Synthetic routes and chemical structural analysis for guiding the strategies on new Pt(II) metallodrug design.

Metals in medicine is a distinct and mature field of investigation. Its progress in recent times cannot be denied, as it provides opportunities to advance our knowledge of the properties, speciation, reactivity and biological effects of metals in a medicinal context. The development of novel Pt(II) compounds to combat cancer continues to make valuable contributions but it has not yet achieved a complete cure. The chemistry of this field is basic for drug design improvements and our analysis of the chemical procedures is a practical tool for achieving effective Pt(II) anticancer drugs. We present chemical approaches in a manner that can be used to strategically plot new synthetic routes choosing right pathways. Clarifying the chemical challenge will help the scientific community to be aware of the ease and/or difficulty of the procedure before and after further studies, such as speciation, reactivity and biological action which are also very arduous and costly. The work provides information to tackle many challenges in chemistry, combining the knowledge on the Pt(II) reagent preparation together with the reactivity of the biological units used in the Pt(II) drug design. We discuss and include the description of the chemical reactions, the importance of multiple steps and the right order of such reactions to achieve the final drugs, analyzing the coordination principles as well as the organic and organometallic basis. This thorough study of the routes helps to detect the simpler or more complicated reactivity and will serve to improve the synthesis performance with possible post-modifications.

Erectile Function and Oncologic Outcomes Following Open Retropubic and Robot-assisted Radical Prostatectomy: Results from the LAParoscopic Prostatectomy Robot Open Trial.

BACKGROUND: Whether surgeons perform better utilising a robot-assisted laparoscopic technique compared with an open approach during prostate cancer surgery is debatable. OBJECTIVE: To report erectile function and early oncologic outcomes for both surgical modalities, stratified by prostate cancer risk grouping. DESIGN, SETTING, AND PARTICIPANTS: In a prospective nonrandomised trial, we recruited 2545 men with prostate cancer from seven open (n=753) and seven robot-assisted (n=1792) Swedish centres (2008-2011). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Clinometrically-validated questionnaire-based patient-reported erectile function was collected before, 3 mo, 12 mo, and 24 mo after surgery. Surgeon-reported degree of neurovascular-bundle preservation, pathologist-reported positive surgical margin (PSM) rates, and 2-yr prostate-specific antigen-relapse rates were measured. RESULTS AND LIMITATIONS: Among 1702 preoperatively potent men, we found enhanced erectile function recovery for low/intermediate-risk patients in the robot-assisted group at 3 mo. For patients with high-risk tumours, point estimates for erectile function recovery at 24 mo favoured the open surgery group. The degree of neurovascular bundle preservation and erectile function recovery were greater correlated for robot-assisted surgery. In pT2 tumours, 10% versus 17% PSM rates were observed for open and robot-assisted surgery, respectively; corresponding rates for pT3 tumours were 48% and 33%. These differences were associated with biochemical recurrence in pT3 but not pT2 disease. The study is limited by its nonrandomised design and relatively short follow-up. CONCLUSIONS: Earlier recovery of erectile function in the robot-assisted surgery group in lower-risk patients is counterbalanced by lower PSM rates for open surgeons in organ-confined disease; thus, both open and robotic surgeons need to consider this trade-off when determining the plane of surgical dissection. Robot-assisted surgery also facilitates easier identification of nerve preservation planes during radical prostatectomy as well as wider dissection for pT3 cases. PATIENT SUMMARY: For prostate cancer surgery, an open operation reduces erection problems in high-risk cancers but has higher relapse rates than robotic surgery. Relapse rates appear similar in low/intermediate-risk cancers and the robot appears better at preserving erections in these cases.

Preparedness for side effects and bother in symptomatic men after radical prostatectomy in a prospective, non-randomized trial, LAPPRO.

BACKGROUND: Many clinicians believe that preparedness before surgery for possible post-surgery side effects reduces the level of bother experienced from urinary incontinence and decreased sexual health after surgery. There are no published studies evaluating this belief. Therefore, we aimed to study the level of preparedness before radical prostatectomy and the level of bother experienced from urinary incontinence and decreased sexual health after surgery. MATERIAL AND METHODS: We prospectively collected data from a non-selected group of men undergoing radical prostatectomy in 14 centers between 2008 and 2011. Before surgery, we asked about preparedness for surgery-induced urinary problems and decreased sexual health. One year after surgery, we asked about bother caused by urinary incontinence and erectile dysfunction. As a measure of the association between preparedness and bothersomeness we modeled odds ratios (ORs) by means of logistic regression. RESULTS: Altogether 1372 men had urinary incontinence one year after surgery as well as had no urinary leakage or a small urinary dribble before surgery. Among these men, low preparedness was associated with bother resulting from urinary incontinence [OR 2.84; 95% confidence interval (CI) 1.59-5.10]. In a separate analysis of 1657 men we found a strong association between preparedness for decreased sexual health and experiencing bother from erectile dysfunction (OR 5.92; 95% CI 3.32-10.55). CONCLUSION: In this large-sized prospective trial, we found that preparedness before surgery for urinary problems or sexual side effects decreases bother from urinary incontinence and erectile dysfunction one year after surgery.

