Cetuximab continuation after first progression in metastatic colorectal cancer (CAPRI-GOIM): a randomized phase II trial of FOLFOX plus cetuximab versus FOLFOX.

BACKGROUND: Cetuximab plus chemotherapy is a first-line treatment option in metastatic KRAS and NRAS wild-type colorectal cancer (CRC) patients. No data are currently available on continuing anti-epidermal growth factor receptor (EGFR) therapy beyond progression. PATIENTS AND METHODS: We did this open-label, 1:1 randomized phase II trial at 25 hospitals in Italy to evaluate the efficacy of cetuximab plus 5-fluorouracil, folinic acid and oxaliplatin (FOLFOX) as second-line treatment of KRAS exon 2 wild-type metastatic CRC patients treated in first line with 5-fluorouracil, folinic acid and irinotecan (FOLFIRI) plus cetuximab. Patients received FOLFOX plus cetuximab (arm A) or FOLFOX (arm B). Primary end point was progression-free survival (PFS). Tumour tissues were assessed by next-generation sequencing (NGS). This report is the final analysis. RESULTS: Between 1 February 2010 and 28 September 2014, 153 patients were randomized (74 in arm A and 79 in arm B). Median PFS was 6.4 [95% confidence interval (CI) 4.7-8.0] versus 4.5 months (95% CI 3.3-5.7); [hazard ratio (HR), 0.81; 95% CI 0.58-1.12; P = 0.19], respectively. NGS was performed in 117/153 (76.5%) cases; 66/117 patients (34 in arm A and 32 in arm B) had KRAS, NRAS, BRAF and PIK3CA wild-type tumours. For these patients, PFS was longer in the FOLFOX plus cetuximab arm [median 6.9 (95% CI 5.5-8.2) versus 5.3 months (95% CI 3.7-6.9); HR, 0.56 (95% CI 0.33-0.94); P = 0.025]. There was a trend in better overall survival: median 23.7 [(95% CI 19.4-28.0) versus 19.8 months (95% CI 14.9-24.7); HR, 0.57 (95% CI 0.32-1.02); P = 0.056]. CONCLUSIONS: Continuing cetuximab treatment in combination with chemotherapy is of potential therapeutic efficacy in molecularly selected patients and should be validated in randomized phase III trials.

Heterogeneity of KRAS, NRAS, BRAF and PIK3CA mutations in metastatic colorectal cancer and potential effects on therapy in the CAPRI GOIM trial.

BACKGROUND: Evidence suggests that metastatic colorectal carcinoma (mCRC) has a high level of intratumor heterogeneity. We carried out a quantitative assessment of tumor heterogeneity for KRAS, NRAS, BRAF and PIK3CA mutations, in order to assess potential clinical implications. PATIENTS AND METHODS: Tumor samples (n = 182) from the CAPRI-GOIM trial of first-line cetuximab + FOLFIRI in KRAS exon-2 wild-type mCRC patients were assessed by next-generation sequencing that allows quantitative assessment of mutant genes. Mutant allelic frequency was normalized for the neoplastic cell content and, assuming that somatic mutations usually affect one allele, the Heterogeneity Score (HS) was calculated by multiplying by 2 the frequency of mutant alleles in neoplastic cells. Therefore, HS virtually corresponds to the fraction of neoplastic cells carrying a specific mutation. RESULTS: The KRAS HS ranged between 12 and 260 with mean value of 87.1 and median value of 84.4, suggesting that in most CRC, the majority of neoplastic cells carry mutant KRAS. Similar findings were observed for NRAS (HS range 35.5-146.7; mean 102.8; median 117.1). In contrast, in BRAF (HS range 17.1-120; mean 54.8; median 54.3) and PIK3CA (HS range 14.3-120; mean 59.5; median 47.3) mutant cases, only a fraction of neoplastic cells seem to carry the mutant allele. The response rate was 70% in KRAS mutant patients with an HS <33 (low KRAS; n = 10) and 45.7% in KRAS HS >33 patients (high KRAS; n = 35); median progression-free survival were 7.97 and 8.37 months, respectively. Low-KRAS tumors had a higher frequency of additional mutations in PIK3CA when compared with high-KRAS (6/10 versus 8/35). CONCLUSIONS: KRAS and NRAS mutations are usually present in the majority of neoplastic cells, whereas BRAF and PIK3CA mutations often affect a limited fraction of transformed cells. Resistance to cetuximab in low-KRAS patients might be driven by the complex mutational profile rather than KRAS mutation load.

