ObjectiveRecent evidence suggests that the fimbriated end of the fallopian tube harbors the precursor cells for many high-grade ovarian cancers, opening the door for development of better screening methods that directly assess the fallopian tube in women at risk for malignancy. Previously we have shown that the karyometric signature is abnormal in the fallopian tube epithelium in women at hereditary risk of ovarian cancer. In this study, we sought to determine whether the karyometric signature in serous tubal intraepithelial carcinoma (STIC) is significantly different from normal, and whether an abnormal karyometric signature can be detected in histologically normal tubal epithelial cells adjacent to STIC lesions.MethodsThe karyometric signature was measured in epithelial cells from the proximal and fimbriated portion of the fallopian tube in fallopian tube specimens removed from women at: 1) average risk for ovarian cancer undergoing surgery for benign gynecologic indications (n = 37), 2) hereditary risk of ovarian cancer (germline BRCA alterations) undergoing risk-reducing surgery (n = 44), and 3) diagnosed with fimbrial STICs (n = 17).ResultsThe karyometric signature in tubes with fimbrial STICs differed from that of tubes with benign histology. The degree of karyometric alteration increased with increasing proximity to fimbrial STICs, ranging from moderate in the proximal portion of the tube, to greatest in both normal appearing fimbrial cells near STICs as well as in fimbrial STIC lesions.ConclusionThese data demonstrate an abnormal karyometric signature in STICs that may extend beyond the STIC, potentially providing an opportunity for early detection of fallopian tube neoplasia.

ADA-07 significantly suppresses SUV-induced skin carcinogenesis in SKH-1 hairless mice (early-stage prevention). A, average body weight of SKH-1 hairless mice. Mice were weighed once a week until the end of the study at week 28. B, external appearance of tumors. SKH-1 hairless mice were treated as described in Materials and Methods. The mice in the control groups (n = 9) received no vehicle/no SUV (n = 3), vehicle/no SUV (n = 3), or 1 mg ADA-07/no SUV (n = 3), respectively. The mice in the SUV treated group received SUV only (n = 12) and the mice in the vehicle/SUV-treated group (n = 12) were treated with oil-in-water emulsion cream before SUV exposure. The mice in the 0.1 mg/SUV or 1 mg/SUV groups (n = 12 each) received treatment with ADA-07 (0.1 or 1 mg, respectively) before SUV exposure. The frequency of irradiation was set at 3 times a week for 15 weeks. The respective doses of oil-in-water emulsion cream or ADA-07 were applied topically to the dorsal area. Tumor incidence and multiplicity were recorded weekly until the end of the experiment at week 28.

Abstract The incidence of skin cancer is higher than all other cancers and continues to increase, with an average annual cost over $8 billion in the United States. As a result, identifying molecular pathway alterations that occur with UV exposure to strategize more effective preventive and therapeutic approaches is essential. To that end, we evaluated phosphorylation of proteins within the PI3K/Akt and MAPK pathways by immunohistochemistry in sun-protected skin after acute doses of physiologically relevant solar-simulated ultraviolet light (SSL) in 24 volunteers. Biopsies were performed at baseline, 5 minutes, 1, 5, and 24 hours after SSL irradiation. Within the PI3K/Akt pathway, we found activation of Akt (serine 473) to be significantly increased at 5 hours while mTOR (serine 2448) was strongly activated early and was sustained over 24 hours after SSL. Downstream, we observed a marked and sustained increase in phospho-S6 (serine 235/S236), whereas phospho-4E-BP1 (threonines 37/46) was increased only at 24 hours. Within the MAPK pathway, SSL-induced expression of phospho-p38 (threonine 180/tyrosine 182) peaked at 1 to 5 hours. ERK 1/2 was observed to be immediate and sustained after SSL irradiation. Phosphorylation of histone H3 (serine 10), a core structural protein of the nucleosome, peaked at 5 hours after SSL irradiation. The expression of both p53 and COX-2 was increased at 5 hours and was maximal at 24 hours after SSL irradiation. Apoptosis was significantly increased at 24 hours as expected and indicative of a sunburn-type response to SSL. Understanding the timing of key protein expression changes in response to SSL will aid in development of mechanistic-based approaches for the prevention and control of skin cancers. Cancer Prev Res; 8(8); 720–8. ©2015 AACR.

