Postoperative complications after esophagectomy for cancer, neoadjuvant chemoradiotherapy compared to neoadjuvant chemotherapy: A single institutional cohort study.

Background: Complications after esophagectomy are common and the possible increase in postoperative complications associated with neoadjuvant chemoradiotherapy is of concern. The aim of our study was to analyze if the addition of radiotherapy to neoadjuvant chemotherapy increases the incidence and severity of postoperative complications, including evaluation of the relation between radiation doses to the heart and lungs and postoperative complications. Methods: The study was based on an institutional surgical database for esophageal cancer. The study period was October 2008 to March 2020. Patients treated with neoadjuvant chemoradiotherapy were compared to patients treated with neoadjuvant chemotherapy and dose/volume parameters for the lungs and heart considered. The primary outcome was 30-day postoperative complications. Results: During the study period, 274 patients underwent surgery for esophageal cancer, 93 patients after neoadjuvant chemotherapy and 181 patients after neoadjuvant chemoradiotherapy. The median prescribed radiation dose to the planning target volume was 41.4 Gy, the median of the mean lung dose was 6.2 Gy, and the median of the mean heart dose was 20.3 Gy. The addition of radiotherapy to neoadjuvant chemotherapy did not increase the incidence of postoperative complications. Neither were radiation doses to the lungs and heart associated with postoperative complications. Taxane-based chemotherapy regimens were however associated with an increased incidence of postoperative complications. Conclusions: In our cohort, the addition of neoadjuvant radiotherapy to chemotherapy was not associated with postoperative complications. However, taxane-based chemotherapy regimens, with or without concomitant radiotherapy, were associated with postoperative complications.

Neoadjuvant Chemoradiotherapy and Surgery for Esophageal Squamous Cell Carcinoma Versus Definitive Chemoradiotherapy With Salvage Surgery as Needed: The Study Protocol for the Randomized Controlled NEEDS Trial.

Background: The globally dominant treatment with curative intent for locally advanced esophageal squamous cell carcinoma (ESCC) is neoadjuvant chemoradiotherapy (nCRT) with subsequent esophagectomy. This multimodal treatment leads to around 60% overall 5-year survival, yet with impaired post-surgical quality of life. Observational studies indicate that curatively intended chemoradiotherapy, so-called definitive chemoradiotherapy (dCRT) followed by surveillance of the primary tumor site and regional lymph node stations and surgery only when needed to ensure local tumor control, may lead to similar survival as nCRT with surgery, but with considerably less impairment of quality of life. This trial aims to demonstrate that dCRT, with selectively performed salvage esophagectomy only when needed to achieve locoregional tumor control, is non-inferior regarding overall survival, and superior regarding health-related quality of life (HRQOL), compared to nCRT followed by mandatory surgery, in patients with operable, locally advanced ESCC. Methods: This is a pragmatic open-label, randomized controlled phase III, multicenter trial with non-inferiority design with regard to the primary endpoint overall survival and a superiority hypothesis for the experimental intervention dCRT with regard to the main secondary endpoint global HRQOL one year after randomization. The control intervention is nCRT followed by preplanned surgery and the experimental intervention is dCRT followed by surveillance and salvage esophagectomy only when needed to secure local tumor control. A target sample size of 1200 randomized patients is planned in order to reach 462 events (deaths) during follow-up. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT04460352.

Short-course compared to long-course palliative radiotherapy for oesophageal cancer: a single centre observational cohort study.

BACKGROUND: Common symptoms of oesophageal cancer are dysphagia, pain, and bleeding. These symptoms can be relieved with palliative radiotherapy. The aim of this study was to analyse the outcome of two different palliative radiotherapy schedules. METHODS: We conducted a retrospective cohort study on palliative radiotherapy for oesophageal cancer given at Karolinska University Hospital. Patients included were treated with either short-course (20 Gy in 4 Gy fractions daily, 5 consecutive workdays) or long-course (30-39 Gy in 3 Gy fractions, 10-13 consecutive workdays) palliative external beam radiotherapy between January 2009 and December 2013. The primary endpoint was dysphagia relief and secondary endpoints were adverse events, re-interventions, and overall survival. Cox regression analyses were used to estimate the effect of treatment schedule on survival. RESULTS: A total of 128 patients received external beam radiotherapy under the study period, of these 75 (58.6%) received short-course radiotherapy and 53 (41.4%) long-course radiotherapy. Sixteen (30.8%) patients experienced dysphagia relief after short-course radiotherapy and 9 (22.0%) patients after long-course radiotherapy (p = 0.341). Acute toxicity was less frequent after short-course radiotherapy than after long-course radiotherapy, particularly oesophagitis (35.4% vs. 56.0%, p = 0.027) and nausea/emesis (18.5% vs. 36.0% p = 0.034). Re-interventions tended to be more common after short-course radiotherapy (32.0%) than after long-course radiotherapy (18.9%) (p = 0.098). There was no difference in overall survival between the two groups. CONCLUSIONS: Short- and long-course palliative radiotherapy for oesophageal cancer were equally effective to relieve dysphagia and no difference was seen in overall survival. Acute toxicity was, however, more frequent and more severe after long-course radiotherapy. Our results suggest that short-course radiotherapy is better tolerated with equal palliative effects as long-course radiotherapy.

