Human papillomavirus (HPV) is widely known as a cause of cervical cancer (CC) and cervical intraepithelial neoplasia (CIN). HPVs related to cancer express two main oncogenes, i.e. E6 and E7, considered as tumorigenic genes; their integration into the host genome results in the abnormal regulation of cell cycle control. Due to their peculiarities, these oncogenes represent an excellent target for cancer immunotherapy. In this work the authors highlight the potential use of therapeutic vaccines as safe and effective pharmacological tools in cervical disease, focusing on vaccines that have reached the clinical trial phase. Many therapeutic HPV vaccines have been tested in clinical trials with promising results. Adoptive T-cell therapy showed clinical activity in a phase II trial involving advanced CC patients. A phase II randomized trial showed clinical activity of a nucleic acid-based vaccine in HPV16 or HPV18 positive CIN. Several trials involving peptide-protein-based vaccines and live-vector based vaccines demonstrated that these approaches are effective in CIN as well as in advanced CC patients. HPV therapeutic vaccines must be regarded as a therapeutic option in cervical disease. The synergic combination of HPV therapeutic vaccines with radiotherapy, chemotherapy, immunomodulators or immune checkpoint inhibitors opens a new and interesting scenario in this disease.
Background Colorectal cancer patients have a median age of incidence >65years although they are largely under-represented in phase-III trials. This large population contains patients unfit for treatment, those suitable for monotherapy or for doublets and the impact of chemotherapy outside clinical trial is unclear. The aim of the study was to retrospectively analyse Overall Survival(OS) of elderly metastatic colorectal cancer(mCRC) patients treated with chemotherapy in daily practice. Methods Kaplan-Meir method was used for OS, the log-rank or Tarone-Ware test for differences between subgroups, Cox's proportional hazard model to assess the impact of known prognostic factors and treatment. Results 751 patients with mCRC observed between January 2000 and January 2013 were collected. Median age was 79 year(75–93); Male/Female 61/39%, ECOG-PS 0-1/2 85/15%; colon/rectum 74/26%; multiple metastatic sites 34%, only liver metastasis in 41% of patients. KRAS status was studied in 35% of patients: 44% of them showed gene mutation. 20.5% of patients did not received any kind of treatment including surgery. Comorbidities observed: cardiovascular 34%, diabetes 14%, hypertension 50%. Primary tumor was resected in 80.6%; surgery of liver metastasis was done in 19% of patients (2.3% of patients >80years). 78% of patients underwent chemotherapy. Median follow up was 12 months(range 1–124). Median OS was 17 months (CI 95%15–19);median OS in no-treated patients was 5 months (4–6); mOS of patients with at least one treatment was 20 months (18–22). In KRAS mutated group median OS was 19months (15–23) while in KRAS wild type patients median OS was 25 months (20–30). At multivariate analysis sex(Female), age(<80y), performance status(0–1), chemotherapy, Surgery of metastasis, Surgery of primary tumor and Site of metastasis(liver) were prognostic factors for OS. Conclusion The results of our study show that in clinical practice treatment has a positive impact on OS of elderly patients, confirmed at multivariate analysis, included patients with age >80 years old or with a poor performance status (respectively p<0.0001 and p<0.0001). KRAS analysis deserve further evaluation.
Purpose: Chemotherapy regimens containing anthracyclines and taxanes represent the landmark of neoadjuvant systemic therapy of breast cancer.In advanced breast cancer patients liposomal anthracyclines (LA) have shown similar efficacy and less cardiac toxicity when compared to conventional anthracyclines.We performed this retrospective analysis in order to evaluate the efficacy and tolerability of neoadjuvant regimens including LA outside of clinical trials in routine clinical practice.Methods: Fifty operable or locally advanced, HER2 negative, breast cancer patients were retrospectively identified in 5 Italian cancer centres.Nineteen patients had received 4 cycles of non-pegylated liposomal doxorubicin (NPLD) and cyclophosphamide, followed by 4 cycles of docetaxel, every 3 weeks.In 25 patients the reverse sequence was employed, and a third subgroup of 6 patients received 4 cycles of NPLD/cyclophosphamide every 3 weeks followed by 4 cycles of weekly carboplatin and paclitaxel.Results: We observed 10 pathological complete responses (pCR) (20.0%, 95%CI, 9% to 31%), and 35 (70%, 95%CI, 57.3% to 82.7%) partial responses (pPR), whereas no patients progressed onto therapy.In the small subset of triple negative tumors the pCR rate was 37.5%, and in tumors expressing ER and/or PgR it was 16.7%.A pCR rate of 26.5% was observed in tumors with high Ki-67, whereas in tumors with low Ki-67 only one (6.2%)pCR was observed (p=0.14).Treatments were well tolerated.The most common toxicities were myelosuppression and palmar-plantar erytrodysesthesia; 4 asymptomatic and transient LVEF decrease have been recorded, without any case of clinical cardiotoxicity.Conclusions: NPLD-cyclophosphamide and taxanes sequential regimens were proven effective and well tolerated in breast cancer patients with contra-indication to conventional anthracyclines undergoing neoadjuvant chemotherapy, even outside of clinical trials in everyday clinical practice.