Splenic injury during resection for esophageal cancer: risk factors and consequences.

OBJECTIVE: Esophageal cancer surgery carries a risk of splenic injury, which may require splenectomy, but predictors of such events remain uncertain. Moreover, the hypothesis that incidental splenectomy carries a worse prognosis deserves attention. DESIGN: A population-based, nationwide cohort study was conducted on 1679 patients who underwent resection for esophageal cancer in Sweden in 1987 to 2010, with follow-up until February 2012. Predictors of splenic injury and incidental splenectomy were analyzed using multivariable logistic regression, providing odds ratios (ORs) with 95% confidence intervals (CIs). Associations between incidental splenectomy and risk of mortality and severe infections were analyzed using multivariable Cox regression, providing hazard ratios (HRs) with 95% CIs. RESULTS: Higher surgeon volume of esophageal cancer resection decreased the risk of splenic injury and incidental splenectomy (OR: 0.58; 95% CI: 0.41-0.80; and OR: 0.41; 95% CI: 0.25-0.66, respectively, comparing the highest to lowest category). In patients with splenic injury, progression to incidental splenectomy decreased by 92% during the study period. Sex, age, tumor stage, previous abdominal surgery, neoadjuvant therapy, and surgical radicality did not influence these risks. Incidental accidental splenectomy increased the overall risk of mortality (HR: 1.29; 95% CI: 1.03-1.61) and severe infections (HR: 2.79; 95% CI: 1.35-5.79). CONCLUSION: The inverse association between surgeon volume and splenic injury supports centralization of esophageal cancer surgery. The increased risk of mortality and severe infections after incidental splenectomy should be kept in mind during surgery, and we should encourage efforts to preserve an injured spleen and stress the relevance of vaccination after splenectomy.

Reoperation after oesophageal cancer surgery in relation to long-term survival: a population-based cohort study.

OBJECTIVES: The influence of reoperation on long-term prognosis is unknown. In this large population-based cohort study, it was aimed to investigate the influence of a reoperation within 30 days of oesophageal cancer resection on survival even after excluding the initial postoperative period. DESIGN: This was a nationwide population-based retrospective cohort study. SETTING: All hospitals performing oesophageal cancer resections during the study period (1987-2010) in Sweden. PARTICIPANTS: Patients operated for oesophageal cancer with curative intent in 1987-2010. PRIMARY AND SECONDARY OUTCOMES: Adjusted HRs of all cause, early and late mortality up to 5 years after reoperation following oesophageal cancer resection. RESULTS: Among 1822 included patients, the 200 (11%) who were reoperated had a 27% increased HR of all-cause mortality (adjusted HR 1.27, 95% CI 1.05 to 1.53) and 28% increased HR of disease-specific mortality (adjusted HR 1.28, 95% CI 1.04 to 1.59), compared to those not reoperated. Reoperation for anastomotic insufficiency in particular was followed by an increased mortality (adjusted HR 1.82, 95% CI 1.19 to 2.76). CONCLUSIONS: This large and population-based nationwide cohort study shows that reoperation within 30 days after primary oesophageal resection was associated with increased mortality, even after excluding the initial 3 months after surgery. This finding stresses the need to consider any actions that might prevent complications and reoperation after oesophageal cancer resection.

Increased risk of colorectal cancer after obesity surgery.