An oil-soluble extract of Rubus idaeus cells enhances hydration and water homeostasis in skin cells.

OBJECTIVE: Raspberry plants, belonging to the species of Rubus idaeus, are known for their excellent therapeutic properties as they are particularly rich in compounds with strong antioxidant activity, which promote health and well-being of human cells. Besides their high content of phenolic compounds, Rubus plants are rich in oil-soluble compounds, which are also primary components of the hydrolipidic film barrier of the skin. As plant cell cultures represented a valuable system to produce interesting compounds and ingredients for cosmetic applications, we developed liquid suspension cultures from Rubus idaeus leaves and used them to obtain an active ingredient aimed at improving hydration and moisturization capacity in the skin. METHODS: Rubus idaeus cells, grown in the laboratory under sterile and controlled conditions as liquid suspension cultures, were processed to obtain an oil-soluble (liposoluble) extract, containing phenolic compounds and a wide range of fatty acids. The extract was tested on cultured keratinocytes and fibroblasts and then on the skin in vivo, to assess its cosmetic activities. RESULTS: When tested on skin cell cultures, the extract induced the genes responsible for skin hydration, such as aquaporin 3, filaggrin, involucrin and hyaluronic acid synthase, and stimulated the expression and the activity of the enzyme glucocerebrosidase, involved in ceramide production. Moreover, the liposoluble extract increased the synthesis of the extracellular matrix components in cultured fibroblasts and showed a remarkable skin-hydrating capacity when tested on human skin in vivo. CONCLUSIONS: Thanks to these activities, the Rubus idaeus liposoluble extract has several potential applications in skin care cosmetics: it can be used as hydrating and moisturizing ingredient in face and body lotions, and as anti-ageing product in face creams specifically designed to fight wrinkle formation.

Clinical activity of FOLFIRI plus cetuximab according to extended gene mutation status by next-generation sequencing: findings from the CAPRI-GOIM trial.

BACKGROUND: Treatment with antiepidermal growth factor receptor (anti-EGFR) monoclonal antibodies has been restricted to metastatic colorectal cancer (mCRC) patients with RAS wild-type tumors. Next-generation sequencing (NGS) allows the assessment in a single analysis of a large number of gene alterations and might provide important predictive and prognostic information. PATIENTS AND METHODS: In the CAPRI-GOIM trial, 340 KRAS exon 2 wild-type mCRC patients received first-line FOLFIRI plus cetuximab. Tumor samples (182/340, 53.5%) were assessed by NGS to search for mutations in 22 genes involved in colon cancer. RESULTS: Objective responses in the NGS cohort were observed in 104/182 patients [overall response rate (ORR) 57.1%; 95% confidence interval (95% CI) 52% to 66.4%] with a median progression-free survival (mPFS) of 9.8 (95% CI 8.7-11.5) months. NGS analysis was successfully completed in all 182 samples. One or more gene mutations (up to five) were detected in 124/182 (68.1%) tumors within 14/22 genes for a total of 206 mutations. KRAS exon 2 mutations were identified in 29/182 (15.9%) samples, defined as wild type by local laboratory assessment. Frequently mutated genes were: TP53 (39.6%), KRAS exons 3/4 (8.8%), NRAS exons 2/3 (7.1%), PIK3CA exons 9/20 (13.2%), BRAF (8.2%). FOLFIRI plus cetuximab treatment determined ORR of 62.0% (95% CI 55.5% to 74.6%) with mPFS of 11.1 (95% CI 9.2-12.8) months in patients with KRAS and NRAS wild-type tumors. Conversely, ORR was 46.6% (95% CI 39.9-57.5%) with mPFS of 8.9 (95% CI 7.4-9.6) months in patients with KRAS or NRAS mutations. Similarly, the subgroup of patients carrying KRAS, NRAS, BRAF, or PIK3CA mutations showed a worse outcome, although this might be due to a prognostic effect. CONCLUSIONS: This study demonstrates that NGS analysis in mCRC is feasible, reveals high level of intra and intertumor heterogeneity, and identifies patients that might benefit of FOLFIRI plus cetuximab treatment.

