Persistent infection with high-risk human papillomaviruses (hrHPV) types is causally linked with the development of cervical precancer and cancer. HPV types 16 and 18 cause approximately 70% of ...cervical cancers worldwide.
To evaluate the harms and protection of prophylactic human papillomaviruses (HPV) vaccines against cervical precancer and HPV16/18 infection in adolescent girls and women.
We searched MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL) and Embase (June 2017) for reports on effects from trials. We searched trial registries and company results' registers to identify unpublished data for mortality and serious adverse events.
Randomised controlled trials comparing efficacy and safety in females offered HPV vaccines with placebo (vaccine adjuvants or another control vaccine).
We used Cochrane methodology and GRADE to rate the certainty of evidence for protection against cervical precancer (cervical intraepithelial neoplasia grade 2 and above CIN2+, CIN grade 3 and above CIN3+, and adenocarcinoma-in-situ AIS), and for harms. We distinguished between the effects of vaccines by participants' baseline HPV DNA status. The outcomes were precancer associated with vaccine HPV types and precancer irrespective of HPV type. Results are presented as risks in control and vaccination groups and risk ratios (RR) with 95% confidence intervals in brackets.
We included 26 trials (73,428 participants). Ten trials, with follow-up of 1.3 to 8 years, addressed protection against CIN/AIS. Vaccine safety was evaluated over a period of 6 months to 7 years in 23 studies. Studies were not large enough or of sufficient duration to evaluate cervical cancer outcomes. All but one of the trials was funded by the vaccine manufacturers. We judged most included trials to be at low risk of bias. Studies involved monovalent (N = 1), bivalent (N = 18), and quadrivalent vaccines (N = 7). Most women were under 26 years of age. Three trials recruited women aged 25 and over. We summarize the effects of vaccines in participants who had at least one immunisation.Efficacy endpoints by initial HPV DNA statushrHPV negativeHPV vaccines reduce CIN2+, CIN3+, AIS associated with HPV16/18 compared with placebo in adolescent girls and women aged 15 to 26. There is high-certainty evidence that vaccines lower CIN2+ from 164 to 2/10,000 (RR 0.01 (0 to 0.05)) and CIN3+ from 70 to 0/10,000 (RR 0.01 (0.00 to 0.10). There is moderate-certainty evidence that vaccines reduce the risk of AIS from 9 to 0/10,000 (RR 0.10 (0.01 to 0.82).HPV vaccines reduce the risk of any CIN2+ from 287 to 106/10,000 (RR 0.37 (0.25 to 0.55), high certainty) and probably reduce any AIS lesions from 10 to 0/10,000 (RR 0.1 (0.01 to 0.76), moderate certainty). The size of reduction in CIN3+ with vaccines differed between bivalent and quadrivalent vaccines (bivalent: RR 0.08 (0.03 to 0.23), high certainty; quadrivalent: RR 0.54 (0.36 to 0.82), moderate certainty). Data in older women were not available for this comparison.HPV16/18 negativeIn those aged 15 to 26 years, vaccines reduce CIN2+ associated with HPV16/18 from 113 to 6 /10,000 (RR 0.05 (0.03 to 0.10). In women 24 years or older the absolute and relative reduction in the risk of these lesions is smaller (from 45 to 14/10,000, (RR 0.30 (0.11 to 0.81), moderate certainty). HPV vaccines reduce the risk of CIN3+ and AIS associated with HPV16/18 in younger women (RR 0.05 (0.02 to 0.14), high certainty and RR 0.09 (0.01 to 0.72), moderate certainty, respectively). No trials in older women have measured these outcomes.Vaccines reduce any CIN2+ from 231 to 95/10,000, (RR 0.41 (0.32 to 0.52)) in younger women. No data are reported for more severe lesions.Regardless of HPV DNA statusIn younger women HPV vaccines reduce the risk of CIN2+ associated with HPV16/18 from 341 to 157/10,000 (RR 0.46 (0.37 to 0.57), high certainty). Similar reductions in risk were observed for CIN3+ associated with HPV16/18 (high certainty). The number of women with AIS associated with HPV16/18 is reduced from 14 to 5/10,000 with HPV vaccines (high certainty).HPV vaccines reduce any CIN2+ from 559 to 391/10,000 (RR 0.70 (0.58 to 0.85, high certainty) and any AIS from 17 to 5/10,000 (RR 0.32 (0.15 to 0.67), high certainty). The reduction in any CIN3+ differed by vaccine type (bivalent vaccine: RR 0.55 (0.43 to 0.71) and quadrivalent vaccine: RR 0.81 (0.69 to 0.96)).In women vaccinated at 24 to 45 years of age, there is