Survival of esophageal and gastric cancer patients with adjuvant and palliative chemotherapy-a retrospective analysis of a register-based patient cohort.

PURPOSE: The survival of esophageal and gastric cancer patients treated with chemotherapy is rarely assessed outside of clinical trials. Therefore, we compared the effectiveness of various curative or palliative chemotherapy regimens on the survival of esophageal and gastric cancer patients in a "real world" clinical setting. METHODS: We identified a cohort of 966 incident esophageal and gastric cancer patients in Stockholm/Gotland County (a low-risk Western population) during 2008-2013. Patients who received chemotherapy with curative intention (n = 279) and palliative intention (n = 182) were analyzed separately. Using Cox proportional hazards regression models, we estimated hazard ratios (HRs) with 95% confidence intervals (CIs) and adjusted for the potential confounding factors: age, sex, TNM stage, radiotherapy, comorbidity, marital status, education, income, and country of birth. RESULTS: In esophageal cancer patients with curative treatment intention, we observed a higher hazard for death among patients who received carboplatin-fluorouracil compared to patients who received cisplatin-fluorouracil, corresponding to a HR of 2.18 (95% CI 1.09-4.37). Conversely, in patients with cancer in the gastroesophageal junction who had a curative treatment intention at diagnosis, we observed a reduced hazard for death among those who received fluorouracil-oxaliplatin, compared to patients who received cisplatin-fluorouracil (HR 0.28; 95% CI 0.08-0.96). CONCLUSION: Among patients with esophageal cancer who received treatment with curative intention, cisplatin-fluorouracil was associated with better survival compared to carboplatin-fluorouracil, while patients with gastroesophageal junction cancer who were treated with cisplatin-fluorouracil had worse survival compared to fluorouracil-oxaliplatin.

[Epidemiology of the two types of gastric adenocarcinoma in Iceland according to the Laurén histological classification 1990-2009].

BACKGROUND: In the mid twentieth century gastric cancer was the most common type of cancer in Iceland. In recent decades, however, the incidence rate of gastric cancer has decreased markedly and currently only represents 2-3% of cancer cases. The Laurén classification system classifies adenocarcinoma into two types, intestinal and diffuse. The main purpose of our study was to describe the epidemiology of the two types of gastric adenocarcinoma in Iceland between the years 1990-2009. METHODS: This is a retrospective cohort study. Information on patients diagnosed with gastric cancer in Iceland between 1990 and 2009 was collected from the population based Cancer Registry. Histological descriptions were reviewed and classified according to the Laurén classification system. The records of patients diagnosed with either having intestinal or diffuse adenocarcinomas were reviewed and epidemiological information gathered. RESULTS: Between 1990 and 2009, 730 patients were diagnosed with gastric adenocarcinoma in Iceland, 447 had intestinal adenocarcinoma and 168 diffuse adenocarcinoma. Patients diagnosed with diffuse adenocarcinoma were significantly younger at diagnosis than those diagnosed with intestinal adenocarcinoma. The sex ratio for intestinal adenocarcinoma was 2.3:1 (M:F) and 1.1:1 (M:F) for diffuse adenocarcinoma. The incidence of intestinal adenocarcinoma decreased more rapidly than that of diffuse adenocarcinoma during this period (0.92/100,000 vs. 0.12/100,000). Median survival rates of intestinal and diffuse adenocarcinomas were 23.7 and 20.6 months, respectively. The difference in survival was found to be statistically significant. The hazard ratio between the two groups was 1.31 (CI 1.03-1.67), corrected for age, sex, stage, year of diagnosis and surgical outcome (radical, non-radical or no operation). CONCLUSION: The overall incidence rate of gastric cancer has decreased dramatically in the past 20 years. However, the reduction is largely limited to the intestinal adenocarcinoma sub-group. We conclude that the Laurén classification predicts prognosis in gastric adenocarcinoma with diffuse adenocarcinoma having worse prognosis. KEY WORDS: gastric cancer, Laurén classification, survival, incidence. Correspondence: Halla Sif Olafsdottir, hsolafsdottir@gmail.com.