A multicenter phase III prospective randomized trial of high-dose epirubicin in combination with cyclophosphamide (EC) versus docetaxel followed by EC in node-positive breast cancer. GOIM (Gruppo Oncologico Italia Meridionale) 9902 study.

BACKGROUND: The Gruppo Oncologico Italia Meridionale 9902 trial compared four cycles of high-dose epirubicin plus cyclophosphamide (EC) with four cycles of docetaxel (Taxotere, D) followed by four cycles of EC as adjuvant treatment of node-positive breast cancer. PATIENTS AND METHODS: Patients were randomly assigned to EC (E 120 mg/m(2), C 600 mg/m(2), arm A) for four cycles or four cycles of D (100 mg/m(2)) followed by four cycles of EC (arm B), both regimens every 21 days. Hormone receptor-positive patients were given hormonal therapy for 5 years. Primary end point was 5-year disease-free survival (DFS). Secondary objectives were overall survival (OS) and safety. RESULTS: There were 750 patients enrolled. With a median follow-up of 64 months, 5-year DFS was 73.4% in both arms, and 5-year OS was 89.5% versus 90.7% in arm A and B [hazard ratio was 0.99 (95% confidence interval for DFS 0.75-1.31; P = 0.95)], respectively. Grade 3-4 toxicity was more common in arm B. CONCLUSIONS: This study did not show advantages from the addition of docetaxel to high-dose EC as adjuvant chemotherapy in node-positive breast cancer. The small sample size and low number of DFS events may have limited the ability to observe statistically significant difference between the two arms.

Effect of a single, oral, high-dose vitamin D supplementation on endothelial function in patients with peripheral arterial disease: a randomised controlled pilot study.

OBJECTIVE: Apart from its role in bone metabolism, vitamin D may also influence cardiovascular disease. The objective of this study was: (1) to determine the effect of a single, oral, high-dose vitamin D supplementation on endothelial function and arterial stiffness in patients with peripheral arterial disease (PAD) and (2) to investigate the impact of this supplementation on coagulation and inflammation parameters. METHODS: In this double-blind, placebo-controlled, interventional pilot study, we screened 76 Caucasian patients with PAD for vitamin D deficiency. Sixty-two were randomised to receive a single, oral supplementation of 100,000 IU vitamin D3 or placebo. At baseline and after 1 month, we measured serum vitamin D and parathormone levels, and surrogate parameters for cardiovascular disease. RESULTS: Sixty-five of 76 patients (86%) had low 25-hydroxyvitamin D levels (<30 ng ml(-1)); of those, 62 agreed to participate in the study. At baseline, only parathormone was related to vitamin D. In supplemented patients, vitamin D levels increased from 16.3 ± 6.7 to 24.3 ± 6.2 ng ml(-1) (P < 0.001), with wide variations between single patients; in the placebo group vitamin levels did not change. Seasonal factors accounted for a decrease of vitamin D levels by 8 ng ml(-1) between summer and winter. After 1 month, none of the measured parameters was influenced by vitamin substitution. CONCLUSION: In this pilot study, most patients with PAD were vitamin D deficient. Vitamin D supplementation increased serum 25-hydroxyvitamin D without influencing endothelial function, arterial stiffness, coagulation and inflammation parameters, although the study was underpowered for definite conclusions.

