Metastatic Bladder Cancer: Role of Chemotherapy and New Agents

The M-VAC chemotherapy regimen has been widely used in locally advanced as well as in metastatic disease. Since only a proportion of patients with advanced disease will survive, there is a dire need to identify patients who will respond to chemotherapy and to identify new agents, targets and strategies to improve treatment outcome. Approaches to the management of advanced urothelial cancer include: intensifying the dose intensity, doublet and triplet combination chemotherapy, sequential regimens, reducing toxicity in unfit or elderly patients, and the use of biologic targeted therapies and promising new chemotherapeutic agents. These include MTA, the epothilones, topoisomerase inhibitors and vinflunine which act upon folate metabolism or upon different phases of the cell cycle. New agents that are coming into clinical trials include farnesyl transferase inhibitors, several growth factors receptor inhibitors, anti-sense therapy and COX-2 inhibitors. Significant progress has been made in understanding the molecular biology of cancer. Numerous novel agents, many of which are in clinical trials, have been developed to target various processes of tumor progression. The rationale behind application of these molecularly targeted therapies is to overcome resistance to cytotoxic therapies. Bladder cancer represents a unique model for targeted therapy. As our understanding increases, integration of newer biologic agents will condition future trials, and our ability to target bladder and urothelial cancers will be enhanced.     

Severe Gastroduodenal Ulcerations Complicating Hepatic Artery Infusion Chemotherapy for Metastatic Colon Cancer

Patients receiving continuous hepatic artery infusion chemotherapy (HAIC) with 5-fluoro-2'-deoxyuridine for colorectal carcinoma metastatic to the liver frequently complain of nonspecific abdominal discomfort. To determine the etiology of these symptoms we performed upper gastrointestinal endoscopy on symptomatic patients during the course of HAIC. Among 40 patients receiving HAIC of 5-fluoro-2'-deoxyuridine, 21 (53%) developed epigastric pain. They all had upper gastrointestinal endoscopy and 19 were found to have gastroduodenal ulcerations and or erosions. In two patients the infusion catheter eroded into the duodenum. The pathogenesis of the mucosal disease is not clear, but because symptoms responded to discontinuation of HAIC but not to therapy with cimetidine, a direct toxic effect of chemotherapy is postulated. We conclude that patients who complain of upper gastrointestinal symptoms while receiving continuous HAIC with 5-fluoro-2'-deoxyuridine should be investigated for the development of gastroduodenal ulcerations and erosions and that chemotherapy should be withheld if such lesions are found.     

Outcomes of Glucocorticoid Treatment in HBV-Associated Acute-on-Chronic Liver Failure Patients: A Retrospective Observational Study

BackgroundOur study aimed to investigate the effects of glucocorticoid (GC) treatment on liver function, hospitalization length, and expenses, as well as 28-day mortality in patients suffered from hepatitis B virus (HBV)-associated acute-on-chronic liver failure (ACLF).MethodsThis is a retrospective study of 349 patients who were hospitalized with HBV-associated ACLF. Biochemical assay results of alanine aminotransferase (ALT) level, aspartate aminotransferase (AST) level, total bilirubin (TBil) level, and creatinine (Cr) level both at admission and before discharge were recorded. GC and antivirus treatment condition, hospitalization length and expenses, as well as 28-day status were also recorded.Results Among 349 patients with HBV-associated ACLF, GC treatment did not benefit in liver function outcomes, and even ended in higher ALT and TBil levels comparing to patients treated without GC. However, patients treated with GC might have lower 28-day mortality. Similar results were shown in patients with or without antivirus treatment. In addition, GC treatment could not shorten hospitalization length and could increase the expenses.Conclusion Using GC in HBV-associated ACLF patients could not improve their liver function, but might reduce the risk of death, no matter the patient had had antivirus treatment or not. In addition, GC treatment could not shorten hospitalization length and could increase the expenses in HBV-associated ACLF patients.     

