Tailored radiation dose according to margin width for patients with ductal carcinoma in situ after breast-conserving surgery.

A 2 mm resection margin is considered adequate for ductal carcinoma in situ (DCIS). We assessed the effectiveness of a tailored radiation dose for margins < 2 mm and the appropriate margin width for high-risk DCIS. We retrospectively evaluated 137 patients who received adjuvant radiotherapy after breast-conserving surgery for DCIS between 2013 and 2019. The patients were divided into three- positive, close (< 2 mm), and negative (≥ 2 mm) margin groups. Radiation dose to the tumor bed in equivalent dose in 2 Gy fractions were a median of 66.25 Gy, 61.81 Gy, and 59.75 Gy for positive, close, and negative margin groups, respectively. During a median follow-up of 58 months, the crude rates of local recurrence were 15.0%, 6.7%, and 4.6% in the positive, close, and negative margin groups, respectively. The positive margin group had a significantly lower 5-year local recurrence-free survival (LRFS) rate compared to the close and negative margin groups in propensity-weighted log-rank analysis (84.82%, 93.27%, and 93.20%, respectively; p = 0.008). The difference in 5-year LRFS between patients with the high- and non-high-grade tumors decreased as the margin width increased (80.4% vs. 100.0% for margin ≥ 2 mm, p < 0.001; 92.3% vs. 100.0% for margin ≥ 6 mm, p = 0.123). With the radiation dose tailored for margin widths, positive margins were associated with poorer local control than negative margins, whereas close margins were not. Widely clear margins (≥ 2 mm) were related to favorable local control for high-grade DCIS.

Effect of high-dose radiation therapy on positive margins after breast-conserving surgery for invasive breast cancer.

PURPOSE: Positive margins after breast-conserving surgery are associated with poor oncological outcomes and warrant additional surgery. This study aimed to evaluate the effectiveness of high-dose radiation therapy for positive margins by comparing local recurrence between patients with positive and negative margins. METHODS: We retrospectively evaluated 550 patients treated with adjuvant radiation therapy after breast-conserving surgery for invasive breast cancer between 2013 and 2019. The total equivalent dose in 2 Gy fractions (EQD2) to the tumor bed ranged from 65.81 to 66.25 Gy for positive margins and 59.31-61.81 Gy for negative margins. The differences in local recurrence between the positive and negative margin groups were analyzed. RESULTS: After a median follow-up of 58 months, the crude local recurrence rate was 7.3% in the positive margin group (n = 55) and 2.4% in the negative margin group (n = 495). Positive margins were associated with higher local recurrence without statistical significance in the entire cohort (p = 0.062). Among patients aged <60 years, those with positive margins had a significantly lower 5-year local recurrence-free survival rate than those with negative margins (89.16% vs. 97.57%, respectively; p = 0.005). In contrast, there was no significant difference in the 5-year local recurrence-free survival rate between patients with positive and negative margins among those aged ≥60 years (100.00% vs. 94.38%, respectively; p = 0.426). CONCLUSION: In this study, positive margins were not associated with poor local control in older patients after a high-dose boosts. Further prospective studies are needed to verify our findings.

High expression of the phosphoinositide 3-kinase p11γ isoform can predict poor prognosis of non-small cell lung cancer.

The protein p110γ is an isoform of the catalytic subunit of class I phosphoinositide 3-kinases (PI3Ks). PI3Ks are involved in the regulation of cell survival, growth, proliferation, and migration and have been implicated in the oncogenesis of various cancers. In this study, p110γ expression in non-small cell lung cancer (NSCLC) and its association with clinicopathological factors and patient survival were evaluated. A total of 230 NSCLC tumors were immunohistochemically stained for p110γ. Of these, 174 (75.7%) and 56 (24.3%) were placed in the low and high expression groups, respectively. The positive rate of p110γ was significantly higher in adenocarcinoma than in squamous cell carcinoma (p⟨0.001). Advanced stage NSCLCs showed higher p110γ expression than those at an early stage (p=0.002). Irrespective of the histological tumor type, the patients with high p110γ expression had significantly worse overall survival than those with low p110γ expression (p=0.004). p110γ expression was an independent poor prognostic factor in the multivariate analysis. Our results suggest that p110γ may be involved in the development and progression of NSCLC, and that p110γ has promising potential as a prognostic factor or novel therapeutic target for NSCLC.