Central nervous system failure in melanoma patients: results of a randomised, multicentre phase 3 study of temozolomide- and dacarbazine- based regimens.

BACKGROUND: This study compared the central nervous system (CNS) metastasis incidence between a temozolomide- and a dacarbazine-based regimen in untreated stage IV melanoma patients. METHODS: A total of 150 patients were randomly assigned to receive either oral temozolomide (200 mg m(-2) per day; days 1-5) or intravenous dacarbazine (800 mg m(-2); day 1), in combination with intravenous cisplatin (75 mg m(-2); day 1) and subcutaneous interleukin-2 (3 MU twice daily; days 9-18), every 28 days (CTI and CDI). RESULTS: A total of 149 patients were eligible for an intention-to-treat analysis (CTI: n=74, CDI: n=75). The 1-year cumulative CNS incidence failure was 20.6% for CTI and 31.1% for CDI (P=0.22). In all 24 patients in CTI (32%) and 34 (45%) in CDI developed CNS metastases; 31 patients died of early systemic progression, before CNS evaluation. Median survival time was 8.4 months in the CTI and 8.7 in the CDI arm; in patients with CNS metastases the median survival time was 13.5 months in the CTI and 11.5 in the CDI arm. No difference in toxicity was observed between the two arms. CONCLUSION: The incidence of CNS failures in metastatic melanoma was not significantly reduced and the clinical course was not modified substituting a dacarbazine-based regimen with a temozolomide-based regimen. Patients who developed CNS metastases did not have a worse prognosis than patients progressing in other sites and should not be excluded from new investigational studies.

FOLFOX6 and bevacizumab in non-optimally resectable liver metastases from colorectal cancer.

BACKGROUND: In patients with colorectal liver metastases (CLM) R0 resection significantly improves overall survival (OS). METHODS: In this report, we present the results of a phase II trial of FOLFOX6+bevacizumab in patients with non-optimally resectable CLM. Patients received six cycles of FOLFOX6+ five of bevacizumab. Patients not achieving resectability received six additional cycles of each. A PET-CT was performed at baseline and again within 1 month after initiating treatment. RESULTS: From September 2005 to July 2009, 21 patients were enrolled (Male/Female: 15/6; median age: 65 years). An objective response (OR) was documented in 12 cases (57.1%; complete responses (CRs): 3, partial response (PR): 9); one patient died from toxicity before surgery. Thirteen patients underwent radical surgery (61.9%). Three (23%) had a pathological CR (pCR). Six patients (46.1%) experienced minor postsurgical complications. After a median 38.8-month follow-up, the median OS was 22.5 months. Patients achieving at least 1 unit reduction in Standard uptake value (SUV)max on PET-CT had longer progression-free survival (PFS) (median PFS: 22 vs 14 months, P=0.001). CONCLUSIONS: FOLFOX6+bevacizumab does not increase postsurgical complications, yields high rates of resectability and pCR. Early changes in PET-CT seem to be predictive of longer PFS.

Rapamycin-induced hypophosphatemia and insulin resistance are associated with mTORC2 activation and Klotho expression.