Switching Treatment from Mepolizumab to Benralizumab for Elderly Patients with Severe Eosinophilic Asthma: A Retrospective Observational Study

Objective Switching from mepolizumab to benralizumab has been reported to significantly improve both asthma control and the lung function. However, the data on its efficacy in elderly patients with severe eosinophilic asthma are limited. This study aimed to assess whether elderly patients with severe eosinophilic asthma could experience an improved asthma control and lung function when switching directly from mepolizumab to benralizumab. Methods In this single-center, retrospective study conducted between February 2017 and September 2018, we assessed the effect of switching the treatment directly from mepolizumab to benralizumab on eosinophil levels, exacerbation rates, and lung function. We compared the treatment responses between the two groups using either Fisher''s exact test or Mann-Whitney U-test, as appropriate. Patients We enrolled 12 elderly patients (age ≥65 years) with severe eosinophilic asthma treated with mepolizumab at Hiroshima Prefectural Hospital (Hiroshima, Japan) during the study period. Six patients were switched from mepolizumab to benralizumab, and six continued with the mepolizumab treatment. Results The switch from mepolizumab to benralizumab caused a near-complete reduction in the eosinophil count (p=0.008). The annual rate of clinically relevant exacerbations and hospitalizations diminished as well, albeit with no statistical significance. We found no improvement in the lung function after switching treatment and no difference in the treatment response between the groups. Conclusion Although this study is based on a small sample of participants, the results indicate that both mepolizumab treatment and switching from mepolizumab to benralizumab treatment without a washout period have clinically relevant asthma control benefits for elderly patients with severe eosinophilic asthma.     

Risk Factors for Encapsulating Peritoneal Sclerosis in Long‐Term Peritoneal Dialysis: A Retrospective Observational Study

Encapsulating peritoneal sclerosis (EPS) is a serious complication that occurs in patients with long‐term peritoneal dialysis (PD). Investigation of risk factors that contribute to EPS in patients on long‐term PD therapy is needed. In a retrospective, observational study, data were collected for 107 patients treated with PD therapy for more than 5 years. Fifty cases of EPS were compared with 57 cases of non‐EPS. To evaluate the impact of PD‐associated peritonitis in EPS, univariate and multivariate logistic regression models were applied. Episodes of peritonitis, number of peritonitis episodes and the duration of peritonitis were included as explanatory variables in addition to previously reported risk factors. D/P Cr and serum β2MG levels in the EPS and non‐EPS groups were: 0.82 ± 0.10 and 0.67 ± 0.12 (P < 0.01), and 33.8 ± 8.54 and 29.2 ± 8.18 mg/L (P < 0.01), respectively. Episodes of peritonitis, number of peritonitis episodes and the duration of peritonitis was 68% and 42% (P < 0.01), 1.80 ± 2.19 and 0.75 ± 1.07 times (P < 0.01), and 18.1 ± 15.3 and 10.2 ± 4.90 days (P < 0.01), in the EPS and non‐EPS groups, respectively. Furthermore, multivariate logistic regression models demonstrated that both D/P Cr and the duration of peritonitis were independently associated with EPS (P < 0.01 and P < 0.05, respectively). In patients on long‐term PD therapy, D/P Cr and the duration of peritonitis are independently associated with EPS. Earlier treatment to promote an early recovery from PD‐associated peritonitis could be critical in preventing EPS.     