Relationship between 18F-FDG uptake and heat shock protein 90α expression in colorectal cancer.

OBJECTIVE: We investigated whether heat shock protein 90α (HSP90α) expression is associated with fluorine-18-labeled fluoro-2-deoxy-D-glucose (18F-FDG) uptake and whether 18F-FDG positron emission tomography/computed tomography (PET/CT) can be used to predict the status of HSP90α expression in colorectal cancer (CRC). SUBJECTS AND METHODS: The medical records and preoperative 18F-FDG PET/CT studies of 51 patients with newly diagnosed CRC who underwent surgical treatment were retrospectively reviewed. The maximum standardized uptake value (SUVmax) of the primary tumor was calculated from the level of 18F-FDG uptake. HSP90α expression was determined by immunohistochemistry. The relationship between SUVmax and HSP90α expression was analyzed. RESULTS: Colorectal cancer with high HSP90α expression had significantly higher SUVmax than CRC with low HSP90α expression (18.88±10.06 vs. 12.38±5.04, P=0.003). There was a significant correlation between HSP90α expression and 18F-FDG uptake (r=0.354, P=0.011). The highest accuracy for determining HSP90α status (68.6%) was obtained with a SUVmax cut-off of 15.4. Maximum SUV was the only predictor of HSP90α expression on multivariate logistic regression analysis (Odds Ratio=5.384, P=0.016). CONCLUSION: The expression status of HSP90α was significantly related to 18F-FDG uptake in CRC.

Prognostic significance of glucose-related protein 94 in colorectal cancer.

AIMS: The expression of glucose-related protein 94 (GRP94), a member of the heat shock protein 90 family, was correlated with a variety of clinicopathological factors and patient survival in a large colorectal cancer (CRC) cohort. We aimed to elucidate the role of GRP94 in the prognosis of CRC patients. METHODS: Tissue microarray blocks were generated from 709 CRC samples and immunohistochemically stained for GRP94. RESULTS: Of the 709 tumours, 164 (23.1%) and 545 (76.9%) were classified in the low and high expression groups, respectively. GRP94 expression was high in CRC cases with larger tumours (p =  0.005) and advanced pT stage (p =  0.021). GRP94 expression was higher in females than males (p =  0.024). In univariate and multivariate survival analyses, high GRP94 expression was unexpectedly associated with better overall survival in CRC patients younger than 65 years of age (p =  0.001) CONCLUSION: Our conflicting results indicate that GRP94 has the ability to switch between oncogenic and tumour-suppressive roles depending on the conditions and microenvironment of the tumour cells. Furthermore, GRP94 could be a candidate biomarker to predict better prognosis in CRC patients.

Differential expression of HSP90 isoforms and their correlations with clinicopathologic factors in patients with colorectal cancer.

Heat shock protein 90 (HSP90), a molecular chaperone, plays critical roles in cellular protection against various stressful stimuli and in the regulation of cellular growth and apoptosis. HSP90 has four human isoforms; HSP90α, HSP90ß, glucose related protein 94 (GRP94), and tumor necrosis factor (TNF) receptor-associated protein 1 (TRAP1). We evaluated the differential expression of these HSP90 isoforms in colorectal cancer (CRC) and correlated their expression levels with clinicopathological factors and patient survival rates. We performed immunohistochemical staining for HSP90α, HSP90ß, GRP94, and TRAP1 in 129 CRC tumor samples and found that HSP90α expression was significantly associated with advanced pT stage (P = 0.011) and shorter recurrence-free survival (RFS) (P = 0.010), whereas GRP94 expression was correlated with low grade (P = 0.029) and better RFS (P < 0.001). HSP90ß and TRAP1 had no prognostic impact, although HSP90ß expression was positively correlated with tumor size (P = 0.008). Based on our results, HSP90α and GRP94 are potential prognostic biomarkers of CRC. In addition, the differences in expression and functional activities among four HSP90 isoforms imply that isoform selectivity should be seriously considered when HSP90 inhibitors are studied or adopted for the treatment of CRC.

