Can we use a simple blood test to reduce unnecessary adverse effects from radiotherapy by timely identification of radiotherapy-resistant rectal cancers? MeD-Seq rectal study protocol.

BACKGROUND: Chemoradiation therapy (CRT) followed by surgery is currently the standard of care to treat patients with locally advanced rectal cancer (LARC). CRT reduces local recurrences, but is associated with significant damage to the surrounding healthy tissue that can severely impact patients quality of life. Additionally, a proportion of patients (hardly) benefit from CRT. We aim to develop a diagnostic innovation, using DNA-methylation, which can enable a more selective and thereby more effective use of the available therapies for rectal cancer patients. METHODS: MeD-Seq Rectal is a prospective single centre, observational study. 75 patients diagnosed with rectal cancer and will receive CRT as neoadjuvant treatment are will be included. DNA-methylation profiling will be performed on liquid biopsies to predict pathological response to CRT. DISCUSSION: To data no clinical or image-based features were found that predict response to CRT. we hypothesize that DNA methylation patterns in liquid biopsies may provide a promising and patient-friendly strategy to predict CRT resistance upfront. TRIAL REGISTRATION: This trial is registered at ClinicalTrials.gov (NCT06035471).

Relation between body composition and severe diarrhea in patients treated with preoperative chemoradiation with capecitabine for rectal cancer: a single-centre cohort study.

BACKGROUND: Chemoradiation with capecitabine followed by surgery is standard care for locally advanced rectal cancer (LARC). Severe diarrhea is considered a dose-limiting toxicity of adding capecitabine to radiation therapy. The aim of this study was to describe the risk factors and the impact of body composition on severe diarrhea in patients with LARC during preoperative chemoradiation with capecitabine. METHODS: A single centre retrospective cohort study was conducted in a tertiary referral centre. All patients treated with preoperative chemoradiation with capecitabine for LARC from 2009 to 2015 were included. Patients with locally recurrent rectal cancer who received chemoradiation for the first time were included as well. Logistic regression analyses were performed to identify risk factors for severe diarrhea. RESULTS: A total of 746 patients were included. Median age was 64 years (interquartile range 57-71) and 477 patients (64%) were male. All patients received a radiation dosage of 25 × 2 Gy during a period of five weeks with either concomitant capecitabine administered on radiation days or continuously during radiotherapy. In this cohort 70 patients (9%) developed severe diarrhea. In multivariable logistic regression analyses female sex (OR: 4.42, 95% CI 2.54-7.91) and age ≥ 65 (OR: 3.25, 95% CI 1.85-5.87) were the only risk factors for severe diarrhea. CONCLUSIONS: Female patients and patients aged sixty-five or older had an increased risk of developing severe diarrhea during preoperative chemoradiation therapy with capecitabine. No relation was found between body composition and severe diarrhea.

Locally recurrent rectal cancer and distant metastases: is there still a chance ofcure?

INTRODUCTION: Patients with locally recurrent rectal cancer (LRRC) generally have poor prognosis, especially those who have (a history of) distant metastases. The aim of this study was to investigate the impact of distant metastases on oncological outcomes in LRRC patients undergoing curative treatment. METHODS: Consecutive patients with surgically treated LRRC between 2005 and 2019 in two tertiary referral hospitals were retrospectively analysed. Oncological survival of patients without distant metastases were compared with outcomes of patients with synchronous distant metastases with the primary tumour, patients with distant metastases in the primary-recurrence interval, and patients with synchronous LRRC distant metastases. RESULTS: A total of 535 LRRC patients were analysed, of whom 398 (74%) had no (history of) metastases, 22 (4%) had synchronous metastases with the primary tumour, 44 (8%) had metachronous metastases, and 71 (13%) had synchronous LRRC metastases. Patients with synchronous LRRC metastases had worse survival compared to patients without metastases (adjusted hazard ratio: 1.56 [1.15-2.12]), whilst survival of patients with synchronous primary metastases and metachronous metastases of the primary tumour was similar as those patients who had no metastases. In LRRC patients who had metastases in primary-recurrence interval, patients with early metachronous metastases had better disease-free survival as patients with late metachronous metastases (3-year disease-free survival: 48% vs 22%, p = 0.039). CONCLUSION: LRRC patients with synchronous distant metastases undergoing curative surgery have relatively poor prognosis. However, LRRC patients with a history of distant metastases diagnosed nearby the primary tumour have comparable (oncological) survival as LRRC patients without distant metastases.