Characteristics and Treatment Outcomes of Small-bowel Angioectasia in Systemic Sclerosis Patients: A Retrospective Observational Study

Objective Systemic sclerosis (SSc) is defined as an autoimmune disease presenting with fibrosis of various organs and vascular endothelial damage. Vascular lesions, including small-bowel angioectasias, are also frequently detected in SSc patients. Polidocanol injection (PDI) is a safe and effective hemostatic treatment for gastrointestinal bleeding. We evaluated the outcomes of PDI for small-bowel angioectasia in SSc patients. Methods We retrospectively evaluated 65 consecutive SSc patients (61 women; mean age, 64.3 years old) who underwent capsule endoscopy (CE) and/or double-balloon endoscopy at Hiroshima University Hospital between April 2012 and December 2019. Patients Patients were stratified according to the presence of small-bowel angioectasia. Among patients who underwent CE during the same period, those with small-bowel angioectasia without concomitant diseases were compared with SSc patients with small-bowel angioectasia. Clinical and endoscopic characteristics, treatment outcomes, and the incidence of metachronous small-bowel angioectasia after PDI were evaluated. Results SSc patients with small-bowel angioectasia exhibited significantly lower hemoglobin levels and a significantly higher incidence of skin telangiectasia than those without small-bowel angioectasia. On a multivariate analysis of the presence of small-bowel angioectasia, anemia and skin telangiectasia were significant independent factors. SSc patients with small-bowel angioectasia included a higher proportion of women and exhibited a significantly higher incidence of metachronous small-bowel angioectasia than X. The characteristics of small-bowel angioectasia and outcomes of PDI were not significantly different between the two groups. No post-treatment rebleeding cases or adverse events were noted. Conclusion CE should be performed for SSc patients with anemia and/or skin telangiectasia. PDI is effective for SSc patients with small-bowel angioectasia.     

The Albumin-bilirubin Score Detects Changes in the Liver Function during Treatment for Budd-Chiari Syndrome: A Retrospective Observational Study

Objective Mapping the long-term prognosis of Budd-Chiari syndrome (BCS) is difficult, as the prognosis is associated with changes in the liver function. The present study evaluated the time course changes in the liver function in a treatment group with percutaneous old balloon angioplasty (POBA) and a non-treatment group using the albumin-bilirubin score (ALBI) and Child-Pugh score during long-term follow-up. Methods In this retrospective study, 13 consecutive patients diagnosed with BCS at our hospital between 2007 and 2020 were categorized into a treatment group (n=8), which received POBA, and a non-treatment group (n=5). Differences in the liver function in the ALBI and Child-Pugh scores between the initial visit and one- and three-year follow-up were calculated and statistically evaluated. We investigated the changes in the liver function during the long-term follow-up, including events such as re-stenosis and re-treatment. Results While the Child-Pugh scores in the treatment group did not differ significantly between the initial visit and 1- or 3-year follow-up, the ALBI scores in this group improved significantly between the initial visit and the 1- or 3-year follow-up visit (p=0.0078 and 0.0156, respectively). The liver function according to the ALBI score in the treatment group showed gradual improvement from the initial value but gradual worsening in the non-treatment group. The ALBI scores also revealed that the liver function varies according to re-stenosis and re-POBA in BCS patients. Conclusion Unlike the Child-Pugh score, the ALBI score was able to capture changes in the liver function of BCS patients during the long-term course of BCS.     

Factors Associated With Outcomes in Endoscopic Submucosal Dissection of Gastric Cardia Tumors: A Retrospective Observational Study

Tumors of the gastric cardia are among the most technically difficult lesions to remove by endoscopic submucosal dissection (ESD). This study aimed to evaluate the therapeutic outcomes of ESD in gastric cardia tumors according to clinicopathologic characteristics, and to assess the predictive factors for incomplete resection.We conducted a retrospective observational study of 82 patients with adenomas and early cancers of the gastric cardia who underwent ESD between January 2006 and December 2013 at the Pusan National University Hospital. Therapeutic outcomes of ESD and procedure-related complications were analyzed.En bloc resection, complete resection, and curative resection rates were 87%, 79%, and 66%, respectively. Deep submucosal invasion was the most common cause of noncurative resection in the cases in which complete resection was achieved. On multivariate analyses, hemispheric distribution (anterior hemisphere; odds ratio [OR] 4.808) and depth of tumor invasion (submucosal cancer; OR 22.056) were independent factors associated with incomplete resection. The rates of procedure-related bleeding, perforation, and stenosis were 6%, 1%, and 0%, respectively; none of the complications required surgical intervention.In conclusion, ESD is a safe, effective, and feasible treatment for gastric cardia tumors. However, the complete resection rate decreases for tumors that are located in the anterior hemisphere or have deep submucosal invasion.     