Perspective on this Article from A Phase 2a Study of Topical Perillyl Alcohol Cream for Chemoprevention of Skin Cancer

PURPOSE:To determine whether the addition of cisplatin-based chemotherapy (CT) to pelvic radiation therapy (RT) will improve the survival of early-stage, high-risk patients with cervical carcinoma. PATIENTS AND METHODS:Patients with clinical stage IA(2), IB, and IIA carcinoma of the cervix, initially treated with radical hysterectomy and pelvic lymphadenectomy, and who had positive pelvic lymph nodes and/or positive margins and/or microscopic involvement of the parametrium were eligible for this study. Patients were randomized to receive RT or RT + CT. Patients in each group received 49.3 GY RT in 29 fractions to a standard pelvic field. Chemotherapy consisted of bolus cisplatin 70 mg/m(2) and a 96-hour infusion of fluorouracil 1,000 mg/m(2)/d every 3 weeks for four cycles, with the first and second cycles given concurrent to RT. RESULTS:Between 1991 and 1996, 268 patients were entered onto the study. Two hundred forty-three patients were assessable (127 RT + CT patients and 116 RT patients). Progression-free and overall survival are significantly improved in the patients receiving CT. The hazard ratios for progression-free survival and overall survival in the RT only arm versus the RT + CT arm are 2.01 (P =.003) and 1.96 (P =. 007), respectively. The projected progression-free survivals at 4 years is 63% with RT and 80% with RT + CT. The projected overall survival rate at 4 years is 71% with RT and 81% with RT + CT. Grades 3 and 4 hematologic and gastrointestinal toxicity were more frequent in the RT + CT group. CONCLUSION:The addition of concurrent cisplatin-based CT to RT significantly improves progression-free and overall survival for high-risk, early-stage patients who undergo radical hysterectomy and pelvic lymphadenectomy for carcinoma of the cervix.

ADA-07 synthesis, MS analysis and cytotoxicity assays.

Supplementary Figure Legends from Activation of the PI3K/Akt/mTOR and MAPK Signaling Pathways in Response to Acute Solar-Simulated Light Exposure of Human Skin

Staining for Ki67 in mouse tumors.

Supplementary Figure 1. Box plot graphs of protein expression in sun-protected skin after 2, 2,5, and 3 MED (x-axis) of SSL-irradiation (SSL) with baseline (green bars), 5 minutes (orange bars), 1 hour (blue bars), 5 hours (red bars), and 24 hours (grey bars) post SSL on the y-axis. Supplementary Figure 2. Box plot graphs of protein expression in sun-protected skin after 2, 2,5, and 3 MED (x-axis) of SSL-irradiation (SSL) with baseline (green bars), 5 minutes (orange bars), 1 hour (blue bars), 5 hours (red bars), and 24 hours (grey bars) post SSL on the y-axis. Supplementary Figure 3. Box plot graphs of protein expression in sun-protected skin after 2, 2,5, and 3 MED (x-axis) of SSL-irradiation (SSL) with baseline (green bars), 5 minutes (orange bars), 1 hour (blue bars), 5 hours (red bars), and 24 hours (grey bars) post SSL on the y-axis.

Measurement of ADA-07 absorbance by spectrophotometer. Absorbance wavelengths of ADA-07 were scanned using a Beckman DU®800 spectrophotometer.

ADA-07 significantly suppresses SUV-induced skin carcinogenesis in SKH-1 hairless mice (late-stage prevention). A, average body weight of SKH-1 hairless mice. Mice were weighed once a week until week 28. B, external appearance of tumors. SKH-1 hairless mice were treated as described in Materials and Methods. The mice in the control groups (n = 9) received no vehicle/no SUV (n = 3), vehicle/no SUV (n = 3), or 1 mg ADA-07/no SUV (n = 3), respectively. The mice in the rest of the groups received SUV irradiation for 15 weeks 3 times a week. The mice in the vehicle/SUV-treated group (n = 12) were treated with oil-in-water emulsion cream 3 times a week until the end of the experiment (28 weeks). The mice in the 0.1 mg/SUV or 1 mg/SUV groups (n = 12 each) received treatment with ADA-07 (0.1 or 1 mg, respectively) 3 times a week until the end of the experiment (28 weeks). The respective doses of oil-in-water emulsion cream or ADA-07 were applied topically to the dorsal area. Tumor incidence and multiplicity were recorded weekly until the end of the experiment at week 28.