The clinical relevance of indeterminate lung nodules in patients with locally recurrent rectal cancer.

AIM: To evaluate the clinical relevance of indeterminate lung nodules (ILN) in patients with locally recurrent rectal cancer (LRRC) treated in a tertiary referral centre. METHODS: All patients with LRRC diagnosed between 2000 and 2017 were retrospectively reviewed. Reports of staging chest CT-scans were evaluated for ILN. Patients with distant metastases including lung metastases at time of LRRC diagnosis were excluded. Overall (OS), progression-free survival (PFS) and the cumulative incidence of lung metastases were compared between patients with and without ILN. RESULTS: In total 556 patients with LRRC were treated during the study period. In the 243 patients eligible for analysis, 68 (28%) had ILN at LRRC diagnosis. Median OS was 37 months for both the patients with and without ILN (p = 0.37). Median PFS was 14 months for the patients with ILN and 16 months for patients without ILN (p = 0.80). After correction for potential confounding, ILN present at LRRC diagnosis was not associated with impaired OS or PFS (adjusted hazards ratio [95% confidence interval]: 0.81 [0.54-1.22] and 1.09 [0.75-1.59]). The 5-year cumulative incidence of lung metastases was 31% in patients with ILN and 28% in patients without ILN (p = 0.19). CONCLUSION: Our study shows that ILN are present in roughly a quarter of patients with LRRC. No differences in OS, PFS, or the cumulative incidence of lung metastases were found between patients with and without ILN at LRRC diagnosis. These results suggest that ILN are of little to no clinical relevance in patients with LRRC.

Locally recurrent rectal cancer; long-term outcome of curative surgical and non-surgical treatment of 447 consecutive patients in a tertiary referral centre.

INTRODUCTION: The majority of patients with locally recurrent rectal cancer (LRRC) present with extensive metastatic disease or an unresectable recurrence, and will be treated palliatively. Only a minority of patients will be eligible for potential cure by surgical treatment. The aim of this study is to evaluate the long-term outcome of surgical treatment and non-surgical treatment of patients with LRRC. METHODS: All patients with LRRC referred to our tertiary institute between 2000 and 2015 were retrospectively analysed. Patients were discussed in a multidisciplinary tumour board (MDT) and eventually received curative surgical or non-surgical treatment. Overall survival (OS) was compared by resection margin status and non-surgical treatment. RESULTS: A total of 447 patients were discussed in our MDT of which 193 patients underwent surgical treatment and 254 patients received non-surgical treatment. Surgically treated patients were significantly younger, received less neoadjuvant therapy for the primary tumour, had less metastasis at diagnosis and more central recurrences. The 5-year OS was 51% for R0-resections and 34% for R1-resections. Although numbers with R2-resections were too small to implicate prognostic significance, there was no difference in 5-year OS between R2-resections and non-surgical treatment (10% vs. 4%, p = 0.282). In a subgroup analysis the OS of R2-patients was even poorer compared to optimal palliative treated patients with combined chemotherapy and radiotherapy (22 vs 29 months, p = 0.413). CONCLUSION: R2-resections do not result in a survival benefit compared to non-surgical treatment in this non-randomized series. Patients with a high chance on a R2-resection could be offered non-surgical treatment, without local resection.

Numerical analysis of solutocapillary Marangoni-induced interfacial waves.

Spreading problems and solutocapillary waves are now routinely treated by semi-analytic lubrication theory leading to a 1D spatiotemporal system to be integrated numerically. In this review, such theories have been shown to be robust predictors of the pseudo-steady propagation at long times with only an initial transient period when the lubrication assumptions breakdown and the wave front is retarded due to bottom friction. Linear stability theory for bottom friction effects leads to 1D evolution equations that predict the scale of Marangoni stresses needed to excite waves and the solitary wave structure of their propagation. In general, applications which are sensitive to Marangoni effects naturally have high values of the Marangoni number (at least hundreds and potentially much higher in evaporation problems). Even when the Marangoni-induced effects are small amplitude, the gradients in stresses are such that numerical resolution requirements are steep. The idealization of interfacial dynamics to a domain with zero thickness (molecular effects) is computationally more demanding than the boundary layers induced in say high Reynolds number laminar flows. Therefore, specialized computational methods for treating open deformable interfaces with high transverse gradients are both required and are being successfully developed as reported here.