Cancer Therapy: New Targets for Chemotherapy

The number two cause of mortality in developed countries is cancer. Despite the enormous effort put into cancer prevention, early diagnosis and treatment, it is likely that the incidence of the cancer morbidity and mortality will increase for the foreseeable future. This is due to various factors such as increased life expectancy, changes in environment and also the socio-economic situation around the world. Some cancer attracts more attention than others and increasingly epidemiological information is reaching the general public and is beginning to influence behavior. It is now well recognized that, for example, 1 of 8 women in the industrialized world will be diagnosed with breast cancer. Additionally, a strong correlation was established between lung cancer incidence and smoking and it is broadly accepted that the incidence of colon cancer is directly related to age and diet, and has been increasing over time. The current failure of preventive measures to significantly reduce the increasing incidence of these common tumors illustrates the importance of effective cancer treatment strategies, including chemotherapy. The combination of various anticancer drugs, given together with surgery and radiotherapy, gives hope to many patients. There has been recent evidence of improved therapeutic outcome with recent approaches and newer agents but for continuing effective chemotherapeutic treatment there is a need for a detailed understanding of their mechanisms of action and on the rationale of their application.

This review attempts to provide up-to-date information regarding the development of new and innovative treatment strategies for cancer chemotherapy. Virtually, every year several of new targets for cancer therapy on both, cellular and molecular levels, are identified and new drugs enter not only clinical trials but also are included in well accepted and documented therapeutic protocols. As this review is in addition to our review published previously (Medical Principles and Practice 11, 2002, 117-125), we have tried to include new and innovative targets and drugs that attract attention at present. Although it is not possible to provide a complete list of all achievements and cover all work done in this field, we hope to be able to give some insight into this rapidly developing area.     

D-Dimer Can Serve as a Prognostic and Predictive Biomarker for Metastatic Gastric Cancer Treated by Chemotherapy

Systemic activation of hemostasis and thrombosis has been implicated in tumor progression and metastasis. D-dimer has been used as an indicator for the thrombosis. Here, we investigated the role of the activation of coagulation in patients with metastatic gastric cancer by measuring D-dimer level.We conducted an observation study of 46 metastatic gastric cancer patients who received palliative chemotherapy (CTx). D-dimer levels were assessed before CTx and at the first response evaluation after CTx.The overall survival (OS) of patients with pretreatment D-dimer levels <1.5 μg/mL was significantly longer than that of patients with D-dimer levels ≥1.5 μg/mL (22.0 vs 7.9 months, P = 0.019). At the first response evaluation, the mean level of D-dimer was significantly decreased by 2.11 μg/mL in patients either with partial response or stable disease (P = 0.011) whereas the mean level of D-dimer, although the difference did not reach statistical significance, was increased by 2.46 μg/mL in patients with progressive disease. In addition, the OS of patients with D-dimer levels <1.0 μg/mL at the first response evaluation was significantly longer than that of patients with D-dimer levels ≥1.0 μg/mL (22.0 vs 7.0 months, P = 0.009). The lower D-dimer levels (<1.0 μg/mL) at the first response evaluation after CTx was independent predictive factor for better survival in multivariate analysis (P = 0.037).This study suggests that D-dimer levels may serve as a biomarker for response to CTx and OS in patients with metastatic gastric cancer.     