OBJECTIVE: The purpose was to determine whether obesity surgery is associated with a long-term increased risk of colorectal cancer. BACKGROUND: Long-term cancer risk after obesity surgery is not well characterized. Preliminary epidemiological observations and human tissue biomarker studies recently suggested an increased risk of colorectal cancer after obesity surgery. METHODS: A nationwide retrospective register-based cohort study in Sweden was conducted in 1980-2009. The long-term risk of colorectal cancer in patients who underwent obesity surgery, and in an obese no surgery cohort, was compared with that of the age-, sex- and calendar year-matched general background population between 1980 and 2009. Obese individuals were stratified into an obesity surgery cohort and an obese no surgery cohort. The standardized incidence ratio (SIR), with 95% confidence interval (CI), was calculated. RESULTS: Of 77,111 obese patients, 15,095 constituted the obesity surgery cohort and 62,016 constituted the obese no surgery cohort. In the obesity surgery cohort, we observed 70 patients with colorectal cancer, rendering an overall SIR of 1.60 (95% CI 1.25-2.02). The SIR for colorectal cancer increased with length of time after surgery, with a SIR of 2.00 (95% CI 1.48-2.64) after 10 years or more. In contrast, the overall SIR in the obese no surgery cohort (containing 373 colorectal cancers) was 1.26 (95% CI 1.14-1.40) and remained stable with increasing follow-up time. CONCLUSIONS: Obesity surgery seems to be associated with an increased risk of colorectal cancer over time. These findings would prompt evaluation of colonoscopy surveillance for the increasingly large population who undergo obesity surgery.

Hospital and surgeon volume in relation to survival after esophageal cancer surgery in a population-based study.

PURPOSE: The influence of hospital and surgeon volume on survival after esophageal cancer surgery deserves clarification, particularly the prognosis after the early postoperative period. The interaction between hospital and surgeon volume, and the influence of known prognostic factors need to be taken into account. METHODS: A nationwide Swedish population-based cohort study of 1,335 patients with esophageal cancer who underwent esophageal resection in 1987 to 2005, with follow-up for survival until February 2011, was conducted. The associations between annual hospital volume, annual surgeon volume, and cumulative surgeon volume and risk of mortality were calculated with multivariable parametric survival analysis, providing hazard ratios (HRs) with 95% CIs. HRs were mutually adjusted for the surgery volume variables and further adjusted for the prognostic factors age, sex, comorbidity, calendar period, tumor stage, tumor histology, and neoadjuvant therapy. RESULTS: There was no independent association between annual hospital volume and overall survival, and hospital volume was not associated with short-term mortality after adjustment for hospital clustering effects. A combination of higher annual and cumulative surgeon volume reduced the mortality occurring at least 3 months after surgery (P trend < .01); the HR was 0.78 (95% CI, 0.65 to 0.92) comparing surgeons with both annual and cumulative volume above the median with those below the median. These results remained when hospital and surgeon clustering were taken into account. CONCLUSION: Because surgeon volume rather than hospital volume independently influences the prognosis after esophageal cancer surgery, centralization of this surgery to fewer surgeons seems warranted.

Influence of major postoperative complications on health-related quality of life among long-term survivors of esophageal cancer surgery.

PURPOSE: To evaluate the effect of major postoperative complications on health-related quality of life (HRQL) in 5-year survivors of esophageal cancer surgery. PATIENTS AND METHODS: This study was based on the Swedish Esophageal and Cardia Cancer register with almost complete nationwide coverage and data on esophageal cancer surgery collected prospectively between 2001 and 2005. Patients who were alive 5 years after surgery were eligible. HRQL was assessed longitudinally until 5 years after surgery by using the validated European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire C30 and OES18. Linear mixed models were used to assess the mean score difference (MD) with 95% CIs of each aspect of HRQL in patients with or without major postoperative complications. Adjustment was made for several potential confounders. RESULTS: Of 153 patients who survived 5 years, 141 patients (92%) answered the 5-year HRQL questionnaires. Of these individuals, 46 patients (33%) sustained a major postoperative complication. Dyspnea (MD, 15; 95% CI, 6 to 23), fatigue (MD, 13; 95% CI, 5 to 20), and eating restrictions (MD, 10; 95% CI, 2 to 17) were clinically and statistically significantly deteriorated throughout the follow-up in patients with major postoperative complications compared with patients without major complications. Although problems with choking declined to levels comparable with patients without major postoperative complications, sleep difficulties and gastroesophageal reflux progressively worsened during follow-up. CONCLUSION: The occurrence of postoperative complications exerts a long-lasting negative effect on HRQL in patients who survive 5 years after esophagectomy for cancer.

Health-related quality of life among 5-year survivors of esophageal cancer surgery: a prospective population-based study.

