0 Gy (RBE) in 4 fractions. RESULTS: In total, 35 patients with HCC were enrolled between October 2010 and May 2016. The median follow-up durations in the survivor group (n = 23) and in the whole cohort were 55.1 and 49.0 months, respectively. The 2-, 3-, and 4-year overall survival rates were 82.8%, 76.7%, and 69.4%, respectively. The 2-, 3-, and 4-year local control (LC) rates were 92.6%, 76.5%, and 76.5%, respectively. The median time-to-progression was 25.6 months (95% confidence interval, 13.7-37.5 months). Grade 4 or 5 toxicities were not observed. Grade 3 acute and late toxicities were observed in 2 patients. There was no significant deterioration in serum albumin, bilirubin, prothrombin time-international normalized ratio, platelet count, or Child-Pugh score after C-ion RT. CONCLUSION: Four fractions of C-ion RT for HCC did not yield serious adverse events and showed promising LC, thus making it a safe and effective modality for this type of malignancy.

[Report on how to stimulate local economy using forest therapy and on effect of forest therapy in Akazawa].

In 2006, the Akazawa National Forest was accredited as a base of forest therapy. On the assumption that forest therapy is effective for the prevention of lifestyle-related diseases, we started a project to prove the medical effectivity of forest therapy. We also attempted to find a way to stimulate the local economy using forest therapy. As an application of forest therapy for local economy stimulation, we established a clinic in the Akazawa National Forest and offered medical advice and suggested hiking routes. About 150 people visit this clinic each year. We are also offering forest therapy in combination with a complete medical check up. We measured the concentration of the amylase in the saliva from the group who underwent forest therapy and from another group who carried out the same task in the city as a control. We found a significant difference between the two groups. We also measured the levels of 8-OHdG and HRV before and after the forest therapy. In the people who showed a markedly high oxidative stress before the therapy, we observed a significant decline of oxidative stress. It was difficult to measure the effects of forest therapy objectively. However, through this project, we consider that we will be able to obtain some positive effects that will support the usefulness of forest therapy. We still need to continue our research and collect data to prove its usefulness.

A case of gastric cancer that developed thrombocytopenia during treatment with nivolumab.

A 72-year-old man was treated by two-regimen chemotherapies for unresectable advanced gastric cancer with metastatic lymph nodes near the pancreatic head, followed by the third-line chemotherapy using nivolumab (Nivo). Ten days after the two-course Nivo chemotherapy, grade 4 thrombocytopenia (TCP) occurred according to the Common Terminology Criteria for Adverse Events. He was treated by steroid and Helicobacter pylori (HP) eradication therapies. Consequently, the platelet count improved rapidly without any complications. Before resuming the Nivo therapy, the platelet count was already improved. Fourth-line chemotherapy was then started using irinotecan. After three courses, his general condition worsened. Unfortunately, the patient died 18 months after gastric cancer diagnosis. Although rare, severe TCP is potentially a fatal complication of chemotherapy using immune checkpoint inhibitors. In addition to standard treatment with steroids, HP eradication therapy may be effective for Nivo-associated TCP.

Lung adenocarcinoma initially presenting as Trousseau's syndrome treated successfully with pembrolizumab: A case report.

A 60-year-old woman was urgently admitted to our hospital because of vertigo and left hemiplegia. Laboratory examination showed thrombocytopenia, high levels of D-dimer and carcinoembryonic antigen. Brain magnetic resonance imaging (MRI) revealed multiple bilateral cerebral infarctions. Chest computed tomography (CT) showed an irregularly shaped tumor in the upper lobe of the left lung and mediastinal node swelling. The histopathological findings revealed adenocarcinoma negative for anaplastic lymphoma kinase fusion gene, sensitive epidermal growth factor receptor mutations. A diagnosis of lung adenocarcinoma initially presenting as arterial thromboembolism was made, and she was treated with direct oral anticoagulant (DOAC). Subsequently, pembrolizumab therapy was initiated because tumor cells were positive for programmed cell death protein 1 (PD-L1;60%), and resulted in reduction of the tumor with normalization of the platelet count and d-dimer. The treatment has been continued for over one year without any recurrence of the disease or thromboembolism.

Basaloid Squamous Cell Carcinoma of the Uterine Cervix: Report of a Case With Molecular Analysis.