Weight gain in adolescents during pregnancy: rate related to birth-weight outcome.

This study of 459 subjects from prenatal clinics for teenagers at three universities across the United States, addresses questions about gestational weight gain in adolescents raised by the 1990 Institute of Medicine Report. Rate and pattern of gain, independent of pregravid weight, are based on serial measures of mothers with favorable and unfavorable outcomes. Rate of gain (determined by using regression statistics) from weeks 15 to 40 was 0.588, 0.510, and 0.488 kg/wk for mothers of term infants weighing 3000-4000 g, term infants weighing < 3000 g, and preterm infants, respectively. The significantly lower percentage of infants weighing 3000-4000 g vs < 3000 g needing intensive care at birth (6% vs 15%, respectively, P < 0.05) further indicates the superior outcome among mothers with higher rates of gain. Rate of gain of mothers of infants weighing 3000-4000 g (favorable outcome) equaled the highest amount provisionally recommended, suggesting that restricting natural gain of adolescents to recommended rates may result in smaller than optimal infants.

Health, developmental, and nutritional status of adolescent alcohol and marijuana abusers.

The impact of alcohol and marijuana abuse on the physical health and nutritional status of adolescents has not been well documented. The health consequences of alcoholism and chemical abuse in adults may not relate to the pediatric population. Forty-nine adolescent boys (mean age 15.8 years) with varying degrees of alcohol and marijuana use by self-report were evaluated as to their general health, pubertal development and nutritional status using health and dietary history, physical examination, anthropometrics, and biochemical assays of liver function and tissue nutrients. Thirteen (27%) were alcohol and marijuana abusers, 20 (41%) marijuana abusers, and 16 (32%) nonusers. There were significant differences between alcohol and marijuana abusers and marijuana abusers compared to nonusers with respect to endorsing symptoms of nutritional deficiency (muscle weakness, bleeding gums, tiredness, etc) (P less than .001). There were no significant differences between subgroups in other nutritional measures except plasma zinc concentration which was low in marijuana abusers (mean 85 micrograms/dL). All adolescents reported consuming adequate nutrients, although alcohol and marijuana abusers reported eating more snack foods and less fruit, vegetables, and milk than other groups. There were no significant differences in hematologic status (complete blood cell count, transferrin, folate), liver function (gamma-glutamyltranspeptidase), or anthropometric and sexual maturational indices of growth. There were no chronic signs of chemical abuse by physical examinations. It appears that health and nutritional disability from chemical abuse in adolescents relates more to poor dietary habits and symptomatic deterioration in general health than to specific effects on growth or nutritional status. Studies with larger numbers of subjects need to document these findings.

Birth weight associated with lowest neonatal mortality: infants of adolescent and adult mothers.

OBJECTIVE: We tested the hypothesis that survival is highest for infants born in the same weight range whether mothers are adolescent or adult, comparing the weights at which infants of these mothers achieve lowest neonatal mortality. METHODS: The relationship between birth weight and neonatal mortality was studied in births to 16.4 million women using the National Center for Health Statistics 1983-1987 national linked birth/infant death data sets. Neonatal mortality rates were calculated for 500 g birth weight categories. Births for maternal ages < or = 15 years, 16 years, and 17 to 18 years were compared with births to adults 19 to 34 years of age, whites and blacks considered separately. The birth weight categories associated with minimum neonatal mortality and the weight range corresponding with greatest survival were determined for each age and racial group. RESULTS: Minimum neonatal mortality rates occurred at the same birth weights (3500 to 4499 g white and 3000 to 3999 g black) whether mothers of the infants were adolescents or adults. The most favorable range of birth weight, in which survival was greatest, commenced at 3000 g for all mothers, terminating at 3999 g for most black adolescents and black adults, 4499 g for most white adolescents, and 4999 g for white adults. Of infants born to mothers < or = 16 years old, 33% were lighter and 1.5% were heavier than the favorable birth weight range. CONCLUSION: The birth weight categories with minimum neonatal mortality and the birth weight range in which neonatal survival was greatest were comparable for infants of adolescents and adults. Lower birth weights, occurring more frequently in births to teenage mothers, were associated with higher neonatal mortality. Assisting adolescent mothers to bear infants with birth weights in the range corresponding with low neonatal mortality is an appropriate goal of clinical management.

The effects of 50 Hz magnetic fields on opioid peptide mediated inhibition of guinea pig ileum.

