To investigate a prognostic role of gross tumor volume (GTV) changes on survival outcomes following concurrent chemoradiotherapy (CCRT) in stage III non-small-cell lung cancer (NSCLC) patients. We enrolled 191 patients with stage III NSCLC from 2001 to 2009 undergoing definitive CCRT. The GTV of 157 patients was delineated at the planning CT prior to CCRT and with a follow-up CT 1 month after CCRT. We assessed the volumetric parameters of pre-treatment GTV (GTVpre) post-treatment GTV (GTVpost), and volume reduction ratio of GTV (VRR). The primary endpoint was overall survival (OS) and secondary endpoints were progression-free survival (PFS) and locoregional progression-free survival (LRPFS). The best cut-off value was defined as that which exhibited the maximum difference between the two groups. The median follow-up duration was 52.7 months in surviving patients. Median survival, 3-year OS, PFS and LRPFS rates were 25.5 months, 36.4%, 23.0%, and 45.0%, respectively. The selected cut-off values were 50 cm3 for GTVpre, 20 cm3 for GTVpost, and 50% for VRR. The smaller GTVpre and GTVpost values were associated with better OS (p < 0.001 and p = 0.015) and PFS (p = 0.001 and p = 0.004), respectively, upon univariate analysis. The higher VRR of > 50% was associated with a trend toward poorer OS (p = 0.004) and PFS (p = 0.054). Upon multivariate analysis, smaller GTVpre indicated significantly improved OS (p = 0.001), PFS (p = 0.013) and LRPFS (p = 0.002), while smaller GTVpost was marginally significant for PFS (p = 0.086). Higher VRR was associated with a trend toward poorer OS (p = 0.075). In patients with stage III NSCLC undergoing definitive CCRT, GTVpre was an independent prognostic factor of survival. Notably, improved outcome was not correlated with higher VRR after short-term follow-up with CT alone.

Background: To investigate the significance of monitoring the levels of the serum squamous cell carcinoma antigen (SCC-Ag) for the detection of recurrent disease in patients with cervical cancer treated by concurrent chemoradiotherapy. Methods: The records of 112 patients with cervical cancer were reviewed. Serum SCC-Ag levels were measured at regular follow-up visits. A SCC-Ag level of 2 ng/mL was considered the upper limit of normal. Biochemical failure was defined as two consecutively increasing SCC-Ag values above normal. Recurrent disease was confirmed by histologic and radiographic studies. Results: Eighteen patients (16%) developed recurrent disease. Sixteen patients had initially elevated SCC-Ag, post-treatment normalization of SCC-Ag, and tumor recurrence. The SCC-Ag difference (ΔSCC-Ag), defined as the difference between the last value after two consecutively increases above normal and the value immediately before the elevation, had good clinical performance in predicting cancer recurrence. The cutoff value of ΔSCC-Ag was 0.95 ng/mL. Conclusions: SCC-Ag is a relatively good method for the detection of disease recurrence in patients with cervical cancer who were treated by concurrent chemoradiotherapy.

We performed a prospective phase II study to compare acute toxicity among five different hypofractionated schedules using proton therapy. This study was an exploratory analysis to investigate the secondary end-point of biochemical failure-free survival (BCFFS) of patients with long-term follow-up. Eighty-two patients with T1-3bN0M0 prostate cancer who had not received androgen-deprivation therapy were randomized to one of five arms: Arm 1, 60 cobalt gray equivalent (CGE)/20 fractions/5 weeks; Arm 2, 54 CGE/15 fractions/5 weeks; Arm 3, 47 CGE/10 fractions/5 weeks; Arm 4, 35 CGE/5 fractions/2.5 weeks; and Arm 5, 35 CGE/5 fractions/4 weeks. In the current exploratory analysis, these ardms were categorized into the moderate hypofractionated (MHF) group (52 patients in Arms 1–3) and the extreme hypofractionated (EHF) group (30 patients in Arms 4–5). At a median follow-up of 7.5 years (range, 1.3–9.6 years), 7-year BCFFS was 76.2% for the MHF group and 46.2% for the EHF group (p = 0.005). The 7-year BCFFS of the MHF and EHF groups were 90.5 and 57.1% in the low-risk group (p = 0.154); 83.5 and 42.9% in the intermediate risk group (p = 0.018); and 41.7 and 40.0% in the high risk group (p = 0.786), respectively. Biochemical failure tended to be a late event with a median time to occurrence of 5 years. Acute GU toxicities were more common in the MHF than the EHF group (85 vs. 57%, p = 0.009), but late GI and GU toxicities did not differ between groups. Our results suggest that the efficacy of EHF is potentially inferior to that of MHF and that further studies are warranted, therefore, to confirm these findings. This study is registered at ClinicalTrials.gov, no. NCT01709253 ; registered October 18, 2012; retrospectively registered).