e14082 Background: Use of adjuvant chemotherapy (AC) in Stage II Colon Cancer (CC) is still under debate. Choice should be based on patients (pts) and disease characteristics. According to worldwide guidelines AC should be considered in high-risk (H) T3N0 pts. No data are available for better option in low-risk (L) pts. Aim of the study is to evaluate relapse-free survival (RFS) and disease-free survival (DFS) retrospectively in T3N0 CC pts related to treatment. Methods: RFS and DFS are evaluated with Kaplan Meier method. In order to find the optimal cut off for node number the receiver operating characteristics curve analysis and Maximally Selected Rank Statistics were performed. Multivariate Cox proportional hazard model was developed using stepwise regression, enter limit and remove limit were p = 0.10 and p = 0.15 respectively. Results: 1,000 pts with T3N0 CC were recruited. To date, data of 926 pts are available. Median age was 69 (29-93), M/F 513/413, Grading 1/2/3 46/668/158; 360 L (39%), 411 H (44%), 155 unknown (17%); 137 (15%) pts showed symptoms (S) at diagnosis: 51 pts had perforation (P) or bowel obstruction (BO). Median sampled lymph nodes (LN) were 15 (1-76); 383 (41%) pts were treated with AC. Median follow up (fu) was 5 years (yr) (range 3-24). Survival analysis was performed only for pts with a minimum fu of 3 yr and younger than 80 (80%). 5 yr RFS was 78% and 5 yr DFS was 76% At multivariate analysis S and AC were prognostic factors for RFS. AC is prognostic factor for all endpoints (data are shown in table). In L group 5 yr RFS was 88% in treated pts and 75% in non-treated pts (p 0.03); in H group was respectively 82% and 72% (p 0.006). Conclusions: Preliminary data confirmed the role of known prognostic factors and suggest the relevance of AC also in L stage II T3N0 CC pts. However, the highest risk in L subgroup should be identified to be submitted to AC. Data collection is ongoing, update results will be presented. [Table: see text]
Background Adjuvant chemotherapy (AC) in Stage II Colon Cancer (CC) is still under debate. Choice should be based on patients and disease characteristics. According to guidelines AC should be considered in high-risk T3N0 patients. No data are available for better option in low-risk patients. The aim of the study is to retrospectively evaluate relapse-free survival (RFS) and disease-free survival (DFS) according to treatment received in T3N0 CC. Methods RFS and DFS are evaluated with Kaplan-Meier method. Multivariate Cox proportional hazard model was developed using stepwise regression, enter limit and remove limit were p = 0.10 and p = 0.15, respectively. Results 834 patients with T3N0 CC were recruited. Median age was 69 (29–93), M/F 463/371, 335 low-risk patients (40.2%), 387 high-risk (46.4%), 112 unknown (13.4%); 127 (15.2%) patients showed symptoms at diagnosis. Median sampled lymph nodes were 15 (1–76); 353 (42.3%) patients were treated with AC. Median follow up was 5 years (range 3–24). The 5-years RFS was 78.4% and the 5-years DFS was 76.7%. At multivariate analysis symptoms, lymph nodes, and adjuvant chemotherapy were prognostic factors for RFS. AC is prognostic factor for all endpoints. In low-risk group 5-years RFS was 87.3% in treated patients and 74.7% in non-treated patients (p 0.03); in high-risk group was respectively 82.7% and 71.4% (p 0.005). Conclusions Data confirmed the role of known prognostic factors and suggest the relevance of adjuvant chemotherapy also in low-risk stage II T3N0 CC patients. However, the highest risk in low-risk subgroup should be identified to be submitted to AC.