A Systematic Review of Hepatic Artery Chemotherapy After Hepatic Resection of Colorectal Cancer Metastatic to the Liver

PURPOSE Colorectal cancer metastatic to the liver, when technically feasible, is resected with a moderate chance of cure. The most common site of failure after resection is in the remaining liver. To enhance survival, chemotherapy has been delivered directly to the liver postresection via the hepatic artery. This study was designed to assess the effect of posthepatic resection, hepatic artery chemotherapy on overall survival.METHODS Trials were sought in Medline, the Cochrane Controlled Trial Register, The Cochrane Hepatobiliary Group Trials Register, and through contact of trial authors and reference lists using key words: colorectal, cancer, hepatic metastases, hepatic artery, chemotherapy, and randomized. Trials were chosen in which patients having resection of colorectal cancer metastatic to the liver were randomized to hepatic artery chemotherapy or any alternative treatment. Survival data were obtained principally from abstraction from survival curves in published studies using the method of Parmar to calculate a study-specific, log-hazard ratio and then combined-effect, log-hazard ratio, as well as a combined Kaplan-Meier survival probability curve.RESULTS Overall survival at five years in the hepatic artery group was 45 percent and 40 percent in the control group. Forty-three individuals developed recurrent liver metastases in the hepatic artery chemotherapy group, and 97 developed liver recurrence in the control group. However, no significant advantage was found in the meta-analysis for hepatic artery chemotherapy measuring overall survival and calculating survival based on intention to treat (log-hazard ratio = 0.0848, favoring the control group; 95 percent confidence interval = ±0.2037). Adverse events related to hepatic artery therapy were common, including five therapy-related deaths.CONCLUSIONS Although recurrence in the remaining liver happened less frequently in the hepatic artery chemotherapy group, overall survival was not improved. The log-hazard ratio even favored the control group, although not significantly. This added intervention for the treatment of metastatic colorectal cancer cannot be recommended at this time.     

Risk of Ulcerative Colitis-Associated Colorectal Cancer in China: A Multi-Center Retrospective Study

Background  

The number of patients with ulcerative colitis (UC) in China has increased in the past 10 years. Thus, it is anticipated that the incidence of UC-associated colorectal cancer (UC-CRC) will also increase. However, the risk of CRC in UC patients is still unknown in Chinese. The aim of this study was to identify the risk and risk factors of UC-CRC in Chinese.     

Salvage Chemotherapy for Patients With Recurrent or Persistent Ovarian Clear Cell Carcinoma: A Retrospective Study of 164 Cases

The purpose of this study was to evaluate the effects of salvage chemotherapy on recurrent or persistent ovarian clear cell carcinoma (CCC) with the goal of identifying a more rational treatment regimen for this lethal disease.The medical records of patients with CCC were retrospectively reviewed to select patients that were subsequently treated for recurrent or persistent disease.Of the 164 women with recurrent or persistent CCC, 485 chemotherapy courses with 1766 cycles were administered. Overall, the clinical benefit rate (CBR) was 39.4%, and the mean progression-free survival (PFS) was 4.5 months. Grade 3/4 toxicities occurred in 94 courses (19.4%). The CBR for TC was 45.1%, with a PFS of 3.7 months. Compared to that of TC, the CBRs for PC and CC were significantly lower (P = 0.020 and 0.021, respectively). The CBRs and PFS for PAF-C were slightly higher (P = 0.518 and 0.077, respectively), but showed a significantly higher adverse event rate (AER, P = 0.039). The CBR for bevacizumab was 50% with an extraordinarily long PFS (49.8 months). Gemcitabine and oxaliplatin had similar values for CBRs (44.4% and 44.1%) and PFS (2.5 and 3.4 months), respectively. Docetaxel (weekly) exhibited a notably low AER of 2.7%, and topotecan was associated with a relatively long PFS (7.7 months).For cis/carboplatin-pretreated patients, the existing active agents, such as oxaliplatin, gemcitabine, topotecan, and especially bevacizumab, are promising. Docetaxel (weekly) is well tolerated and might offer a particularly viable option for heavily pretreated patients. However, additional research to identify for a continued search for the optimal combination of chemotherapeutics or novel agents is still warranted.     