Loss-of-function variants in ATM confer risk of gastric cancer.

Gastric cancer is a serious health problem worldwide, with particularly high prevalence in eastern Asia. Genome-wide association studies (GWAS) in Asian populations have identified several loci that associate with gastric cancer risk. Here we report a GWAS of gastric cancer in a European population, using information on 2,500 population-based gastric cancer cases and 205,652 controls. We found a new gastric cancer association with loss-of-function mutations in ATM (gene test, P = 8.0 × 10(-12); odds ratio (OR) = 4.74). The combination of the loss-of-function variants p.Gln852*, p.Ser644* and p.Tyr103* (combined minor allele frequency (MAF) = 0.3%) also associates with pancreatic and prostate cancers (OR = 3.81 and 2.18, respectively) and gives an indication of risk of breast and colorectal cancers (OR = 1.82 and 1.97, respectively). Cancers in those carrying loss-of-function ATM mutations are diagnosed at a significantly earlier age than in non-carriers. Our results confirm an association between gastric cancer in Europeans and three loci previously reported in Asians, MUC1, PRKAA1 and PSCA, refine the association signal at PRKAA1 and support a pathogenic role for the tandem repeat identified in MUC1.

[Kawasaki disease in Iceland 1996-2005, epidemiology and complications]. / Kawasaki-sjúkdómur á Íslandi 1996-2005, faraldsfrædi og fylgikvillar.

OBJECTIVE: To analyze the epidemiology of Kawasaki disease in Icelandic children and its complications. METHODS: A retrospective analysis of all cases of Kawasaki disease and atypical Kawasaki disease in children in Iceland from 1996-2005. Chart records were reviewed and children diagnosed at Landspítali - University Hospital invited for a Follow up study with emphasis on heart complications. RESULTS: Thirty children were diagnosed with Kawasaki disease, annual incidence was 10.7/100.000 children <5 years of age. The boy:girl ratio was 2.3:1. All 30 children were treated with IVIG, without any major adverse events related to the treatment. The median time from the initial symptoms to treatment was six days (range 3-31 days). There was no mortality. Two children developed coronary aneurysms and three coronary ectasia. Follow up echocardiography was preformed in 23 of the children four to twelve years after Kawasaki disease. Two of the children still had coronary ectasia, and six (26%) had mitral regurgitation. CONCLUSIONS: The incidence of Kawasaki disease in Iceland was comparable to an earlier Icelandic study and reported incidence in the Nordic countries. Coronary involvement during the acute phase was mild, and all coronary aneurysm regressed. Serious cardiac complications were not seen. Children with Kawasaki disease in Iceland have favorable prognosis. Interestingly, mild mitral regurgitation and coronary ectasia were common at mid-term follow up.

On the measurement of movement difficulty in the standard approach to Fitts' law.

Fitts' law is an empirical rule of thumb which predicts the time it takes people, under time pressure, to reach with some pointer a target of width W located at a distance D. It has been traditionally assumed that the predictor of movement time must be some mathematical transform of the quotient of D/W, called the index of difficulty (ID) of the movement task. We ask about the scale of measurement involved in this independent variable. We show that because there is no such thing as a zero-difficulty movement, the IDs of the literature run on non-ratio scales of measurement. One notable consequence is that, contrary to a widespread belief, the value of the y-intercept of Fitts' law is uninterpretable. To improve the traditional Fitts paradigm, we suggest grounding difficulty on relative target tolerance W/D, which has a physical zero, unlike relative target distance D/W. If no one can explain what is meant by a zero-difficulty movement task, everyone can understand what is meant by a target layout whose relative tolerance W/D is zero, and hence whose relative intolerance 1-W/D is 1 or 100%. We use the data of Fitts' famous tapping experiment to illustrate these points. Beyond the scale of measurement issue, there is reason to doubt that task difficulty is the right object to try to measure in basic research on Fitts' law, target layout manipulations having never provided users of the traditional Fitts paradigm with satisfactory control over the variations of the speed and accuracy of movements. We advocate the trade-off paradigm, a recently proposed alternative, which is immune to this criticism.

Mechanical analysis and hierarchies of multidigit synergies during accurate object rotation.

