Pilot study of plasma creatine riboside as a potential biomarker for cervical cancer.

This pilot study aimed primarily to evaluate plasma levels of a novel metabolite, creatine riboside, in patients with cervical cancer (discovery and validation cohorts, n = 11 for each) compared with non-cancer subjects (controls, n = 30). We found that the pre-treatment plasma creatine riboside level was significantly higher in the discovery cohort than in controls. The cut-off value determined from the discovery cohort distinguished 90.9% of the patients in the validation cohort from controls. Unbiased principal component analysis of plasma metabolites in high-creatine riboside samples demonstrated enrichment of pathways involved in arginine and creatine metabolism. These data indicate the potential utility of plasma creatine riboside as a biomarker of cervical cancer.

The Efficacy of Radiotherapy without Surgery for External Auditory Canal Squamous Cell Carcinoma.

External auditory canal (EAC) cancer is a rare disease for which there are no adequate evidence-based treatment strategies. Radiotherapy is often used as the initial treatment to preserve the organ. This study aimed to elucidate the efficacy of radiotherapy for EAC squamous cell carcinoma (SCC). Patients with T1 disease were treated with radiotherapy alone. Patients with T2-4 disease were treated with chemoradiotherapy. The median follow-up period was 30.4 months. The 3-year local control (LC) rate for all patients was 51%, the disease-free survival (DFS) rate was 44%, and the overall survival (OS) rate was 73%. For T1-3 disease, the 3-year LC rate was 74%, DFS was 62%, and OS was 89%. However, for T4 disease, the 3-year LC rate was 17%, DFS was 17%, and OS was 50%. In a univariate analysis, only the T-category was a significant factor for LC and DFS (p = 0.006 and 0.02, respectively). All local recurrences were within the high-dose irradiated area. The results of this study suggest chemoradiotherapy can be an alternative to a combination of surgery and postoperative radiation for T1-3 SCC of the EAC. However, the efficacy of chemoradiotherapy in T4 cases was inadequate.

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.

64Cu-ATSM Predicts Efficacy of Carbon Ion Radiotherapy Associated with Cellular Antioxidant Capacity.

Carbon ion radiotherapy is an emerging cancer treatment modality that has a greater therapeutic window than conventional photon radiotherapy. To maximize the efficacy of this extremely scarce medical resource, it is important to identify predictive biomarkers of higher carbon ion relative biological effectiveness (RBE) over photons. We addressed this issue by focusing on cellular antioxidant capacity and investigated 64Cu(II)-diacetyl-bis(N4-methylthiosemicarbazone) (64Cu-ATSM), a potential radioligand that reflects an over-reduced intracellular environment. We found that the carbon ion RBE correlated with 64Cu-ATSM uptake both in vitro and in vivo. High RBE/64Cu-ATSM cells showed greater steady-state levels of antioxidant proteins and increased capacity to scavenge reactive oxygen species in response to X-rays than low RBE/64Cu-ATSM counterparts; this upregulation of antioxidant systems was associated with downregulation of TCA cycle intermediates. Furthermore, inhibition of nuclear factor erythroid 2-related factor 2 (Nrf2) sensitized high RBE/64Cu-ATSM cells to X-rays, thereby reducing RBE values to levels comparable to those in low RBE/64Cu-ATSM cells. These data suggest that the cellular activity of Nrf2-driven antioxidant systems is a possible determinant of carbon ion RBE predictable by 64Cu-ATSM uptake. These new findings highlight the potential clinical utility of 64Cu-ATSM imaging to identify high RBE tumors that will benefit from carbon ion radiotherapy.

Metabolic Alteration in Cancer Cells by Therapeutic Carbon Ions.

BACKGROUND/AIM: Carbon-ion radiotherapy has strong antitumor effects in X-ray-resistant tumors. However, the mechanisms underlying the strong antitumor effect, especially on metabolic alterations, are not fully elucidated. This study aimed to determine the effect of therapeutic carbon ions on metabolic alterations in cancer cells. MATERIALS AND METHODS: Five human cancer cell lines were used in this study. The change in 333 metabolite levels in response to carbon ions was analyzed using gas chromatography-mass spectrometry. RESULTS: Fifty-two metabolites were commonly detected in all cell lines. The levels of five metabolites significantly changed in four or more cell lines. Three of the five metabolites (i.e., 2-ketoglutaric acid, fumaric acid and 2-hydroxyglutaric acid) were associated with the TCA cycle. TCA cycle intermediates and the downstream oncometabolite 2-hydroxyglutaric acid were up-regulated by carbon ions. CONCLUSION: We demonstrated for the first time that TCA cycle intermediates and 2-hydroxyglutaric acid are up-regulated after carbon-ion irradiation.

Carbon-ion radiotherapy subsequent to balloon-occluded retrograde transvenous obliteration for hepatocellular carcinoma with hepatic encephalopathy: a multidisciplinary approach.