There is a lack of knowledge about molecular alterations in basaloid squamous cell carcinoma (BSCC) of the uterine cervix. A 72-year-old woman with a history of previous subtotal hysterectomy and current vaginal bleeding was referred to our hospital. Initially, adenoid cystic carcinoma (ACC) was diagnosed upon cervical cytology and biopsy. Chest imaging showed multiple metastatic lesions in both lungs. The surgical specimen showed BSCC with diffuse p16 immunoreactivity and negativity for S-100, c-kit, and neuroendocrine markers. There was a focal minor ACC component, which could have explained the previous cytology and biopsy diagnosis. Next-generation sequencing with two different panels showed coexisting PIK3CA mutation and NTRK2 fusion with 10 additional variants of unknown significance (ATR, DAXX, FAM123B, JAK1, KEL, MLL2, NOTCH2, PALB2, POLD1, POLE). The MYB gene fusions were not identified. The patient received chemotherapy with TRK inhibitor larotrectinib and carboplatin, which caused shrinkage of metastatic lung nodules. This is the first report of cervical BSCC with extensive molecular workup, which detected multiple genetic events, including targetable ones, which are potentially implicated in the development of a tumor. The accumulation of data and further studies on this tumor are necessary to define its diagnostic criteria and its clinical and biological behavior.

Technical communication: percutaneous radiofrequency mandibular nerve rhizotomy guided by high-speed real-time computed tomography fluoroscopy.

We present a new method of percutaneous radiofrequency mandibular nerve rhizotomy for pain relief in the mandibular region, in which needle placement is guided by high-speed real-time computed tomography (CT) fluoroscopy. Eleven patients (13 procedures) with idiopathic trigeminal neuralgia underwent the procedure. CT fluoroscopy simultaneously provided 3 slices (1-mm interval series, craniocaudally) in 1 fluoroscopic view, allowing for accurate needle placement. Trigeminal neuralgia improved in all patients without severe complications. The mean numerical rating scales of pain intensity (+ or - sd) decreased from 6.5 (+ or - 1.8, pretreatment) to 1.8 (+ or - 1.7, 1 month after treatment) and to 0.9 (+ or - 1.0, 3 months after treatment). Our limited-case series suggests potential advantages for the new CT fluoroscopy guidance, but these findings await confirmation from randomized controlled trials and large-case series.

Percutaneous radio-frequency thermocoagulation of the Gasserian ganglion guided by high-speed real-time CT fluoroscopy.

INTRODUCTION: Although Gasserian ganglion block is an established treatment for trigeminal neuralgia, the foramen ovale cannot always be clearly visualized by classical X-ray radiography. We present a new method for percutaneous radio-frequency thermocoagulation of the Gasserian ganglion, in which computed tomography (CT) fluoroscopy is used to guide needle placement. METHODS: In the present study, 15 patients with trigeminal neuralgia underwent percutaneous radio-frequency thermocoagulation of the Gasserian ganglion guided by high-speed real-time CT fluoroscopy. RESULTS: Trigeminal neuralgia was improved in all patients after treatment without any severe complications. Moderate dysesthesia occurred in only one case. CONCLUSION: CT fluoroscopy-guided percutaneous radio-frequency thermocoagulation of the Gasserian ganglion was safe, quick, and effective for patients with intractable idiopathic trigeminal neuralgia.

betaKlotho is required for fibroblast growth factor (FGF) 21 signaling through FGF receptor (FGFR) 1c and FGFR3c.

Fibroblast growth factor (FGF) 21, a structural relative of FGF23 that regulates phosphate homeostasis, is a regulator of insulin-independent glucose transport in adipocytes and plays a role in the regulation of body weight. It also regulates ketogenesis and adaptive responses to starvation. We report that in a reconstituted receptor activation assay system using BaF3 cells, which do not endogenously express any type of FGF receptor (FGFR) or heparan sulfate proteoglycan, FGF21 alone does not activate FGFRs and that betaKlotho is required for FGF21 to activate two specific FGFR subtypes: FGFR1c and FGFR3c. Coexpression of betaKlotho and FGFR1c on BaF3 cells enabled FGF21, but not FGF23, to activate receptor signaling. Conversely, coexpression of FGFR1c and Klotho, a protein related to betaKlotho, enabled FGF23 but not FGF21 to activate receptor signaling, indicating that expression of betaKlotho/Klotho confers target cell specificity on FGF21/FGF23. In all of these cases, heparin enhanced the activation but was not essential. In 3T3-L1 adipocytes, up-regulation of glucose transporter (GLUT) expression by FGF21 was associated with expression of betaKlotho, which was absent in undifferentiated 3T3-L1 fibroblasts. It is thus suggested that betaKlotho expression is a crucial determinant of the FGF21 specificity of the target cells upon which it acts in an endocrine fashion.