Rapamycin, an immunosuppressive drug used to prevent rejection after kidney transplantation, influences phosphate homeostasis, induces insulin resistance and has been shown to prolong lifespan in animal models. Because Klotho is an aging-suppressor gene controlling phosphate metabolism and insulin sensitivity, we investigated the influence of rapamycin on Klotho expression. A total of 100 kidney transplant recipients, 50 chronically treated with rapamycin and 50 with calcineurin inhibitors, were enrolled; 20 healthy subjects were employed as control. In the rapamycin group, serum phosphate was lower than in the CNI group with an increase in phosphate excretion and a reduction in its reabsorption. In addition, rapamycin increased insulin resistance as shown by HOMA index. Rapamycin treatment of an immortalized proximal tubular cell line induced the expression of Klotho, the phosphorylation of AKT in Ser473, downstream target of mTORC2 and the expression of RICTOR, mTORC2 main component. AKT inhibition reduced the rapamycin-induced expression of Klotho. In vivo rapamycin treatment induced higher degree of RICTOR and AKT Ser(473) expression directly correlating with long-term rapamycin exposure, FE(PO4) and HOMA index. In conclusion, our data would suggest that rapamycin may influence phosphate homeostasis and insulin resistance modulating Klotho expression through mTORC2 activation.

A multicenter phase II randomized trial of docetaxel/gemcitabine versus docetaxel/capecitabine as first-line treatment for advanced breast cancer: a Gruppo Oncologico Italia Meridionale study.

OBJECTIVE: To evaluate two docetaxel-based regimens as first-line treatment in advanced breast cancer patients. METHODS: Patients were randomly assigned to docetaxel/gemcitabine (arm A: docetaxel 75 mg/m(2) on day 1, gemcitabine 1,000 mg/m(2) on days 1 and 8) or docetaxel/capecitabine (arm B: docetaxel 75 mg/m(2) on day 1, capecitabine 1,250 mg/m(2) twice daily on days 1-14); both chemotherapy regimens were repeated every 21 days. The primary objective of the study was to evaluate the response rate. RESULTS: Seventy-two patients were enrolled (36 each in arms A and B). Responses according to intention-to-treat analysis were as follows: arm A, 41.7% [95% confidence interval (CI) 25.6-57.8]; arm B, 38.9% (95% CI 23-54.8). Median progression-free survival was 10.9 months (95% CI 8.1-13.7) in arm A and 10 months (95% CI 8.8-11.2) in arm B. Overall survival was 26 months (95% CI 22.0-30.0) in arm A and 28 months (95% CI 23.4-32.6) in arm B. Both treatments were well tolerated; myelosuppression was the dose-limiting toxicity, with grade 3-4 neutropenia in 13.8 and 19.4% of the patients in arms A and B, respectively. No relevant differences in other toxicities were observed in the two arms, except for diarrhea (13.9%) and hand-foot syndrome (11.1%), which occurred only in arm B. CONCLUSIONS: Both regimens were active and well tolerated in advanced breast cancer.

Cryoglobulinemic membranoproliferative glomerulonephritis: beyond conventional therapy.

Membranoproliferative glomerulonephritis associated with Type II cryoglobulinemia is the predominant type of HCV-related glomerulonephritis. Immunosuppressive and anti-viral therapy is alternately used to treat it, but the results are not always satisfactory or lasting. In this paper we report 3 cases of cryoglobulinemic membranoproliferative glomerulonephritis, treated with different and personalized therapeutic approaches by using conventional therapy and new drugs such as mycophenolate mofetil and rituximab. Our case series report emphasizes the importance of choosing the treatment for each patient, taking into account many factors: age, severity of liver and renal involvement, extra-renal manifestations, any previous treatment, contraindications or adverse events and last but not least the balance between immunosuppression and virus activity.

Treatment of hepatocellular carcinoma.

As a result of progresses in surveillance programs and improvements in diagnosis, an increased number of hepatocellular carcinomas are diagnosed in early stage, when effective treatment options are available. Surgical resection, liver transplantation and radiofrequency ablation are considered potentially curative treatments and may be successfully applied when the disease is limited. In intermediate and advanced stages only palliative therapies can be employed and chemoembolization and the oral dual inhibitor sorafenib are considered the treatments of choice. Future directions will explore the role of sorafenib in the adjuvant setting, the addition of sorafenib to chemoembolization procedures and the combination of sorafenib with chemotherapeutic agents or other biological drugs in advanced stages of disease.