moderate-certainty evidence that the risks of CIN2+ associated with HPV16/18 and any CIN2+ are similar between vaccinated and unvaccinated women (RR 0.74 (0.52 to 1.05) and RR 1.04 (0.83 to 1.30) respectively). No data are reported in this age group for CIN3+ or AIS.Adverse effectsThe risk of serious adverse events is similar between control and HPV vaccines in women of all ages (669 versus 656/10,000, RR 0.98 (0.92 to 1.05), high certainty). Mortality was 11/10,000 in control groups compared with 14/10,000 (9 to 22) with HPV vaccine (RR 1.29 0.85 to 1.98; low certainty). The number of deaths was low overall but there is a higher number of deaths in older women. No pattern in the cause or timing of death has been established.Pregnancy outcomesAmong those who became pregnant during the studies, we did not find an increased risk of miscarriage (1618 versus 1424/10,000, RR 0.88 (0.68 to 1.14), high certainty) or termination (931 versus 838/10,000 RR 0.90 (0.80 to 1.02), high certainty). The effects on congenital abnormalities and stillbirths are uncertain (RR 1.22 (0.88 to 1.69), moderate certainty and (RR 1.12 (0.68 to 1.83), moderate certainty, respectively).
There is high-certainty evidence that HPV vaccines protect against cervical precancer in adolescent girls and young women aged 15 to 26. The effect is higher for lesions associated with HPV16/18 than for lesions irrespective of HPV type. The effect is greater in those who are negative for hrHPV or HPV16/18 DNA at enrolment than those unselected for HPV DNA status. There is moderate-certainty evidence that HPV vaccines reduce CIN2+ in older women who are HPV16/18 negative, but not when they are unselected by HPV DNA status.We did not find an increased risk of serious adverse effects. Although the number of deaths is low overall, there were more deaths among women older than 25 years who received the vaccine. The deaths reported in the studies have been judged not to be related to the vaccine. Increased risk of adverse pregnancy outcomes after HPV vaccination cannot be excluded, although the risk of miscarriage and termination are similar between trial arms. Long-term of follow-up is needed to monitor the impact on cervical cancer, occurrence of rare harms and pregnancy outcomes.
Cervical cancer screening has traditionally been based on cervical cytology. Given the aetiological relationship between human papillomavirus (HPV) infection and cervical carcinogenesis, HPV testing ...has been proposed as an alternative screening test.
To determine the diagnostic accuracy of HPV testing for detecting histologically confirmed cervical intraepithelial neoplasias (CIN) of grade 2 or worse (CIN 2+), including adenocarcinoma in situ, in women participating in primary cervical cancer screening; and how it compares to the accuracy of cytological testing (liquid-based and conventional) at various thresholds.
We performed a systematic literature search of articles in MEDLINE and Embase (1992 to November 2015) containing quantitative data and handsearched the reference lists of retrieved articles.
We included comparative test accuracy studies if all women received both HPV testing and cervical cytology followed by verification of the disease status with the reference standard, if positive for at least one screening test. The studies had to include women participating in a cervical cancer screening programme who were not being followed up for previous cytological abnormalities.
We completed a 2 x 2 table with the number of true positives (TP), false positives (FP), true negatives (TN), and false negatives for each screening test (HPV test and cytology) used in each study. We calculated the absolute and relative sensitivities and the specificities of the tests for the detection of CIN 2+ and CIN 3+ at various thresholds and computed sensitivity (TP/(TP + TN) and specificity (TN/ (TN + FP) for each test separately. Relative sensitivity and specificity of one test compared to another test were defined as sensitivity of test-1 over sensitivity of test-2 and specificity of test-1 over specificity of test-2, respectively. To assess bias in the studies, we used the Quality Assessment of Diagnostic test Accuracy Studies (QUADAS) tool. We used a bivariate random-effects model for computing pooled accuracy estimates. This model takes into account the within- and between-study variability and the intrinsic correlation between sensitivity and specificity.