Prognostic significance of phosphoinositide 3-kinase p110α and p110ß isoforms in non-small cell lung cancer.

The proteins p110α and p110ß are isoforms of the catalytic subunit of class I phosphoinositide 3-kinases (PI3Ks). Class I PI3Ks are involved in the regulation of cell survival, growth, proliferation, and migration, and their aberrant activation contributes to the oncogenesis of various human cancers. In this study, we assessed expression of p110α and p110ß in non-small cell lung cancer (NSCLC) and their association with clinicopathological factors and patient survival. Seventy-six NSCLC cases were analyzed by immunohistochemical staining for p110α and p110ß. Of the 76 tumors, 18 (23.7%) and 43 (56.6%) were classified in the high p110α and p110ß expression groups, respectively. Expression of p110α was higher in smokers compared with non-smokers (P = 0.042). No other clinicopathological factors showed significant association with p110α or p110ß expression. In univariate and multivariate survival analyses, high p110ß expression was associated with worse overall survival (OS) in stage I NSCLCs (P < 0.001), whereas the high p110α expression group had shorter OS in stage II to IV NSCLCs (P = 0.005). Our results suggest that p110α and p110ß play different roles depending on tumor stage, and that both p110α and p110ß have potential as independent prognostic biomarkers of NSCLC.

Association between active brown adipose tissue and coronary artery calcification in healthy men.

AIM: We compared various clinical factors between persons with active brown adipose tissue (ABAT) and matched controls, and investigated the relationship between the presence of ABAT and coronary artery calcification (CAC) with respect to arterial inflammation. METHODS: We retrospectively reviewed fluorine-18-labeled fluoro-2-deoxy-D-glucose (F-18 FDG) positron emission tomography/computed tomography (PET/CT) data from men who underwent general health check-ups. Sixty-seven men with ABAT were identified and were matched with controls at a 1:1 ratio. Peripheral blood samples were obtained and the levels of various laboratory parameters were measured just before FDG PET/CT studies. Arterial inflammation was measured in the ascending aorta, venous mean standardized uptake value (SUV) was collected from the superior vena cava as FDG uptake on PET, and background-corrected SUV was calculated as the target-to-background ratio (TBR) and blood-subtracted SUVmax (bsSUVmax). CAC was assessed using CT images acquired from a PET/CT scanner. RESULTS: The prevalence of fatty liver (p = 0.048) and CAC (p = 0.026) was lower in men with ABAT compared to matched controls. Arterial SUVmax (1.72 ± 0.23 vs. 1.88 ± 0.23, p < 0.001), TBR (1.18 ± 0.14 vs. 1.29 ± 0.13, p < 0.001), and bsSUVmax (0.25 ± 0.18 vs. 0.41 ± 0.16, p < 0.001) were significantly lower in men with ABAT. ABAT (odds ratio [OR] = 0.19, p = 0.024) and high-density lipoprotein cholesterol (OR = 0.95, p = 0.037) were independent factors associated with CAC according to multiple logistic regression analysis. CONCLUSION: ABAT is associated with down-regulated arterial inflammation and may exert a protective effect against the development of atherosclerosis. (p = 0,026) war geringer bei Männern mit ABAT im Vergleich zu gematchten Kontrollen. Arterieller SUVmax (1,72 ± 0,23 vs. 1,88 ± 0,23, p < 0,001), TBR (1,18 ± 0,14 vs. 1,29 ± 0,13, p < 0,001) und bsSUVmax (0,25 ± 0,18 vs. 0,41 ± 0,16, p < 0,001) waren bei Männern mit ABAT signifikant geringer. ABAT (Odds ratio [OR] = 0,19, p = 0,024) und HDL-Cholesterol (OR = 0,95, p = 0,037) waren in einer multiplen logistischen Regressionsanalyse unabhängige Faktoren, die mit CAC assoziiert waren. Schlussfolgerung : ABAT ist assoziiert mit einer herunterregulierten arteriellen Entzündung und übt möglicherweise einen schützenden Effekt gegen die Entwicklung einer Atherosklerose aus.