MicroRNAs as a new potential therapeutic opportunity in gastrointestinal cancer.

MicroRNAs (miRNAs) comprise an abundant class of small non-coding RNAs that act as important post-transcriptional regulators of gene expression. Accumulating evidence shows that aberrantly expressed miRNAs play important roles in human cancers and underscores them as potential targets for therapeutic intervention. Basic research has provided strong evidence about the role of miRNA as oncogenes and as tumor suppressor genes in cancer. In accord with this finding, miRNA-based cancer therapy is a very interesting field of investigation that offers the appeal of targeting multiple gene networks controlled by a single, aberrantly expressed miRNA. A new door in cancer research is opening and it may lead to the modulation of miRNAs.

A cohort study of results following elective colonic and rectal resection within an enhanced recovery programme.

OBJECTIVE: The use of laparoscopic surgery coupled with an enhanced recovery programme (ERP) has resulted in hospital stays of 4 or less days for colonic and 6 days following rectal resection, in previously reported small selected groups of patients. This report analyses an unselected cohort to determine if such benefits are reproducible. METHOD: Consecutive patients undergoing elective colonic or rectal surgery at a single centre between January 2002 and January 2006 were followed. All were included in the ERP and underwent either laparoscopic or open surgery. RESULTS: The study group comprised 241 patients (mean age of 67 +/- standard deviation 14 years and 49% male sex distribution) who underwent elective colorectal resection within the context of an ERP. One hundred and fifty-one (62.7%) patients had malignant disease. Overall, 191 (79.3%) patients underwent a laparoscopic procedure and the remaining underwent an open operation. Postoperative stay was shorter in patients undergoing laparoscopic vs open, colonic surgery (4 days vs 6 days, P = 0.002). A nonsignificant trend towards reduced postoperative stay was observed for patients undergoing laparoscopic vs open, rectal surgery (6 days vs 9 days, P = 0.088). Patients undergoing laparoscopic colectomy demonstrated significantly lower 30-day mortality rates than those undergoing traditional colectomy (3/131 vs 3/39, P = 0.049). CONCLUSION: Laparoscopic colonic surgery in the context of an ERP offers reduced hospital stay and may confer a survival advantage over traditional techniques. These results confirm that previously reported benefits of laparoscopic surgery are reproducible within an unselected population.

Trends in colorectal day case surgery in NHS Trusts between 1998 and 2005.

OBJECTIVE: Day case surgery is safe and offers potential benefits to both patients and healthcare providers. This study aimed to describe national changes in colorectal day case workload between 1998 and 2005. METHODS: Admission data relating to Office of Population Censuses and Surveys Classification of Surgical Operations and Procedures (4th revision) (OPCS-4) coloproctology operation codes were analysed using the Hospital Episode Statistics (HES) database. Day case rates (DCRs) were calculated as the proportion of elective cases performed on an ambulatory basis. RESULTS: In total, 3 119 058 colorectal admissions were recorded on the HES database between 1998 and 2005; 1 891 474 (61%) of these were for lower gastrointestinal endoscopies. Emergency cases accounted for 527 665 (17%), elective inpatient cases for 406 368 (13%) and elective day cases for 293 551 (9%) admissions. Throughout the study period the DCRs for five commonly performed elective colorectal procedures were: 0.70 for anal lesion excisions (OPCS-4 codes: H48.1, H48.2 and H48.3); 0.16 for haemorrhoidectomy (OPCS-4 code: H51.1); 0.63 for anal fissure procedures (OPCS-4 codes: H56.2 and H56.4); 0.39 for elective procedures for anal fistula (OPCS-4 codes: H55.1, H55.2, H55.3 and H55.4); 0.37 for elective pilonidal surgery (OPCS-4 codes: H59 and H60.2). Two emergency operations, drainage of perianal and pilonidal abscesses (OPCS-4 codes: H58.2 and H60.3 respectively), were identified as operations potentially amenable to day surgery. Over the seven study years, an annual average of 8559 (+/-SD 307) admissions were coded to drainage of a perianal abscess and 4676 (+/-SD 478) admissions to drainage of pilonidal abscess. The average annual bed usage associated with these procedures was 18 831 (+/-SD 718) and 7623 (+/-SD 436) bed days respectively. CONCLUSIONS: Colorectal day case surgery is currently under-exploited in the NHS. By lifting some of the barriers to day case surgery significant resource savings may be possible.