We included a total of 40 studies in the review, with more than 140,000 women aged between 20 and 70 years old. Many studies were at low risk of bias. There were a sufficient number of included studies with adequate methodology to perform the following test comparisons: hybrid capture 2 (HC2) (1 pg/mL threshold) versus conventional cytology (CC) (atypical squamous cells of undetermined significance (ASCUS)+ and low-grade squamous intraepithelial lesions (LSIL)+ thresholds) or liquid-based cytology (LBC) (ASCUS+ and LSIL+ thresholds), other high-risk HPV tests versus conventional cytology (ASCUS+ and LSIL+ thresholds) or LBC (ASCUS+ and LSIL+ thresholds). For CIN 2+, pooled sensitivity estimates for HC2, CC and LBC (ASCUS+) were 89.9%, 62.5% and 72.9%, respectively, and pooled specificity estimates were 89.9%, 96.6%, and 90.3%, respectively. The results did not differ by age of women (less than or greater than 30 years old), or in studies with verification bias. Accuracy of HC2 was, however, greater in European countries compared to other countries. The results for the sensitivity of the tests were heterogeneous ranging from 52% to 94% for LBC, and 61% to 100% for HC2. Overall, the quality of the evidence for the sensitivity of the tests was moderate, and high for the specificity.The relative sensitivity of HC2 versus CC for CIN 2+ was 1.52 (95% CI: 1.24 to 1.86) and the relative specificity 0.94 (95% CI: 0.92 to 0.96), and versus LBC for CIN 2+ was 1.18 (95% CI: 1.10 to 1.26) and the relative specificity 0.96 (95% CI: 0.95 to 0.97). The relative sensitivity of HC2 versus CC for CIN 3+ was 1.46 (95% CI: 1.12 to 1.91) and the relative specificity 0.95 (95% CI: 0.93 to 0.97). The relative sensitivity of HC2 versus LBC for CIN 3+ was 1.17 (95% CI: 1.07 to 1.28) and the relative specificity 0.96 (95% CI: 0.95 to 0.97).
Whilst HPV tests are less likely to miss cases of CIN 2+ and CIN 3+, these tests do lead to more unnecessary referrals. However, a negative HPV test is more reassuring than a negative cytological test, as the cytological test has a greater chance of being falsely negative, which could lead to delays in receiving the appropriate treatment. Evidence from prospective longitudinal studies is needed to establish the relative clinical implications of these tests.
Helicobacter pylori(H.pylori)infection is well known to be associated with the development of precancerous lesions such as chronic atrophic gastritis(AG),or gastric intestinal metaplasia(GIM),and ...cancer.Various molecular alterations are identified not only in gastric cancer(GC)but also in precancerous lesions.H.pylori treatment seems to improve AG and GIM,but still remains controversial.In contrast,many studies,including meta-analysis,show that H.pylori eradication reduces GC.Molecular markers detected by genetic and epigenetic alterations related to carcinogenesis reverse following H.pylori eradication.This indicates that these changes may be an important factor in the identification of high risk patients for cancer development.Patients who underwent endoscopic treatment of GC are at high risk for development of metachronous GC.A randomized controlled trial from Japan concluded that prophylactic eradication of H.pylori after endoscopic resection should be used to prevent the development of metachronous GC,but recent retrospective studies did not show the tendency.Patients with precancerous lesions(molecular alterations)that do not reverse after H.pylori treatment,represent the"point of no return"and may be at high risk for the development of GC.Therefore,earlier H.pylori eradication should be considered for preventing GC development prior to the appearance of precancerous lesions.
Chronic inflammation, regardless of infectious agents, plays important roles in the development of various cancers, particularly in digestive organs, including Helicobacter pylori –associated gastric ...cancer, hepatitis C virus–positive hepatocellular carcinoma, and colitis-associated colon cancers. Cancer development is characterized by stepwise accumulation of genetic and epigenetic alterations of various proto-oncogenes and tumor-suppressor genes. During chronic inflammation, infectious agents such as H pylori and hepatitis C virus as well as intrinsic mediators of inflammatory responses, including proinflammatory cytokines and reactive oxygen and nitrogen species, can induce genetic and epigenetic changes, including point mutations, deletions, duplications, recombinations, and methylation of various tumor-related genes through various mechanisms. Furthermore, inflammation also modulates the expressions of microRNAs that influence the production of several tumor-related messenger RNAs or proteins. These molecular events induced by chronic inflammation work in concert to alter important pathways involved in normal cellular function, and hence accelerate inflammation-associated cancer development. Among these, recent studies highlighted an important role of activation-induced cytidine deaminase, a nucleotide-editing enzyme essential for somatic hypermutation and class-switch recombination of the immunoglobulin gene, as a genomic modulator in inflammation-associated cancer development.