Phosphorylated 4E-binding protein 1 expression is associated with poor prognosis in small-cell lung cancer.

Phosphorylation of eukaryotic translation initiation factor 4E (eIF4E) binding protein (4E-BP1) results in release of eIF4E, which sequentially relieves translational repression and enhances oncogenic protein synthesis. We assessed the expression of phosphorylated 4E-BP1 (p-4E-BP1) in small-cell lung cancer (SCLC) and its correlation with clinicopathological factors and patient survival. This study included 117 SCLCs, which comprised 108 primary and 9 metastatic tumor tissues. We performed immunohistochemical staining for p-4E-BP1 in 117 tumors and found that 77 (66 %) were positive for p-4E-BP1 with cytoplasmic and/or nuclear immunostaining. The positive rate of p-4E-BP1 staining was significantly higher in never smokers (p = 0.034) and metastatic tumor tissues (p = 0.027). Patients with p-4E-BP1-positive SCLC tended to have poor performance status, although the difference was not statistically significant (p = 0.087). High p-4E-BP1 expression was significantly correlated with worse overall survival (OS) in all cohorts (p = 0.016). After stratification by clinical stage, p-4E-BP1 expression showed a stronger relationship with OS in patients with limited disease (p = 0.008). In addition, when stratified by treatment status, p-4E-BP1 expression was still significantly associated with worse OS in a subgroup of patients who completed treatment (p = 0.021). Our results indicate that p-4E-BP1 expression could represent oncogenic potential and contribute to the progression and aggressiveness of SCLC, suggesting it could be a candidate prognostic biomarker of SCLC, especially in limited disease.

Differential expression of heat shock protein 90 isoforms in small cell lung cancer.

Heat shock protein 90 (HSP90), a molecular chaperone, plays important roles in cellular protection against various stressful stimuli and in the regulation of cellular growth and apoptosis. HSP90 has 4 different types of human isoforms; HSP90α, HSP90ß, glucose related protein 94 (GRP94) and tumor necrosis factor (TNF) receptor-associated protein 1 (TRAP1). We assessed the differential expression of these HSP90 isoforms in small-cell lung cancer (SCLC) and the correlation of their expression levels with clinicopathological factors and patient survival rates. This study included 117 SCLCs, comprised of 108 primary and 9 metastatic tumor tissues. We performed immunohistochemical staining for HSP90α, HSP90ß, GRP94 and TRAP1 in 117 tumors and found that HSP90α and HSP90ß were positive in 11 (9%) and 61 tumors (52%), respectively, most of which showed weak expression, whereas GRP94 and TRAP1 were positive in 115 (98%) and 117 tumors (100%), respectively, the majority of which showed moderate or strong expression. None of the HSP90 isoforms showed significant associations with clinicopathological factors or survival status in patients with SCLC. Our results indicate that GRP94 and TRAP1 might contribute more to the carcinogenesis or biology of SCLC than HSP90α and HSP90ß, and that isoform selectivity should be considered when HSP90 inhibitors are studied or utilized for the treatment of SCLC.

Comparison of myocardial F-18 FDG uptake between overnight and non-overnight fasting in non-diabetic healthy subjects.