Cetuximab in colon cancer.

In the last decade remarkable progress has been made in the treatment of metastatic colorectal cancer due to the introduction of oxaliplatin and irinotecan in clinical practice. The addition of biological agents seems to offer a chance to further enhance the activity of conventional chemotherapy. Cetuximab, a chimeric mouse-human monoclonal antibody targeting the extracellular domain of the epidermal growth factor receptor (EGFR), has shown low but detectable activity when employed in pretreated patients either as a single agent or in combination with irinotecan. Cetuximab in combination with irinotecan has been registered in the USA and Europe for the treatment of patients with metastatic colorectal cancer expressing the EGFR after failure of prior irinotecan-based cytotoxic therapy. The role of cetuximab in first-line therapy is still investigational. Some phase II trials assessing cetuximab plus chemotherapy demonstrated a high objective response rate and promising results in terms of time to progression and overall survival; data from phase III trials are pending. Further studies are needed to investigate the efficacy of cetuximab in combination with conventional chemotherapy in the adjuvant/neoadjuvant setting and to define criteria for a better selection of patients for this type of treatment.

A novel engineered dermis for in vitro photodamage research.

The realization of biologically relevant human tissue equivalents as an in vitro model to investigate human diseases, as well as to test the efficacy or toxicity of novel compounds, is emerging as a new challenge in tissue engineering. Currently, the in vitro three-dimensional (3D) dermis model mainly involves the use of cells embedded in exogenous non-human matrices. However, such models feature biological and functional disparities with native dermis, therefore limiting their relevance to the in vivo situation. The purpose of this study was to provide a reliable endogenous human dermal equivalent (HDE) able to recapitulate the extracellular matrix (ECM) remodelling of the native dermis occurring after external damage. To this end, UVA irradiation was used to induce photodamage to both the HDE and to a fibroblast-populated collagen matrix. The photodamage was investigated at the cellular and ECM level and the results showed that, although a cellular response was detected in both systems, no ECM reorganization characteristic of the in vivo photo-aged dermis could be detected in the fibroblast-populated collagen matrix. In contrast in the HDE, the neosynthesized ECM recapitulated the characteristic ageing behaviour of the dermis found in vivo, in terms of collagen and hyaluronic acid synthesis as well as collagen organization remodelling. This study therefore demonstrates the role of the endogenous ECM in recapitulating in vitro the functionality of the human dermis and the proposed HDE as a novel tool for photoprotection trials. Copyright © 2016 John Wiley & Sons, Ltd.

Hibiscus syriacus Extract from an Established Cell Culture Stimulates Skin Wound Healing.

Higher plants are the source of a wide array of bioactive compounds that support skin integrity and health. Hibiscus syriacus, family Malvaceae, is a plant of Chinese origin known for its antipyretic, anthelmintic, and antifungal properties. The aim of this study was to assess the healing and hydration properties of H. syriacus ethanolic extract (HSEE). We established a cell culture from Hibiscus syriacus leaves and obtained an ethanol soluble extract from cultured cells. The properties of the extract were tested by gene expression and functional analyses on human fibroblast, keratinocytes, and skin explants. HSEE treatment increased the healing potential of fibroblasts and keratinocytes. Specifically, HSEE significantly stimulated fibronectin and collagen synthesis by 16 and 60%, respectively, while fibroblasts contractility was enhanced by 30%. These results were confirmed on skin explants, where HSEE accelerated the wound healing activity in terms of epithelium formation and fibronectin production. Moreover, HSEE increased the expression of genes involved in skin hydration and homeostasis. Specifically, aquaporin 3 and filaggrin genes were enhanced by 20 and 58%, respectively. Our data show that HSEE contains compounds capable of stimulating expression of biomarkers relevant to skin regeneration and hydration thereby counteracting molecular pathways leading to skin damage and aging.