Supported by Jubiläumsfonds der Österreichischen Nationalbank (16678) and the Department of Innovation, Research and University of the Autonomous Province of Bolzano/Bozen, Italy. Potential conflict of interest: Nothing to report. Assay of γ‐glutamyltransferase (GGT) activity is a widely used test to indicate and monitor liver and biliary tract injury. We observed dominant inheritance of highly elevated plasma GGT levels, designated GGTemia, in two unrelated families. Neither clinical symptoms nor alterations of GGT substrates were associated with GGTemia. A plasma GGT fraction pattern distinguishes this trait from common liver diseases. Heterozygous γ‐glutamyltransferase 1 (GGT1) mutations that disrupt the GGT1 transmembrane domain were identified. We establish GGTemia as a benign condition; GGT1 mutation testing can prevent repeated and invasive diagnostic workup in such patients. Case Series Dominant inheritance of isolated GGT plasma elevations in the range of 2,500‐9,600 U/L (reference 9‐55 U/L)—GGTemia—was observed in two families (Fig. 1A); part of family 1 was reported.1 The index patients were identified by routine testing; congenital onset and lifelong persistence of this trait were suggested by observing GGTemia in a 4‐year‐old and a 70‐year‐old patient. GGTemia was not associated with clinical complaints (Supporting Information). The persistently high plasma GGT activity was not associated with altered levels of known GGT substrates: we observed normal levels of amino acids, ammonia, and cysteinyl leukotrienes in plasma, total glutathione in whole blood, and leukotriene E4 in urine.Figure 1: Dominantly inherited GGTemia in two unrelated families shows a characteristic pattern of GGT plasma fractions, an increase of plasma GGT protein, and loss from expressing cells. (A) Family 1 is from Italy, and family 2 is from Slovakia. Squares denote male individuals, circles denote female individuals, filled symbols indicate GGTemia trait carriers. Asterisks denote individuals available for mutation segregation analysis. Arrows denote individuals in whom whole‐genome sequencing was performed. (B‐D) GGT fraction analysis: (B) control, (C) GGTemia (inserted graph: 100‐fold diluted serum), (D) GGTemia and alcoholism (inserted graph: 100‐fold diluted serum). (E) GGT1 serum western blot analysis in family 1. Lanes a‐d, control members of the family (exposition time 30 minutes); lanes e‐n, GGTemia (exposition 3 minutes). (F) Cell homogenate western blot analysis. Lane 1, c21‐Leu15Arg (70 μg protein, 0.6 mU GGT activity); lane 2, c21 wild type (8 μg protein, 0.6 mU GGT activity). (G,H) Cytochemical staining for GGT activity is present in cells transfected with wild‐type GGT1 cDNA (magnification ×20 and ×40) and absent in cells transfected with mutated GGT cDNA (I, J; magnification ×20 and ×40). (K) GGT activity in culture media of cells transfected with wild‐type (dotted line) or mutated (continuous line) GGT cDNA. The inserted graph shows a normal serum sample. Abbreviations: m‐GGT, medium GGT; s‐GGT, small GGT; wt, wild type.An unprecedented GGT fraction pattern was found in GGTemia: all four recognized GGT fractions were present; big‐GGT (b‐GGT) activity values were in the reference range, but medium, small, and free GGT (f‐GGT) activities were highly elevated over the higher reference limits,2 with f‐GGT activity representing about 97% of total activity (Supporting Table S1; Fig. 1B,C). A mixed pattern of GGTemia and alcoholism was seen in one individual (Fig. 1D). We first mapped the trait locus, and whole‐genome sequencing identified heterozygous GGT1 variants in families 1 and 2: a missense mutation, c.44T>G (p.Leu15Arg), and an inframe deletion, c.28_54del (p.Leu10_Val18del) (Supporting Fig. S1). These variants were considered pathogenic as they (1) segregated with GGTemia in families, (2) were absent from control populations, and (3) were predicted to affect protein structure (Supporting Information). GGT1 complementary DNA (cDNA) sequencing and real‐time expression analyses revealed equal expression of mutant and wild‐type alleles, indicating that GGTemia is not caused by increased transcription. However, immunoblotting showed a highly increased serum GGT protein amount in patients (Fig. 1E). The inframe deletion removes half of the N‐terminal GGT1 transmembrane domain, and transient expression of the p.Leu15Arg mutation in c21 cells resulted in nearly absent cell‐attached GGT1 expression and higher GGT activity in the culture medium compared with wild type (Fig. 1F), as was confirmed by cytochemical staining of cells expressing mutant (Fig. 1G,H) and wild type (Fig. 1I,J) GGT1. c21‐p.Leu15Arg cells secreted almost exclusively f‐GGT, while wild‐type cells secreted similar quantities of b‐GGT and f‐GGT (Fig. 1K). Discussion We show that GGTemia is a benign condition that represents a differential diagnosis of elevated GGT plasma levels. The identified mutations disrupt the GGT1 transmembrane domain so that the enzymes retain their activities but are not attached anymore to the plasma membrane. GGT1 mutation and plasma GGT fraction analyses should be considered in patients with unexplained elevation of GGT levels. Prior to our study, only one pathogenic GGT1 variant was reported, associated with total loss of GGT activity and intellectual disability.3 The presence of a GGT1 wild‐type copy in GGTemia likely precludes any symptoms of GGT deficiency. The GGT1 protein is conserved in all prokaryotes and eukaryotes, emphasizing its critical role in all organisms; and serum GGT levels have been linked to an array of chronic diseases.4 Plasma GGT is supposed to originate mostly from liver, and a distinct plasma GGT fraction pattern is observed for GGTemia and several liver diseases.2 b‐GGT is contained in vesicles, which are shed from the plasma membrane in both bile and plasma5 and carry GGT as a marker of its cellular origin. The lower‐weight GGT fractions supposedly arise from modifications of the b‐GGT fraction.5 f‐GGT represents a free‐soluble form of the enzyme that lacks the N‐terminal anchoring peptide, which is primarily produced from the mutant alleles in GGTemia. Author Contributions A.D.G., M.F., S.R., and A.R.J. were responsible for study concept and design; S.R., M.D., E.R.‐D., G.Z., P.P.P., T.M., and A.R.J. were responsible for patient recruitment and characterization; R.R., A.C., S.S.‐B., E.M., D.H., and A.R.J. were responsible for data acquisition and analysis; A.P., A.P., M.E., H.W., H.Z., H.T., P.P.P., and T.M. were responsible for data analysis and conceptual advice; A.R.J. was responsible for manuscript preparation; all authors provided input and critical revision to the manuscript and approved the final version.
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