PURPOSE: To evaluate whether an overnight or non-overnight fast for suppressing physiological FDG uptake by the myocardium is better in non-diabetic healthy subjects before F-18 FDG PET/CT studies. MATERIALS AND METHODS: One hundred two subjects who underwent whole-body F-18 FDG PET/CT for routine health checkups were retrospectively reviewed. For quantitative assessment, a region of interest was drawn around the entire left ventricle visible in the axial view containing the highest visual uptake in order to measure the maximum standardized uptake value (SUV max). FDG uptake in the myocardium was visually graded as follows: grade 0 = minimal, 1 = mostly minimal or mild, 2 = mostly intense or moderate, and 3 = homogeneously intense. Adequate suppression of myocardial uptake was quantitatively defined as a SUV max ≤ 5.0 and grade 0 by visual assessment. RESULTS: With regard to the SUV max, myocardial uptake was not different between the overnight and the non-overnight fasting subjects (P = 0.753). In subjects who had adequate suppression of myocardial uptake, no significant difference was observed between the overnight and non-overnight fasting subjects either in terms of visual or quantitative assessment (P = 0.539 and P = 0.678, respectively). CONCLUSION: Both overnight and non-overnight fasts are not adequate for suppressing the physiological uptake of FDG by the myocardium.

Prognostic value of metabolic tumor volume and total lesion glycolysis in head and neck cancer: a systematic review and meta-analysis.

UNLABELLED: We conducted a comprehensive systematic review of the literature on volumetric parameters and a meta-analysis of the prognostic value of metabolic tumor volume (MTV) and total lesion glycolysis (TLG) in patients with head and neck cancer (HNC). METHODS: A systematic search of MEDLINE and EMBASE was performed using the key words PET, head and neck, and volume. Inclusion criteria were (18)F-FDG PET used as an initial imaging tool; studies limited to HNC; patients who had not undergone surgery, chemotherapy, or radiotherapy before PET scans; and studies reporting survival data. Event-free survival and overall survival were considered markers of outcome. The impact of MTV or TLG on survival was measured by the effect size hazard ratio (HR). Data from each study were analyzed using Review Manager. RESULTS: Thirteen studies comprising 1,180 patients were included in this study. The combined HR for adverse events was 3.06 (2.33-4.01, P < 0.00001) with MTV and 3.10 (2.27-4.24, P < 0.00001) with TLG, meaning that tumors with high volumetric parameters were associated with progression or recurrence. Regarding overall survival, the pooled HR was 3.51 (2.62-4.72, P < 0.00001) with MTV and 3.14 (2.24-4.40, P < 0.00001) with TLG. There was no evidence of significant statistical heterogeneity at an I(2) of 0%. CONCLUSION: MTV and TLG are prognostic predictors of outcome in patients with HNC. Despite clinically heterogeneous HNC and the various methods adopted between studies, we can confirm that patients with a high MTV or TLG have a higher risk of adverse events or death.

Effect of dialysis on cerebral blood flow in depressive end-stage renal disease patients.

OBJECTIVE: The aim of this study was to investigate regional cerebral blood flow (rCBF) changes of end-stage renal disease (ESRD) patients with depressive symptoms during dialysis. METHODS: Fourteen patients with ESRD underwent Tc-99m ethylcysteinate dimer (Tc-99m ECD) brain single photon emission computed tomography (SPECT) and were evaluated the severity of depressive mood at pre-dialytic period and at least 6 months after dialysis initiation. rCBF was analyzed using statistical parametric mapping (SPM) in brain SPECT image. The responder was defined as a decrease of ≥25% in Hamilton Depression Rating Scale (HDRS) score from baseline HDRS score. RESULTS: Pre-dialysis brain SPECT did not show any rCBF differences between responders and non-responders. The follow-up brain SPECT revealed a significant higher perfusion in left middle temporal gyrus of responder group when compared with non-responder (hemisphere coordinate X, Y, Z; -58, -2, -16, peak Z = 3.36, p = 0.046). In responder, a significant increase in rCBF was found in right parahippocampal gyrus (hemisphere coordinate X, Y, Z; 30, -40, -14, peak Z = 3.51, p = 0.043). In non-responder, there were significant decreases in rCBF in left superior frontal gyrus (hemisphere coordinate X, Y, Z; -22, 30, 42, peak Z = 3.86, p = 0.032) and right orbitofrontal cortex (hemisphere coordinate X, Y, Z; 10, 58, -6, peak Z = 3.81, p = 0.046). CONCLUSION: The present findings showed the characteristic patterns of rCBF changes in depressive ESRD patients having maintenance dialysis. Further investigations in brain blood flow and glucose metabolism are needed to elucidate the effect of dialysis itself and the difference of according to dialysis modality in patients having depression and ESRD.

