Non-hereditary early onset gastric cancer: An unmet medical need.

Gastric cancer (GC) is a lethal disease and the diagnosis in the young population is a major challenge from both individual and social point of views. Early-onset GC accounts for ∼5% of GC; among them, 3% are part of a hereditary syndrome and the majority are sporadic. However, even if the early-onset forms were less frequent in the past, the increasing number in the last decades has improved the interest and awareness of them in the society and in the scientific community. In particular, the different behaviour and characteristics of early-onset GC suggest that it is a completely different entity, which requires a tailored and personalized management. Here we provide an updated overview about non-hereditary early-onset GC, which is an unmet clinical need today, along with future perspectives in this field.

Resistance to Antiangiogenic Therapy in Hepatocellular Carcinoma: From Molecular Mechanisms to Clinical Impact.

Antiangiogenic drugs were the only mainstay of advanced hepatocellular carcinoma (HCC) treatment from 2007 to 2017. However, primary or secondary resistance hampered their efficacy. Primary resistance could be due to different molecular and/or genetic characteristics of HCC and their knowledge would clarify the optimal treatment approach in each patient. Several molecular mechanisms responsible for secondary resistance have been discovered over the last few years; they represent potential targets for new specific drugs. In this light, the advent of checkpoint inhibitors (ICIs) has been a new opportunity; however, their use has highlighted other issues: the vascular normalization compared to a vessel pruning to promote the delivery of an active cancer immunotherapy and the development of resistance to immunotherapy which leads to a better selection of patients as candidates for ICIs. Nevertheless, the combination of antiangiogenic therapy plus ICIs represents an intriguing approach with high potential to improve the survival of these patients. Waiting for results from ongoing clinical trials, this review depicts the current knowledge about the resistance to antiangiogenic drugs in HCC. It could also provide updated information to clinicians focusing on the most effective combinations or sequential approaches in this regard, based on molecular mechanisms.

Efficacy of Surgery for the Treatment of Gastric Cancer Liver Metastases: A Systematic Review of the Literature and Meta-Analysis of Prognostic Factors.

BACKGROUND: In the last 10 years, the management of patients with gastric cancer liver metastases (GCLM) has changed from chemotherapy alone, towards a multidisciplinary treatment with liver surgery playing a leading role. The aim of this systematic review and meta-analysis is to assess the efficacy of hepatectomy for GCLM and to analyze the impact of related prognostic factors on long-term outcomes. METHODS: The databases PubMed (Medline), EMBASE, and Google Scholar were searched for relevant articles from January 2010 to September 2020. We included prospective and retrospective studies that reported the outcomes after hepatectomy for GCLM. A systematic review of the literature and meta-analysis of prognostic factors was performed. RESULTS: We included 40 studies, including 1573 participants who underwent hepatic resection for GCLM. Post-operative morbidity and 30-day mortality rates were 24.7% and 1.6%, respectively. One-year, 3-years, and 5-years overall survival (OS) were 72%, 37%, and 26%, respectively. The 1-year, 3-years, and 5-years disease-free survival (DFS) were 44%, 24%, and 22%, respectively. Well-moderately differentiated tumors, pT1-2 and pN0-1 adenocarcinoma, R0 resection, the presence of solitary metastasis, unilobar metastases, metachronous metastasis, and chemotherapy were all strongly positively associated to better OS and DFS. CONCLUSION: In the present study, we demonstrated that hepatectomy for GCLM is feasible and provides benefits in terms of long-term survival. Identification of patient subgroups that could benefit from surgical treatment is mandatory in a multidisciplinary setting.

How to Treat Hepatocellular Carcinoma in Elderly Patients.

Hepatocellular carcinoma (HCC) is the primary tumour of the liver with the greatest incidence, particularly in the elderly. Additionally, improvements in the treatments for chronic liver diseases have increased the number of elderly patients who might be affected by HCC. Little evidence exists regarding HCC in old patients, and the elderly are still underrepresented and undertreated in clinical trials. In fact, this population represents a complex subgroup of patients who are hard to manage, especially due to the presence of multiple comorbidities. Therefore, the choice of treatment is mainly decided by the physician in the clinical practice, who often tend not to treat elderly patients in order to avoid the possibility of adverse events, which may alter their unstable equilibrium. In this context, the clarification of the optimal treatment strategy for elderly patients affected by HCC has become an urgent necessity. The aim of this review is to provide an overview of the available data regarding the treatment of HCC in elderly patients, starting from the definition of "elderly" and the geriatric assessment and scales. We explain the possible treatment choices according to the Barcelona Clinic Liver Cancer (BCLC) scale and their feasibility in the elderly population.