Gastric cancer remains the second leading cause of cancer death worldwide. About half of the incidence of gastric cancer is observed in East Asian countries,which show a higher mortality than other ...countries. The effectiveness of 3 new gastric cancer screening techniques,namely,upper gastrointestinal endoscopy,serological testing,and "screen and treat" method were extensively reviewed. Moreover,the phases of development for cancer screening were analyzed on the basis of the biomarker development road map. Several observational studies have reported the effectiveness of endoscopic screening in reducing mortality from gastric cancer. On the other hand,serologic testing has mainly been used for targeting the high-risk group for gastric cancer. To date,the effectiveness of new techniques for gastric cancer screening has remained limited. However,endoscopic screening is presently in the last trial phase of development before their introduction to population-based screening.To effectively introduce new techniques for gastric cancer screening in a community,incidence and mortality reduction from gastric cancer must be initially and thoroughly evaluated by conducting reliable studies.In addition to effectiveness evaluation,the balance of benefits and harms must be carefully assessed before introducing these new techniques for population-based screening.
Pancreatic cancer: Advances in treatment Mohammed, Somala; Van Buren, 2nd, George; Fisher, William E
World journal of gastroenterology : WJG,
07/2014, Letnik:
20, Številka:
28
Journal Article
Pancreatic cancer is a leading cause of cancer mortality and the incidence of this disease is expected to continue increasing.While patients with pancreatic cancer have traditionally faced a dismal ...prognosis,over the past several years various advances in diagnosis and treatment have begun to positively impact this disease.Identification of effective combinations of existing chemotherapeutic agents,such as the FOLFIRINOX and the gemcitabine+nab-paclitaxel regimen,has improved survival for selected patients although concerns regarding their toxicity profiles remain.A better understanding of pancreatic carcinogenesis has identified several pre-malignant precursor lesions,such as pancreatic intraepithelial neoplasias,intraductal papillary mucinous neoplasms,and cystic neoplasms.Imaging technology has also evolved dramatically so as to allow early detection of these lesions and thereby facilitate earlier management.Surgery remains a cornerstone of treatment for patients with resectable pancreatic tumors,and advances in surgical technique have allowed patients to undergo resection with decreasing perioperative morbidity and mortality.Surgery has also become feasible in selected patients with borderline resectable tumors as a result of neoadjuvant therapy.Furthermore,pancreatectomy involving vascular reconstruction and pancreatectomy with minimally invasive techniques have demonstrated safety without significantly compromising oncologic outcomes.Lastly,a deeper understanding of molecular aberrations contributing to the development of pancreatic cancer shows promise for future development of more targeted and safe therapeutic agents.
Patients with chronic atrophic gastritis or intestinal metaplasia (IM) are at risk for gastric adenocarcinoma. This underscores the importance of diagnosis and risk stratification for these patients. ...High definition endoscopy with chromoendoscopy (CE) is better than high definition white-light endoscopy alone for this purpose. Virtual CE can guide biopsies for staging atrophic and metaplastic changes and can target neoplastic lesions. Biopsies should be taken from at least two topographic sites (antrum and corpus) and labelled in two separate vials. For patients with mild to moderate atrophy restricted to the antrum there is no evidence to recommend surveillance. In patients with IM at a single location but with a family history of gastric cancer, incomplete IM, or persistent
gastritis, endoscopic surveillance with CE and guided biopsies may be considered in 3 years. Patients with advanced stages of atrophic gastritis should be followed up with a high quality endoscopy every 3 years. In patients with dysplasia, in the absence of an endoscopically defined lesion, immediate high quality endoscopic reassessment with CE is recommended. Patients with an endoscopically visible lesion harboring low or high grade dysplasia or carcinoma should undergo staging and treatment.
eradication heals nonatrophic chronic gastritis, may lead to regression of atrophic gastritis, and reduces the risk of gastric cancer in patients with these conditions, and it is recommended.
eradication is also recommended for patients with neoplasia after endoscopic therapy. In intermediate to high risk regions, identification and surveillance of patients with precancerous gastric conditions is cost-effective.