The Prognostic Value of the Metabolic Tumor Volume in FIGO stage IA to IIB Cervical Cancer for Tumor Recurrence: Measured by F-18 FDG PET/CT.

PURPOSE: The purpose of this study was to evaluate the prognostic value of the metabolic tumor volume (MTV), in FIGO stage IA-IIB cervical cancer patients, measured by F-18 fluorodeoxyglucose positron emission tomography (FDG-PET) imaging. METHODS: Forty-five patients with invasive cervical cancer who underwent FDG-PET imaging were recruited. Metabolically active tumor regions were delineated on the pretreatment FDG-PET scans by encompassing regions equal to or greater than an standardized uptake value (SUV) of 40% of the peak tumor intensity. The relationship of the metabolic tumor volume (MTV) to the disease-free survival was analyzed. The MTV of the cervical cancer was compared with pathological and clinical prognostic factors, including lymph node metastasis, parametrial invasion, the depth of invasion, resection margins, tumor differentiation and FIGO stages. RESULTS: Cox proportional hazard regression analysis showed that the MTV was a significant independent predictor of recurrence of cervical cancer (p = 0.027). Patients with an MTV of >20 cm(3) had a significantly reduced disease-free survival compared with patients with an MTV ≤ 20 cm(3) (p = 0.029). The correlation of the MTV with traditional prognostic factors showed significantly higher values in patients that were lymph node (LN) metastasis positive (p = 0.028) and parametrial invasion positive (p = 0.022). The MTV significantly differed among the groups according to tumor differentiation (p = 0.0319) and FIGO stage (p = 0.001). CONCLUSION: The MTV measured by FDG-PET was an independent prognostic factor for tumor recurrence in patients with stage IA-IIB cervical cancer. These findings must be confirmed by large population based prospective studies.

The clinical implication and prediction of diffuse splenic FDG uptake during cancer surveillance.

OBJECTIVE: The purpose of this study was to investigate correlations between diffuse splenic FDG uptake and hematological and inflammatory parameters to clarify the significance of splenic FDG uptake on PET/CT images. METHODS: We retrospectively analyzed the consecutive records of F-18 FDG PET/CT scans and selected 31 patients with diffuse splenic FDG uptake as patient group. A total of 25 patients who underwent F-18 FDG PET/CT scans for simple health checkup were enrolled as control group. ROIs were placed on the liver and spleen to measure maximal standardized uptake value (SUVmax). The spleen SUVmax was divided by the liver SUVmax to calculate the spleen/liver ratio. The correlations between the S/L ratio and various hematological parameters were evaluated. RESULTS: The S/L ratio was positively correlated with serum C-reactive protein level, white blood cell count, and neutrophil count and negatively correlated with hemoglobin, hematocrit, and red blood cell count. Under multiple regression analysis, the Hb level and the C-reactive protein level were the significant predictors for diffuse splenic FDG uptake. CONCLUSION: In conclusion, our study suggests that concurrent inflammation or anemia at the time of PET/CT study could be one of various causes of diffuse splenic FDG uptake.