Radical treatments of hepatocellular carcinoma (HCC) with hepatic encephalopathy (HE) can be often difficult due to poor liver function or disturbance of consciousness. An effective treatment requires a combinatorial approach incorporating a treatment for HE and radical therapy for HCC that does not compromise liver function. Here, we report a case of a 78-year-old Japanese male with HCC and HE caused by splenorenal shunt. Serum ammonia levels were high. He was not suitable for surgery, percutaneous radiofrequency ablation, or transarterial chemoembolization due to the location of the tumor and poor liver function, which included HE. Thus, he underwent BRTO, with an immediate improvement in both HE and serum ammonia levels. After BRTO, he received C-ion RT as a radical treatment for HCC. After treatment, HCC was well controlled; however, at 35 months post-initiation of C-ion RT, he developed local recurrence without a further reduction in liver function status. Therefore, we repeated C-ion RT. The patient remains alive at 3 months post-treatment, with no evidence of local recurrence, distant metastasis, or toxicity. Although this is a single case report, it suggests that a combinatorial treatment consisting of BRTO and C-ion RT may increase survival rates of patients with HCC and HE.

Rectal dose-sparing effect with bioabsorbable spacer placement in carbon ion radiotherapy for sacral chordoma: dosimetric comparison of a simulation study.

It is difficult to treat patients with an inoperable sarcoma adjacent to the gastrointestinal (GI) tract using carbon ion radiotherapy (C-ion RT), owing to the possible development of serious GI toxicities. In such cases, spacer placement may be useful in physically separating the tumor and the GI tract. We aimed to evaluate the usefulness of spacer placement by conducting a simulation study of dosimetric comparison in a patient with sacral chordoma adjacent to the rectum treated with C-ion RT. The sacral chordoma was located in the third to fourth sacral spinal segments, in extensive contact with and compressing the rectum. Conventional C-ion RT was not indicated because the rectal dose would exceed the tolerance dose. Because we chose spacer placement surgery to physically separate the tumor and the rectum before C-ion RT, bioabsorbable spacer sheets were inserted by open surgery. After spacer placement, 67.2 Gy [relative biological effectiveness (RBE)] of C-ion RT was administered. The thickness of the spacer was stable at 13-14 mm during C-ion RT. Comparing the dose-volume histogram (DVH) parameters, Dmax for the rectum was reduced from 67 Gy (RBE) in the no spacer plan (simulation plan) to 45 Gy (RBE) in the spacer placement plan (actual plan) when a prescribed dose was administered to the tumor. Spacer placement was advantageous for irradiating the tumor and the rectum, demonstrated using the DVH parameter analysis.

Carbon ion radiotherapy for patients with hepatocellular carcinoma in the caudate lobe carbon ion radiotherapy for hepatocellular carcinoma in caudate lobe.

AIM: The treatment of hepatocellular carcinoma in the caudate lobe (HCCCL) is technically challenging. We aimed to investigate the efficacy and toxicity of carbon ion radiotherapy (C-ion RT) for HCCCL. METHODS: Patients with HCCCL treated with C-ion RT at our hospital between January 2011 and December 2018 were evaluated. The total dose was 52.8 or 60 Gy (relative biological effectiveness) in four or 12 fractions depending on the distance between the tumor and the gastrointestinal tract. The survival outcome, the presence or absence of recurrence (local recurrence, intrahepatic recurrence outside the irradiation field, or extrahepatic recurrence), and acute/late adverse events were evaluated. RESULTS: Nine patients were included. The median tumor size was 3.4 cm, and the median follow-up duration was 18.3 months for all patients. No patient developed local recurrence during follow-up. Five patients subsequently developed intrahepatic recurrence outside the irradiation field and two had extrahepatic metastasis. Five patients died of hepatocellular carcinoma. No acute adverse events of grade ≥2 were observed. Two patients experienced grade 2 or 3 late adverse events, including obstructive jaundice, hepatic encephalopathy, ascites, and edema. CONCLUSION: Carbon ion radiotherapy for HCCCL achieved excellent local control with acceptable adverse events and can thus be a curative treatment option for HCCCL.

Relative Biological Effectiveness of Carbon Ions for Head-and-Neck Squamous Cell Carcinomas According to Human Papillomavirus Status.

Carbon-ion radiotherapy (CIRT) has strong antitumor effects and excellent dose conformity. In head-and-neck squamous cell carcinoma (HNSCC), human papillomavirus (HPV) status is a prognostic factor for photon radiotherapy outcomes. However, the effect of HPV status on the sensitivity of HNSCCs to carbon ions remains unclear. Here, we showed that the relative biological effectiveness (RBE) of carbon ions over X-rays was higher in HPV-negative cells than in HSGc-C5 cells, which are used for CIRT dose establishment, whereas the RBE in HPV-positive cells was modest. These data indicate that CIRT is more advantageous in HPV-negative than in HPV-positive HNSCCs.