We studied the mechanical variables (the grip force and the total moment of force) and multidigit synergies at two levels (the virtual finger-thumb level, VF-TH, and the individual finger level, IMRL) of a hypothetical control hierarchy during accurate rotation of a hand-held instrumented handle. Synergies were defined as covaried changes in elemental variables (forces and moments of force) that stabilize the output at a particular level. Indices of multidigit synergies showed higher values at the hierarchically higher level (VF-TH) for both normal and tangential forces. The moment of force was stabilized at both hierarchical levels during the steady-state phases but not during the movement. The results support the principles of superposition and of mechanical advantage. They also support an earlier hypothesis on an inherent tradeoff between synergies at the two hierarchical levels, although the controller showed more subtle and versatile synergic control than the one hypothesized earlier.

The effects of strength training on finger strength and hand dexterity in healthy elderly individuals.

We investigated the effect of 6 wk of strength training on maximal pressing (MVC) force, indexes of finger individuation (enslaving), and performance in accurate force production tests and in functional hand tests in healthy, physically fit, elderly individuals. Twelve participants (average age 76 yr) exercised with both hands. One of the hands exercised by pressing with the proximal phalanges (targeting mainly intrinsic hand muscles), whereas the other hand exercised by pressing with the finger tips (targeting mainly extrinsic hand muscles). Training led to higher MVC forces, higher enslaving indexes, and improved performance on the pegboard grooved test. Changes in an index of multi-finger force stabilizing synergy showed a significant correlation with changes in the index of force variability in the accurate force production test. Strong transfer effects were seen to the site that did not perform strength training exercise within each hand. Effects of exercise at the proximal site were somewhat stronger compared with those of exercise at the finger tips, although the differences did not reach significance level. Control tests showed that repetitive testing by itself did not significantly change the maximal finger force and enslaving. The results suggest that strength training is an effective way to improve finger strength. It can also lead to changes in finger interaction and in performance of accurate force production tasks. Adaptations at a neural level are likely to mediate the observed effects. Overall, the data suggest that strength training can also improve the hand function of less healthy elderly subjects.

Anticipatory synergy adjustments in preparation to self-triggered perturbations in elderly individuals.

We tested the ability of healthy elderly persons to use anticipatory synergy adjustments (ASAs) prior to a self-triggered perturbation of one of the fingers during a multifinger force production task. An index of a force-stabilizing synergy was computed reflecting covariation of commands to fingers. The subjects produced constant force by pressing with the four fingers of the dominant hand on force sensors against constant upwardly directed forces. The middle finger could be unloaded either by the subject pressing the trigger or unexpectedly by the experimenter. In the former condition, the synergy index showed a drop (interpreted as ASA) prior to the time of unloading. This drop started later and was smaller in magnitude as compared with ASAs reported in an earlier study of younger subjects. At the new steady state, a new sharing pattern of the force was reached. We conclude that aging is associated with a preserved ability to explore the flexibility of the mechanically redundant multifinger system but a decreased ability to use feedforward adjustments to self-triggered perturbations. These changes may contribute to the documented drop in manual dexterity with age.

Age-related changes in multifinger synergies in accurate moment of force production tasks.

The purpose of this investigation was to document and quantify age-related differences in the coordination of fingers during a task that required production of an accurate time profile of the total moment of force by the four fingers of a hand. We hypothesized that elderly subjects would show a decreased ability to stabilize a time profile of the total moment of force, leading to larger indexes of moment variability compared with young subjects. The subjects followed a trapezoidal template on a computer screen by producing a time profile of the total moment of force while pressing down on force sensors with the four fingers of the right (dominant) hand. To quantify synergies, we used the framework of the uncontrolled manifold hypothesis. The elderly subjects produced larger total force, larger variance of both total force and total moment of force, and larger involvement of fingers that produced moment of force against the required moment direction (antagonist moment). This was particularly prominent during supination efforts. Young subjects showed covariation of commands to fingers across trials that stabilized the moment of total force (moment-stabilizing synergy), while elderly subjects failed to do so. Both subject groups showed similar indexes of covariation of commands to the fingers that stabilized the time profile of the total force. The lack of moment-stabilizing synergies may be causally related to the documented impairment of hand function with age.

Elderly show decreased adjustments of motor synergies in preparation to action.