PURPOSE: To clarify whether health-related quality of life (HRQL) can be restored in 5-year survivors of esophageal cancer surgery. PATIENTS AND METHODS: The nationwide Swedish prospective and population-based cohort for this study consisted of patients with esophageal cancer who were treated surgically between 2001 and 2005 and were alive 5 years after surgery. The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) and EORTC QLQ-OES18 (the disease site-specific module for esophageal cancer) were used to assess HRQL 6 months, 3 years, and 5 years postoperatively. Paired t tests were used to evaluate changes in HRQL over time. Patients' HRQL was classified as improved, stable, or deteriorated. Multivariable linear regression was used to calculate mean score difference in HRQL with 95% CIs between patients and a background population according to HRQL category. RESULTS: Among 153 eligible patients alive after 5 years, 117 (76%) answered all HRQL assessments. Among a random sample of 6,969 Swedish adults representing the corresponding background population, 4,910 (70.5%) participated. For most patients, HRQL remained stable or improved over time, and their HRQL was comparable to that of the background population. Patients who deteriorated over time reported large and clinically significant mean score differences for all measures. For example, 5 years after surgery, physical function was stable or improved in 86% of patients and their mean score (87) was similar to that of the background population (88), but the 14% who deteriorated had a substantially lower mean score of 56. CONCLUSION: HRQL recovers to a level comparable to that in the background population in most patients who survive 5 years after esophagectomy for cancer, although a subgroup of patients has substantially worse HRQL.

Validation of oesophageal cancer surgery data in the Swedish Patient Registry.

BACKGROUND: The Swedish Patient Registry provides data about diagnoses and surgical procedures for research purposes. There are, however, almost no validation studies of the data on surgical procedures, and none of oesophageal cancer surgery. MATERIAL AND METHODS: This was a validation study of the accuracy of codes representing oesophageal cancer resection, surgical approach and oesophageal substitute in the Swedish Patient Registry during the period 1987-2005. The registered data were compared with a thorough review of the corresponding operation charts collected from medical records. RESULTS: Among 1358 patients with a code representing oesophageal resection in the Patient Registry, the positive predictive value was 99.6%. The dominant surgical procedures in terms of surgical approach (transthoracic) and type of oesophageal substitute (gastric conduit) had positive predictive values of 99.8% and 99.4%, respectively. The more rare procedures with regards to approach (transhiatal) and substitute (bowel) had lower positive predictive values of 68.8% and 68.5%, respectively. CONCLUSION: The high accuracy of the data regarding oesophageal cancer resection in the Swedish Patient Registry stresses its appropriateness for research purposes.

Reference values of oesophago-gastric symptoms (EORTC QLQ-OG25) in a population-based setting.

AIM: Health-related quality of life (HRQL) has been recognised as an important outcome in clinical cancer research. A problem in HRQL studies is the lack of true baseline measures since patients already suffer from symptoms at time of diagnosis. The aim of this study is to provide valid reference values regarding symptoms common among oesophageal and gastric cancer patients, based on an unselected adult population. METHODS: In 2008 the EORTC QLQ-OG25 questionnaire was sent to randomly selected people in the adult Swedish population. Mean scores with standard deviation were calculated. Frequencies of symptoms were categorised into 'symptoms' or 'no symptoms'. The analyses were subcategorised for age groups, gender, and cancer diagnosis. RESULTS: In total, 4910 (70.5%) people responded to the questionnaire. Reflux was reported by 22.5% of the population, 25.6% reported pain and discomfort in the stomach area, 25.5% dry mouth and 32.0% had trouble with coughing. Other symptoms were dysphagia (3.5%), odynophagia (5.1%), and trouble eating with others (2.9%). Reflux, pain and discomfort and dry mouth were more often reported among women, while trouble with coughing was overrepresented among men. The symptoms dry mouth and trouble with coughing increased with age in both sexes. CONCLUSION: This comprehensive study is the first to provide reference values for the EORTC QLQ-OG25 questionnaire. These can be used as baseline surrogate in clinical research in oesophago-gastric cancer patients.

Reference values for the EORTC QLQ-C30 quality of life questionnaire in a random sample of the Swedish population.

AIM: To obtain reference values for health-related quality of life (HRQL) measured with the European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life Questionnaire (QLQ-C30) in a random sample of the adult Swedish population. METHODS: A population-based survey of a random sample of 7002 Swedish adults aged 40-79 years, frequency-matched to reflect the age and sex distribution of upper gastrointestinal cancer patients. Scales were scored on a 0-100 metric according to standard procedures. Functions and symptoms were dichotomized into "poor" versus "good" function, and "symptomatic" and "no or minor symptoms", respectively. The results were stratified for age and gender. RESULTS: The questionnaire was completed by 4910 (70.5%) of 6969 eligible participants. Missing values were limited. HRQL was found to vary according to age and sex. Generally, men reported better functioning and fewer symptoms than women. The most common symptoms were fatigue, pain, and insomnia. CONCLUSION: The reference values provided can be used as a surrogate baseline measure in HRQL research, and when evaluating the effect of interventions on HRQL in cancer patients.