Gemcitabine and cisplatin for inoperable and/or metastatic biliary tree carcinomas: a multicenter phase II study of the Gruppo Oncologico dell'Italia Meridionale (GOIM).

BACKGROUND: The aim of the study was to test the clinical efficacy and toxicity profile of gemcitabine (GEM) in combination with cisplatin (CDDP) in a series of patients affected by unresectable and/or metastatic biliary tree carcinoma (BTC) previously untreated with chemotherapy. PATIENTS AND METHODS: Overall 38 consecutive patients who satisfied eligibility criteria (10 with gall-bladder carcinoma and 28 with bile duct carcinoma) were included in this phase II study. Median age was 61 years with median PS 1. Treatment included GEM 1000 mg/m(2)/week as 30 min i.v. on days 1 and 8, and CDDP 75-80 mg/m(2) on day 1 with adequate hydration protocol and forced diuresis. Treatment was repeated every 3 weeks for three cycles before first re-evaluation of disease status. RESULTS: According to an intent-to-treat analysis a complete response (CR) was achieved in 1 patient (3%) with duration of 8 months. A partial response (PR) was recorded in 11 cases (29%; 95% CI 6% to 48%) with a median duration of 6.4 months (range 5-11 months) for an overall response rate (ORR) of 32%. Stable disease (SD) was seen in eight cases (21%), while the remaining 18 patients showed progressive disease (PD). Tumor growth control rate was 53%. Objective responses were recorded at loco-regional disease, liver and nodal metastases. Lung and peritoneal metastases did not respond. Time-to-progression was 4 months (range 2-11 months) and median overall survival was 8+ months (range 2-15 months). Side-effects were mild with few cases of grade 4 hematological toxicity. Transient and reversible liver toxicity was recorded in nearly one-quarter of patients. Infection without severe grade 4 neutropenia was observed in three cases. In no case was chemotherapy withdrawn for toxicity. CONCLUSION: The GEM/CDDP regimen is active against advanced and/or metastatic BTC with a favourable toxicity profile. This regimen represents a reasonable therapeutic choice for palliation of advanced BTC. Inferences concerning overall survival are difficult to draw due to the phase II nature of the study.

Patterns of genomic instability in gastric cancer: clinical implications and perspectives.

In gastric cancer (GC) the loss of genomic stability represents a key molecular step that occurs early in the carcinogenesis process and creates a permissive environment for the accumulation of genetic and epigenetic alterations in tumor suppressor genes and oncogenes. It is widely accepted that GC can follow at least two major genomic instability pathways, microsatellite instability (MSI) and chromosome instability (CIN). MSI is responsible for a well-defined subset of GCs. CIN represents a more common pathway comprising heterogeneous subsets of GC. In addition to MSI and CIN, the CpG islands methylator phenotype (CIMP) plays an important role in gastric carcinogenesis. CIMP may lead to the transcriptional silencing of various genes in gastric carcinogenesis. Intriguingly, more recently in addition to CpG island hypermethylation, a global DNA demethylation, that precedes genomic damage, has been observed in GC. Thus, epigenetic alterations may play a relevant role in gastric carcinogenesis as alternative mechanisms. Evidence suggests that although MSI, CIN and CIMP phenotypes can be distinguished from one another, there might be some degree of overlap. This review describes our current knowledge of the instability pathways in gastric carcinogenesis and the potential clinical applications for different forms of genomic instability in GC.