OBJECTIVE:The Lifestyle Intervention for oVarian cancer Enhanced Survival (LIVES) is a national study of a combined diet and physical activity intervention for stage II-IV ovarian cancer survival, an under-represented cancer in lifestyle behavioral intervention research. Here, we present the data on recruitment, retention, and baseline demographic, clinical and lifestyle behavior characteristics of the LIVES study participants. METHODS:The LIVES study (NRG Oncology/GOG 0225) is a Phase III diet plus physical activity intervention trial testing the hypothesis that ovarian cancer survivors in the lifestyle intervention will demonstrate better progression-free survival than those in the control condition. Study interventions were delivered via centralized telephone-based health coaching. Baseline descriptive statistics were computed for demographic, clinical, and lifestyle behavior characteristics. RESULTS:The LIVES study exceeded its recruitment goals, enrolling 1205 ovarian cancer survivors from 195 NRG/NCORP-affiliated oncology practices across 49 states from 2012 to 2018. The mean age of enrollees was 59.6 years; the majority (69.4%) with stage III disease; 89% White, 5.5% Hispanic; 64% overweight/obese. Baseline self-reported diet showed a mean daily intake of 6.6 servings of fruit and vegetables, 62.7 fat grams, and 21.7 g of fiber. Physical activity averaged 13.0 MET-hours/week of moderate to vigorous physical activity; 50.9 h/week of sedentary time. Retention rates exceeded 88%. CONCLUSION:The LIVES study demonstrates efficiency in recruiting and retaining ovarian cancer survivors in a 24-month study of diet and physical activity intervention with a primary endpoint of progression free survival that will be reported. TRIAL REGISTRATION:ClinicalTrials.govNCT00719303.

Schema representing UV-induced signaling, rapamycin and PHT-427-regulated pathways in keratinocytes.

The expression level of TOPK in normal skin cells (JB6 P+, NHDF) and skin cancer cells (A431 and SCC12). TOPK expression was assessed by Western blot using a specific antibody and β-actin was used as a loading control.

The binding between ADA-07 and TOPK is illustrated by Maestro in the Schrödinger Suite. The binding model shows that the hydrogen atom (white color) of glycine binds with oxygen (red color) and nitrogen (blue color) of ADA-07 to form hydrogen bonds. The oxygen atom of glycine binds with hydrogen of ADA-07 to form a hydrogen bond.

Supplementary Figure S1 from Loss of Inositol Polyphosphate 5-Phosphatase Is an Early Event in Development of Cutaneous Squamous Cell Carcinoma