Risk Prediction in Acute Calculous Cholecystitis: A Systematic Review and Meta-Analysis of Prognostic Factors and Predictive Models.

Background: Laparoscopic cholecystectomy is the main treatment of acute cholecystitis. Although considered relatively safe, it carries 6%-9% risk of major complications and 0.1%-1% risk of mortality. There is no consensus regarding the evaluation of the preoperative risks, and the management of patients with acute cholecystitis is usually guided by surgeon's personal preferences. We assessed the best method to identify patients with acute cholecystitis who are at high risk of complications and mortality. Methods: We performed a systematic review of studies that reported the preoperative prediction of outcomes in people with acute cholecystitis. We searched the Cochrane Library, MEDLINE, EMBASE, WHO ICTRP, ClinicalTrials.gov, and Science Citation Index Expanded until April 27, 2019. We performed a meta-analysis when possible. Results: Six thousand eight hundred twenty-seven people were included in one or more analyses in 12 studies. Tokyo guidelines 2013 (TG13) predicted mortality (two studies; Grade 3 versus Grade 1: odds ratio [OR] 5.08, 95% confidence interval [CI] 2.79-9.26). Gender predicted conversion to open cholecystectomy (two studies; OR 1.59, 95% CI 1.06-2.39). None of the factors reported in at least two studies had significant predictive ability of major or minor complications. Conclusion: There is significant uncertainty in the ability of prognostic factors and risk prediction models in predicting outcomes in people with acute calculous cholecystitis. Based on studies of high risk of bias, TG13 Grade 3 severity may be associated with greater mortality than Grade 1. Early referral of such patients to high-volume specialist centers should be considered. Further well-designed prospective studies are necessary.

2020 World Society of Emergency Surgery updated guidelines for the diagnosis and treatment of acute calculus cholecystitis.

BACKGROUND: Acute calculus cholecystitis (ACC) has a high incidence in the general population. The presence of several areas of uncertainty, along with the availability of new evidence, prompted the current update of the 2016 WSES (World Society of Emergency Surgery) Guidelines on ACC. MATERIALS AND METHODS: The WSES president appointed four members as a scientific secretariat, four members as an organization committee and four members as a scientific committee, choosing them from the expert affiliates of WSES. Relevant key questions were constructed, and the task force produced drafts of each section based on the best scientific evidence from PubMed and EMBASE Library; recommendations were developed in order to answer these key questions. The quality of evidence and strength of recommendations were reviewed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria (see https://www.gradeworkinggroup.org/ ). All the statements were presented, discussed and voted upon during the Consensus Conference at the 6th World Congress of the World Society of Emergency Surgery held in Nijmegen (NL) in May 2019. A revised version of the statements was voted upon via an online questionnaire until consensus was reached. RESULTS: The pivotal role of surgery is confirmed, including in high-risk patients. When compared with the WSES 2016 guidelines, the role of gallbladder drainage is reduced, despite the considerable technical improvements available. Early laparoscopic cholecystectomy (ELC) should be the standard of care whenever possible, even in subgroups of patients who are considered fragile, such as the elderly; those with cardiac disease, renal disease and cirrhosis; or those who are generally at high risk for surgery. Subtotal cholecystectomy is safe and represents a valuable option in cases of difficult gallbladder removal. CONCLUSIONS, KNOWLEDGE GAPS AND RESEARCH RECOMMENDATIONS: ELC has a central role in the management of patients with ACC. The value of surgical treatment for high-risk patients should lead to a distinction between high-risk patients and patients who are not suitable for surgery. Further evidence on the role of clinical judgement and the use of clinical scores as adjunctive tools to guide treatment of high-risk patients and patients who are not suitable for surgery is required. The development of local policies for safe laparoscopic cholecystectomy is recommended.

Immune Checkpoint Inhibitors in Hepatocellular Carcinoma: Current Status and Novel Perspectives.