Activatable fluorescent molecular imaging of peritoneal metastases following pretargeting with a biotinylated monoclonal antibody.

Optical probes that yield high target-to-background ratios are necessary to detect microfoci of cancer that would otherwise escape detection with white light imaging. Target-specific activation of the optical signal at tumor foci is one mechanism by which high target and low background signal can be achieved. Here, we describe a two-step activation process in which the tumors are first pretargeted with a nonfluorescent biotinylated monoclonal antibody [cetuximab (Erbitux) targeting human epidermal growth factor receptor type 1 (HER1)]. Following this, a second agent, neutravidin-BODIPY-FL fluorescent conjugate, is given and binds to the previously targeted antibody, resulting in an approximately 10-fold amplification of the optical fluorescence signal, leading to high tumor-to-background ratios. Spectral fluorescence imaging was done in a mouse model of peritoneal metastasis using a HER1-overexpressing cell line (A431) after pretargeting with biotinylated cetuximab and 3 h after administration of neutravidin-conjugated BODIPY-FL. Both aggregated tumors as well as small cancer implants were clearly visualized in vivo. For lesions approximately 0.8 mm or greater in diameter, the spectral fluorescence imaging had a sensitivity of 96% (178 of 185) and a specificity of 98% (188 of 191). This two-step activation paradigm (pretargeting followed by neutravidin-biotin binding with an attached activatable fluorophore) could be useful in tumor-specific molecular imaging of various targets to guide surgical resections.

A target cell-specific activatable fluorescence probe for in vivo molecular imaging of cancer based on a self-quenched avidin-rhodamine conjugate.

A target cell-specific activation strategy for improved molecular imaging of peritoneal implants has been proposed, in which fluorophores are activated only in living targeted cells. A current example of an activatable fluorophore is one that is normally self-quenched by attachment to a peptide backbone but which can be activated by specific proteases that degrade the peptide resulting in "dequenching." In this study, an alternate fluorescence activation strategy is proposed whereby self-quenching avidin-rhodamine X, which has affinity for lectin on cancer cells, is activated after endocytosis and degradation within the lysosome. Using this approach in a mouse model of peritoneal ovarian metastases, we document target-specific molecular imaging of submillimeter cancer nodules with minimal contamination by background signal. Cellular internalization of receptor-ligand pairs with subsequent activation of fluorescence via dequenching provides a generalizable and highly sensitive method of detecting cancer microfoci in vivo and has practical implications for assisting surgical and endoscopic procedures.

A feasibility study of high-dose hypofractionated carbon ion radiation therapy using four fractions for localized hepatocellular carcinoma measuring 3 cm or larger.

BACKGROUND AND PURPOSE: To evaluate the safety of carbon-ion radiotherapy (C-ion RT) using 60 Gy (relative biological effectiveness, RBE) in four fractions for patients with hepatocellular carcinoma (HCC). MATERIALS AND METHODS: The primary outcome was acute toxicities within 90 days. The secondary outcomes were late toxicities, local control, and progression-free survival and overall survival rates. The key inclusion criteria were as follows: (1) 3 cm or larger HCC without major vascular invasion and not adjacent to the alimentary tract; (2) Child-Pugh's grade A/B; and (3) without extrahepatic metastasis. RESULTS: A total of 21 cases were analyzed between October 2012 and April 2016. The median follow-up period among the 17 survivors was 24.2 (range: 6.3-43.7) months. Grade 3 or higher acute toxicity was not observed, while three (14.3%) of the 21 patients experienced grade 3 late toxicities. The 1- and 2-year local control, progression-free survival, and overall survival rates were 100% and 92.3%, 81.0% and 50.0%, and 90.5% and 80.0%, respectively. CONCLUSION: C-ion RT using 60 Gy (RBE) in four fractions was safe and achieved promising local tumor control.