BACKGROUND: Aging is associated with decreased manual dexterity. Recent findings have identified changes in multi-finger synergies in elderly individuals. The purpose of current work was to study age-related changes in adjustments of multi-finger synergies in preparation to a quick targeted force pulse production task. METHODS: Right-handed elderly and young subjects produced quick force pulses by pressing on individual force sensors with the four fingers of the right hand. Prior to the force pulse, the subjects produced a constant low level of the total force. An index of multi-finger synergies was computed across trials for each time sample for each subject and each condition. FINDINGS: During steady-state force production, subjects showed co-variation of commands to fingers that stabilized the total force. An index of this co-variation started to decrease prior to the initiation of the force pulse (anticipatory synergy adjustment). Anticipatory synergy adjustments in young subjects started earlier and were larger than in elderly subjects. In particular, young and elderly subjects showed significant anticipatory synergy adjustments starting about 150ms and about 50ms prior to the force pulse initiation, respectively. There were no significant differences between the two groups in other indices of performance such as reaction time, time to peak force, and magnitude of the peak force. INTERPRETATION: We conclude that healthy aging is associated with decreased feed-forward adjustments of multi-finger synergies in preparation to action. This may contribute to the age-related decline in the hand function. Based on similarities in age-related changes in anticipatory postural adjustments and anticipatory synergy adjustments we suggest a hypothesis that the two phenomena may share common mechanisms.

Anticipatory covariation of finger forces during self-paced and reaction time force production.

We tested a hypothesis that humans can change patterns of finger force covariation in a task-specific manner in preparation to a change in the total force. Subjects performed quick targeted force pulses by pressing with four fingers on force sensors from a certain background force level to a target level. In self-paced trials, finger force modes (hypothetical commands to fingers) showed changes in covariation, computed across trials, more than 100 ms before changes in the total force. Half of the subjects showed large early changes in force mode covariation, while in the other half these changes were much smaller and were followed by a larger positive covariation of finger modes potentially destabilizing the total force profile. Such early covariation changes were absent under the simple reaction time instruction. We conclude that anticipatory covariation reflects control processes that can be expressed differently in different persons and modified depending on the available time for action preparation.

The emergence and disappearance of multi-digit synergies during force-production tasks.

We analyzed patterns of covariation among forces produced by the five digits of the human hand during tasks that required the production of a pattern of the total force consisting of ramp-up, constant force, and ramp-down segments with the time of the ramps ranging from 0 to 3000 ms. Patterns of the variance of the total force and the sum of the variances of individual digit forces were compared over sets of 12 trials at each task. The initiation of the ramp-up segment was associated with positive covariation of digit forces. Negative covariation among digit forces (force-stabilizing synergies) emerged after a critical time of 600-800 ms, which was only weakly dependent on the ramp time. These synergies persisted over the steady-state phase. A quantitative index of digit force covariation was introduced; it showed a drop about 100 ms before initiation of the ramp-down phase; we termed this phenomenon "anticipatory covariation" (ACV). The ramp-down phase was associated with rapid disappearance of the force-stabilizing synergy over a time period that ranged from 0 to 600 ms and scaled strongly with the duration of the force ramp. Thumb-virtual finger synergies showed qualitatively similar behavior to the multi-finger synergies (virtual finger is an imagined digit whose action is mechanically equivalent to the action of the four fingers). We conclude that abrupt changes in a time profile of total force are associated with transient destabilization of the total force. Changes in force-stabilizing synergies may occur in preparation to changes in the total force.

Is the thumb a fifth finger? A study of digit interaction during force production tasks.

We studied indices of digit interaction in single- and multi-digit maximal voluntary contraction (MVC) tests when the thumb acted either in parallel or in opposition to the fingers. The peak force produced by the thumb was much higher when the thumb acted in opposition to the fingers and its share of the total force in the five-digit MVC test increased dramatically. The fingers showed relatively similar peak forces and unchanged sharing patterns in the four-finger MVC task when the thumb acted in parallel and in opposition to the fingers. Enslaving during one-digit tasks showed relatively mild differences between the two conditions, while the differences became large when enslaving was quantified for multi-digit tasks. Force deficit was pronounced when the thumb acted in parallel to the fingers; it showed a monotonic increase with the number of explicitly involved digits up to four digits and then a drop when all five digits were involved. Force deficit all but disappeared when the thumb acted in opposition to the fingers. However, for both thumb positions, indices of digit interaction were similar for groups of digits that did or did not include the thumb. These results suggest that, given a certain hand configuration, the central nervous system treats the thumb as a fifth finger. They provide strong support for the hypothesis that indices of digit interaction reflect neural factors, not the peripheral design of the hand. An earlier formal model was able to account for the data when the thumb acted in parallel to the fingers. However, it failed for the data with the thumb acting in opposition to the fingers.