Immune checkpoint inhibitors (ICIs) represent a promising treatment for many kinds of cancers, including hepatocellular carcinoma (HCC). The rationale for using ICIs in HCC is based on the immunogenic background of hepatitis and cirrhosis and on the observation of high programmed death-ligand 1 (PD-L1) expression and tumor-infiltrating lymphocytes in this cancer. Promising data from phase I/II studies in advanced HCC, showing durable objective response rates (~20% in first- and second-line settings) and good safety profile, have led to phase III studies with ICIs as single agents or in combination therapy, both in first and second line setting. While the activity of immunotherapy agents as single agents seems to be limited to an "ill-defined" small subset of patients, the combination of the anti PD-L1 atezolizumab and anti-vascular endothelial growth factor bevacizumab revealed a benefit in the outcomes when compared to sorafenib in the first line. In addition, the activity and efficacy of the combinations between anti-PD-1/anti-PD-L1 antibody and other ICIs, tyrosine kinase inhibitors, or surgical and locoregional therapies, has also been investigated in clinical trials. In this review, we provide an overview of the role of ICIs in the management of HCC with a critical evaluation of the current status and future directions.

Changing outlook for colorectal liver metastasis resection in the elderly.

BACKGROUND: This study sought to evaluate the impact of the advancements in clinical care, obtained over the last 20 years, for patients aged 70 and older undergoing liver resection for colorectal liver metastases (CRLM). METHODS: Consecutive patients age 70 or older who underwent liver resection for CRLM at Aintree University Hospital (Liverpool, UK) between May 2008 and May 2015 were compared to a dataset of consecutive patients, meeting the same criteria, between 1990 and 2007. An enhanced recovery programme after surgery (ERAS) combined with cardiopulmonary exercise testing (CPET) was introduced in January 2008. RESULTS: The proportion of patients over 70 years undergoing liver resection for CRLM increased over the study period (6% in 1990, 16.3% in 2000, 26.5% in 2005 and 25.8% in 2007). The patients in the later group were more often treated with neoadjuvant chemotherapy (58 vs 34, p = 0.006) and underwent parenchymal sparing surgery, resulting in fewer major hepatectomies (51 vs 111, p < 0.001) and less perioperative morbidity (49 vs 70, p = 0.043) and mortality (3 vs 9, p = 0.229). Although there was shorter disease free survival (DFS) in the later group (DFS at 1, 3 and 5 years was 52.1%, 31.6%, 29% vs. 71.8%, 49.1%, 44.0%)(p < 0.01), similar overall survival (OS) was achieved (OS at 1, 3 and 5 years was 85.4%, 51.6%, 32.8% vs. 81.7%, 42.1%, 27.3%)(p = 0.21). CONCLUSIONS: This study demonstrates that, with modern management (ERAS, CPET, neoadjuvant chemotherapy and parenchymal sparing surgery), a greater number of patients with CRLM, over the age of seventy, can undergo liver resection, with improved perioperative outcomes.

Hepatectomy for octogenarians with colorectal liver metastasis in the era of enhanced recovery.

BACKGROUND: Concern exists regarding the use of hepatectomy to treat colorectal liver metastasis (CRLM) in octogenarians due to prior studies suggesting elevated morbidity and mortality. Cardiopulmonary exercise testing (CPET) within pre-operative assessment and enhanced recovery after surgery (ERAS) have both been shown to be associated with low morbidity and mortality in patients undergoing hepatectomy. This study sought to compare the outcomes of octogenarians with patients aged 70-79 undergoing hepatectomy for CRLM, within a center utilizing both CPET and ERAS. METHODS: Consecutive patients age 70 or older who underwent hepatectomy for CRLM at Aintree University Hospital (Liverpool,UK), between May 2008 and May 2015 were identified from a prospectively maintained cancer database. Data were extracted and comparisons drawn. RESULTS: 127 patients aged 70-79 years and 34 octogenarians underwent respectively 137 and 35 hepatectomy for CRLM. There was no difference in hospital stay (6 days), morbidity and mortality between the groups. OS at 1, 3 and 5 years were 86.7%, 55% and 35.8% for those aged 70-79 compared to 79.4%, 37.3% and 20.4% for the octogenarians (p=0.127). DFS at 1,3 and 5 years was 52.5%, 31.7% and 31.7% for 70-79 group compared to 46.2%, 31.5% and 16.8% for the octogenarians (p=0.838). On multivariate analysis major hepatectomy was associated with an increased risk of post-operative complications, inferior OS and DFS. Chronological age was not a predictor of postoperative complications, poorer OS or DFS. CONCLUSIONS: Appropriately selected octogenarians can have similar postoperative outcomes to patients aged 70-79 when undergoing hepatectomy for CRLM using ERAS combined with CPET. This study advocates using CPET and ERAS in the selection and management of octogenarian patients with CRLM undergoing hepatectomy.