Most patients with pancreatic ductal adenocarcinoma (PDAC) present with symptomatic, surgically unresectable disease. Although the goal of early detection of PDAC is laudable and likely to result in ...significant improvement in overall survival, the relatively low prevalence of PDAC renders general population screening infeasible. The challenges of early detection include identification of at-risk individuals in the general population who would benefit from longitudinal surveillance programs and appropriate biomarker and imaging-based modalities used for PDAC surveillance in such cohorts. In recent years, various subgroups at higher-than-average risk for PDAC have been identified, including those with familial risk due to germline mutations, a history of pancreatitis, patients with mucinous pancreatic cysts, and elderly patients with new-onset diabetes. The last 2 categories are discussed at length in terms of the opportunities and challenges they present for PDAC early detection. We also discuss current and emerging imaging modalities that are critical to identifying early, potentially curable PDAC in high-risk cohorts on surveillance.
Upon the aberrant activation of oncogenes, normal cells can enter the cellular senescence program, a state of stable cell-cycle arrest, which represents an important barrier against tumour ...development in vivo. Senescent cells communicate with their environment by secreting various cytokines and growth factors, and it was reported that this 'secretory phenotype' can have pro- as well as anti-tumorigenic effects. Here we show that oncogene-induced senescence occurs in otherwise normal murine hepatocytes in vivo. Pre-malignant senescent hepatocytes secrete chemo- and cytokines and are subject to immune-mediated clearance (designated as 'senescence surveillance'), which depends on an intact CD4(+) T-cell-mediated adaptive immune response. Impaired immune surveillance of pre-malignant senescent hepatocytes results in the development of murine hepatocellular carcinomas (HCCs), thus showing that senescence surveillance is important for tumour suppression in vivo. In accordance with these observations, ras-specific Th1 lymphocytes could be detected in mice, in which oncogene-induced senescence had been triggered by hepatic expression of Nras(G12V). We also found that CD4(+) T cells require monocytes/macrophages to execute the clearance of senescent hepatocytes. Our study indicates that senescence surveillance represents an important extrinsic component of the senescence anti-tumour barrier, and illustrates how the cellular senescence program is involved in tumour immune surveillance by mounting specific immune responses against antigens expressed in pre-malignant senescent cells.
This review aims to outline the most up-to-date knowledge of pancreatic adenocarcinoma risk, diagnostics, treatment and outcomes, while identifying gaps that aim to stimulate further research in this ...understudied malignancy. Pancreatic adenocarcinoma is a lethal condition with a rising incidence, predicted to become the second leading cause of cancer death in some regions. It often presents at an advanced stage, which contributes to poor five-year survival rates of 2%-9%, ranking firmly last amongst all cancer sites in terms of prognostic outcomes for patients. Better understanding of the risk factors and symptoms associated with this disease is essential to inform both health professionals and the general population of potential preventive and/or early detection measures. The identification of high-risk patients who could benefit from screening to detect pre-malignant conditions such as pancreatic intraepithelial neoplasia, intraductal papillary mucinous neoplasms and mucinous cystic neoplasms is urgently required, however an acceptable screening test has yet to be identified. The management of pancreatic adenocarcinoma is evolving, with the introduction of new surgical techniques and medical therapies such as laparoscopic techniques and neo-adjuvant chemoradiotherapy, however this has only led to modest improvements in outcomes. The identification of novel biomarkers is desirable to move towards a precision medicine era, where pancreatic cancer therapy can be tailored to the individual patient, while unnecessary treatments that have negative consequences on quality of life could be prevented for others. Research efforts must also focus on the development of new agents and delivery systems. Overall, considerable progress is required to reduce the burden associated with pancreatic cancer. Recent, renewed efforts to fund large consortia and research into pancreatic adenocarcinoma are welcomed, but further streams will be necessary to facilitate the momentum needed to bring breakthroughs seen for other cancer sites.
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