To evaluate the role of risk-adapted proton beam therapy (PBT) in hepatocellular carcinoma (HCC) patients, a total of 243 HCC patients receiving risk-adapted PBT with three dose-fractionation regimens (regimen A [n = 40], B [n = 60], and C [n = 143]) according to the proximity of their gastrointestinal organs (<1 cm, 1–1.9 cm, and ≥2 cm, respectively) were reviewed: The prescribed doses to planning target volume 1 (PTV1) were 50 gray equivalents (GyE) (EQD2 [equivalent dose in 2 Gy fractions], 62.5 GyE₁₀), 60 GyE (EQD2, 80 GyE₁₀), and 66 GyE (EQD2, 91.3 GyE₁₀) in 10 fractions, respectively, and those of PTV2 were 30 GyE (EQD2, 32.5 GyE₁₀) in 10 fractions. In all patients, the five-year local recurrence-free survival (LRFS) and overall survival (OS) rates were 87.5% and 48.1%, respectively, with grade ≥3 toxicity of 0.4%. In regimens A, B, and C, the five-year LRFS and OS rates were 54.6%, 94.7%, and 92.4% (p < 0.001), and 16.7%, 39.2%, and 67.9% (p < 0.001), respectively. The five-year OS rates of the patients with the Modified Union for International Cancer Control (mUICC) stages I, II, III, and IVA and Barcelona Clinic Liver Cancer (BCLC) stages A, B, and C were 69.2%, 65.4%, 43.8%, and 26.6% (p < 0.001), respectively, and 65.1%, 40%, and 32.2% (p < 0.001), respectively. PBT could achieve promising long-term tumor control and have a potential role as a complementary or alternative therapeutic option across all stages of HCC.

High-fat (HF) diet-induced obesity precipitates multiple metabolic disorders including insulin resistance, glucose intolerance, oxidative stress, and inflammation, resulting in the initiation of cell death programs. Previously, we demonstrated murine germline knockout of calcium-independent phospholipase A₂γ (iPLA₂γ) prevented HF diet-induced weight gain, attenuated insulin resistance, and decreased mitochondrial permeability transition pore (mPTP) opening leading to alterations in bioenergetics. To gain insight into the specific roles of hepatic iPLA₂γ in mitochondrial function and cell death under metabolic stress, we generated a hepatocyte-specific iPLA₂γ-knockout (HEPiPLA₂γKO). Using this model, we compared the effects of an HF diet on wild-type versus HEPiPLA₂γKO mice in eicosanoid production and mitochondrial bioenergetics. HEPiPLA₂γKO mice exhibited higher glucose clearance rates than WT controls. Importantly, HF-diet induced the accumulation of 12-hydroxyeicosatetraenoic acid (12-HETE) in WT liver which was decreased in HEPiPLA₂γKO. Furthermore, HF-feeding markedly increased Ca²⁺ sensitivity and resistance to ADP-mediated inhibition of mPTP opening in WT mice. In contrast, ablation of iPLA₂γ prevented the HF-induced hypersensitivity of mPTP opening to calcium and maintained ADP-mediated resistance to mPTP opening. Respirometry revealed that ADP-stimulated mitochondrial respiration was significantly reduced by exogenous 12-HETE. Finally, HEPiPLA₂γKO hepatocytes were resistant to calcium ionophore-induced lipoxygenase-mediated lactate dehydrogenase release. Collectively, these results demonstrate that an HF diet increases iPLA₂γ-mediated hepatic 12-HETE production leading to mitochondrial dysfunction and hepatic cell death.