Follow-up: the evidence.

There is currently no consensus on the best strategy for the follow-up of patients who have undergone surgical treatment with curative intent for gastric cancer. The wide variation in recommendations for surveillance among international experts and hospital schedules clearly reflects a lack of an established body of evidence on this subject. Consequently, most of the international guidelines aimed at early detection of disease recurrence gloss over details concerning the mode, duration, and intensity of surveillance since they cannot be based on an acceptable grade of recommendation. Very few report anything other than the detection of recurrences or death as the primary endpoints, and, given the poor survival of patients with recurrent gastric cancer, the prognostic effect of early detection seems doubtful. In recent years, an increasing focus on evidence-based medicine, which has coincided with a growing concern about costs and efficiency in medicine, has caused a reevaluation of most surveillance practices. In this paper, we review and discuss the current body of evidence and follow-up practices after curative resection of gastric cancer.

Psoas syndrome: a frequently missed diagnosis.

Psoas syndrome is an easily missed diagnosis. However, it is important to consider this condition as part of the differential diagnosis for patients presenting with low back pain--particularly for osteopathic physicians, because patients may view these practitioners as experts in musculoskeletal conditions. The authors describe the case of a 48-year-old man with a 6-month history of low back pain that had been attributed to "weak core muscles." The diagnosis of psoas syndrome was initially overlooked in this patient. After the correct diagnosis was made, he was treated by an osteopathic physician using osteopathic manipulative treatment, in conjunction with at-home stretches between office treatments. At his 1-month follow-up appointment, he demonstrated continued improvement of symptoms and a desire for further osteopathic manipulative treatment.

Log odds of positive lymph nodes in colon cancer: a meaningful ratio-based lymph node classification system.

BACKGROUND: The log odds of positive lymph nodes (LODDS), defined as the log of the ratio between the numbers of positive and negative lymph nodes, has recently been proposed as a new prognostic index in surgical oncology. The aim of the present study was to investigate whether the LODDS system of lymph node classification was a more accurate prognostic tool than the tumor node metastasis (TNM) and lymph node ratio (LNR) classifications in colon cancer patients. MATERIALS AND METHODS: Clinicopathologic data from 258 colon cancer patients who had undergone surgical resection were reviewed. Lymph node parameters were categorized according to the Internation Union Against Cancer/American Joint Cancer Commission (UICC/AJCC) TNM staging system, the LNR (LNR0 with ratio ≤ 0.05, LNR1 with 0.05 < ratio ≤ 0.20, LNR2 with ratio > 0.20), and the log odds ratio (LODDS0 ≤ -1.36, -1.36 < LODDS1 ≤ -0.53, and LODDS2 > -0.53). RESULTS: The LODDS was able to identify patients who would have been included in different prognostic categories, according to both the TNM and LNR. In addition, LODDS was significantly related to the number of positive and negative lymph nodes, as well as the number of examined lymph nodes. In multivariate analysis, LODDS classification (LODDS0: HR 1; LODDS1: HR 3.687, p = 0.003; LODDS2: HR 9.440, p < 0.001) was identified as an independent prognostic factor. DISCUSSION: The LODDS system is a highly reliable staging system with strong predictive ability for patient outcome. Compared with other nodal staging systems, the prognostic power of LODDS is less influenced by the number of lymph nodes dissected and examined.

R0 resection in the treatment of gastric cancer: room for improvement.

Gastric carcinoma is one of the most frequent malignancies in the world and its clinical behavior especially depends on the metastatic potential of the tumor. In particular, lymphatic metastasis is one of the main predictors of tumor recurrence and survival, and current pathological staging systems reflect the concept that lymphatic spread is the most relevant prognostic factor in patients undergoing curative resection. This is compounded by the observation that two-thirds of gastric cancer in the Western world presents at an advanced stage, with lymph node metastasis at diagnosis. All current therapeutic efforts in gastric cancer are directed toward individualization of therapeutic protocols, tailoring the extent of resection and the administration of preoperative and postoperative treatment. The goals of all these strategies are to improve prognosis towards the achievement of a curative resection (R0 resection) with minimal morbidity and mortality, and better postoperative quality of life.