Objectives: The primary objective of this analysis of GOG 252 is to assess the overall survival of the subgroup of participants with metastatic epithelial ovarian cancer, with no more than microscopic residual disease, following their primary cytoreductive surgery followed by three chemotherapy regimens and bevacizumab. The results of the response to chemotherapy based on the CA-125 nadir are also included. Methods: Patients were randomly assigned to six cycles of IV paclitaxel 80 mg/m2 weekly, with IV carboplatin AUC 6 on day 1 (IV carbo arm), versus IV paclitaxel 80 mg/m2 weekly, with IP carboplatin AUC 6 on day 1 (IP carbo arm) versus IV paclitaxel 135 mg/m2 IV on day 1 every three weeks, IP cisplatin 75 mg/m2 on day 2, and IP paclitaxel 60 mg/m2 on day 8 (IP Cisplatin arm). All participants received bevacizumab 15 mg/kg IV on day 1 every three weeks for cycles 2-22. CA-125 was drawn before each cycle of chemotherapy, and q3 months for the first two years and q6 months for the next three years and then annually. CT was performed postoperatively and before enrollment, and then every six months for five years and then annually. Results: A total of 1560 patients were enrolled of whom 900 (57.7%) had no more than microscopic residual disease as assessed by the surgeon. For this analysis, an excellent response to front line chemotherapy was to see a nadir of CA-125 < 10 before cycle 4. The median duration of follow up was 9.2 years. There were 573 with recurrent disease (63.7%) and 413 deaths (45.9%). There was no statistically significant difference in PFS between treatment groups (p=0.735, log-rank Chi square = 0.617 with 2 DF). The hazard of progression or death is relatively high for the first 3-4 years and then declines. The estimates of proportion of patients alive and recurrence-free at 10 years were 0.32, 0.33, and 0.32, respectively. The probability of living at least 10 years was 0.473, 0.467 and 0.470. The CA-125 nadir after cycle 1 and before cycle 4 of less than 10 was 53.5% 51.5%, and 34.4% in the three arms, respectively. The median PFS was 28.5 months for those with CA-125 nadir > 10 IU and 44.2 months for those less than or equal to 10 IU. The median survival for CA-125 nadir greater than 10 was 89 months. Objectives: The primary objective of this analysis of GOG 252 is to assess the overall survival of the subgroup of participants with metastatic epithelial ovarian cancer, with no more than microscopic residual disease, following their primary cytoreductive surgery followed by three chemotherapy regimens and bevacizumab. The results of the response to chemotherapy based on the CA-125 nadir are also included. Methods: Patients were randomly assigned to six cycles of IV paclitaxel 80 mg/m2 weekly, with IV carboplatin AUC 6 on day 1 (IV carbo arm), versus IV paclitaxel 80 mg/m2 weekly, with IP carboplatin AUC 6 on day 1 (IP carbo arm) versus IV paclitaxel 135 mg/m2 IV on day 1 every three weeks, IP cisplatin 75 mg/m2 on day 2, and IP paclitaxel 60 mg/m2 on day 8 (IP Cisplatin arm). All participants received bevacizumab 15 mg/kg IV on day 1 every three weeks for cycles 2-22. CA-125 was drawn before each cycle of chemotherapy, and q3 months for the first two years and q6 months for the next three years and then annually. CT was performed postoperatively and before enrollment, and then every six months for five years and then annually. Results: A total of 1560 patients were enrolled of whom 900 (57.7%) had no more than microscopic residual disease as assessed by the surgeon. For this analysis, an excellent response to front line chemotherapy was to see a nadir of CA-125 < 10 before cycle 4. The median duration of follow up was 9.2 years. There were 573 with recurrent disease (63.7%) and 413 deaths (45.9%). There was no statistically significant difference in PFS between treatment groups (p=0.735, log-rank Chi square = 0.617 with 2 DF). The hazard of progression or death is relatively high for the first 3-4 years and then declines. The estimates of proportion of patients alive and recurrence-free at 10 years were 0.32, 0.33, and 0.32, respectively. The probability of living at least 10 years was 0.473, 0.467 and 0.470. The CA-125 nadir after cycle 1 and before cycle 4 of less than 10 was 53.5% 51.5%, and 34.4% in the three arms, respectively. The median PFS was 28.5 months for those with CA-125 nadir > 10 IU and 44.2 months for those less than or equal to 10 IU. The median survival for CA-125 nadir greater than 10 was 89 months.

There has been increasing interest in measuring concentrations of retinol, α-tocopherol, and β-carotene in human serum, plasma, and other tissues. This interest has carried over into the measurement of other retinoids and carotenoids. It is clear that high pressure liquid chromatography (HPLC) has become the method of choice for separating these analytes of interest from other substances, and UV detection has emerged as the most widely used method for quantifying the analytes separated by the chromotographic procedure. The application of HPLC to the separation and detection of retinoids in biological samples has proven to be a powerful and valuable tool for pharmacologic studies. The use of HPLC offers several advantages over conventional methods such as colorimetry, thin layer chromatography, gas chromatography (GC), or GC/mass spectromotry. Rapid separation, excellent resolution, quantitative recovery, and the capability of separating a wide range of retinoids and metabolites with only minor manipulation of the chromatographic conditions are a few of these advantages.