Surgery for Liver Metastases From Gastric Cancer: A Meta-Analysis of Observational Studies

The role of surgical therapy in patients with liver metastases from gastric cancer is still controversial. In this study, we investigated the results obtained with local treatment of hepatic metastases in patients with gastric cancer, by performing a systematic literature review and meta-analysis.We performed a systematic review and meta-analysis of observational studies published between 1990 and 2014. These works included multiple studies that evaluated the different survival rate among patients who underwent local treatment, such as hepatectomy or radiofrequency ablation, for hepatic metastases derived from primary gastric cancer. The collected studies were evaluated for heterogeneity, publication bias, and quality, and a pooled hazard ratio (HR) was calculated with a confidence interval estimated at 95% (95% CI).After conducting a thorough research among all published works, 2337 studies were found and after the review process 11 observational studies were included in the analysis. The total amount of patients considered in the survival analysis was 1010. An accurate analysis of all included studies reported a significantly higher survival rate in the group of patients who underwent the most aggressive local treatment for hepatic metastases (HR 0.54, 95% CI 0.46–0.95) as opposed to patients who underwent only palliation or systemic treatment. Furthermore, palliative local treatment of hepatic metastases had a higher survival rate if compared to surgical (without liver surgery) and systemic palliation (HR 0.50, 95% CI 0.26–0.96). Considering the only 3 studies where data from multivariate analyses was available, we found a higher survival rate in the local treatment groups, but the difference was not significant (HR 0.50, 95% CI 0.22–1.15).Curative and also palliative surgery of liver metastases from gastric cancer may improve patients’ survival. However, further trials are needed in order to better understand the role of surgery in this group of patients.     

Association Between the Neutrophil/Lymphocyte Ratio and Acute Kidney Injury After Cardiovascular Surgery: A Retrospective Observational Study

A high neutrophil-lymphocyte ratio (N/L ratio) was associated with the development of acute kidney injury (AKI) in patients with severe sepsis. We sought to investigate the association between the perioperative N/L ratios and postoperative AKI in patients undergoing high-risk cardiovascular surgery.A retrospective medical chart review was performed of 590 patients who underwent cardiovascular surgeries, including coronary artery bypass, valve replacement, patch closure for atrial or ventricular septal defect and surgery on the thoracic aorta with cardiopulmonary bypass (CPB). Baseline perioperative clinical parameters, including N/L ratios measured before surgery, immediately after surgery, and on postoperative day (POD) one were obtained. Multivariate logistic regression analysis was used to evaluate risk factors.A total of 166 patients (28.1%) developed AKI defined by the KDIGO (kidney disease improving global outcomes) criteria in the first 7 PODs. Independent risk factors for AKI included old age, decreased left ventricular systolic function, preoperative high serum creatinine, low serum albumin and high uric acid levels, intraoperative large transfusion amount, oliguria, hyperglycemia, and elevated N/L ratio measured immediately after surgery and on POD one. The quartiles of immediately postoperative N/L ratio were associated with graded increase in risk of AKI development (fourth quartile [N/L ratio≥10] multivariate odds ratio 5.90, 95% confidence interval [CI] 2.74–12.73; P < 0.001), a longer hospital stay, and a higher in-hospital and 1-year mortality rate (fourth quartile [N/L ratio≥10] adjusted hazard ratio for 1-year mortality [8.40, 95% CI 2.50–28.17]; P < 0.001).In patients undergoing cardiovascular surgery with CPB, elevated N/L ratios in the immediately postoperative period and on POD one were associated with an increased risk of postoperative AKI and 1-year mortality. The N/L ratio, which is easily calculable from routine work-up, can therefore assist with risk stratification of AKI and mortality in high-risk surgical patients.