Strips of guinea pig ileum were mounted in a tissue bath within the poles of a magnet capable of generating a 50 Hz field of intensity up to 1 mT. In the absence of magnetic field the preparations were stimulated transmurally at tetanic frequency (10 Hz). The post-tetanic inhibition was antagonised by naloxone. When this inhibitory phase was repeated in the presence of a magnetic field of 0.5 mT there was a small but significant increase in the inhibition when compared with paired controls.

Changes in plasma opioid concentrations after physiotherapeutic exercises for arthritic patients.

Plasma concentrations of [met]enkephalin (ME) and beta-endorphin (beta E) were measured in samples obtained immediately before and after physiotherapeutic exercises for patients with ankylosing spondylitis (AS), osteoarthritis (OA), or knee injuries. Correlations were sought between opioid peptide concentrations or changes therein, and nature, severity and duration of disease, age, severity of pain reported and pain threshold. No correlation was found with any of the pain parameters. However, there was a possible relationship between age or duration of disease and changes in ME concentrations.

Management of obesity in adolescence.

A great deal of the discouragement about treating adolescents who are obese is related to the traditional treatment approaches. Obesity is a complex problem needing comprehensive treatment. Focusing on weight loss as a short-term goal is unreasonable because of individual variation in the physiologic potential to lose weight. Short-term goals and rewards are related to adopting daily habits that will lead to a decrease in energy storage in the long term. Support for changing habits and improving psychosocial adjustment is a necessary component of effective treatment, enabling patients and their families to make changes.

In vitro actions of NN-dimethyl-2-aminoindane and related compounds.

The actions of 2-aminoindane, 2-amino-1,2,3,4-tetrahydronaphthalene and amphetamine and their N-methyl and NN-dimethyl derivatives on the guinea-pig ileum were compared. All, except the tertiary 2-aminoindane, inhibited the responses to electrical stimulation and it is suggested that this is not fully explained by their sympathomimetic properties. NN-Diemthyl-2-aminoindane increased these responses and caused contractions of the unstimulated ileum due to a nicotine-like action. The indane series was more effective in producing contractions of the ileum than the other compounds. The three tertiary derivatives antagonized competitively the actions of histamine on the ileum and those of 5-hydroxy-tryptamine on the rat uterus.

The effects of phenylpropanolamine and other sympathomimetics on food consumption and motor activity in mice.

The effects of phenylpropanolamine on motor activity and on food intake were compared with those of S-amphetamine, ephedrine, 2-aminoindane and fenfluramine in groups of mice. Motor activity was additionally measured in mice pretreated with levodopa and benserazide, and food intake in mice pretreated with alpha-methyl-p-tyrosine. Amphetamine (2.5 mg kg-1) increased motor activity, phenylpropanolamine (10-40 mg kg-1) and 2-aminoindane (2.5-10 mg kg-1) decreased activity whilst ephedrine (2.5-40 mg kg-1) had a biphasic effect. Fenfluramine (10-40 mg kg-1) had negligible effect on activity. In mice pretreated with levodopa and benserazide both phenylpropanolamine and 2-aminoindane caused a massive increase in motor activity whilst fenfluramine's action was not affected in the same way. Whilst the anorectic action of fenfluramine was considerably potentiated in mice pretreated with alpha-methyl-p-tyrosine, that of amphetamine, ephedrine, 2-aminoindane and phenylpropanolamine was either unaffected or initially antagonized. It is concluded that the mechanisms of motor and anorectic actions of phenylpropanolamine are similar to those of amphetamine.

Sympathomimetic effects of exo- and endo-isomers of 2-aminobenzonorbornene in vitro and in vivo.

A stereospecific synthesis of endo-2-aminobenzornorbornene is described. Its sympathomimetic activities and those of its N-methyl derivative were compared with the equivalent exo-isomers using the isolated rat anococcygeus muscle and the anaesthetized rat blood pressure preparations. On the anococcygeus muscle preparation the endo- and exo-isomers of the primary amines had similar indirectly acting sympathomimetic activities. In contrast the exo-N-methyl derivative was a far more potent sympathometic in vitro than the endo-N-methyl isomer. In the anaesthetized rat the exo- and endo-isomers of 2-aminobenzonorbornene and their N-methyl derivatives all had similar pressor activities, though the successive injections of the two exo-derivatives suggested an additional alpha-adrenoceptor blocking activity. The actions of these rigid sympathomimetics are compared with those of the flexible amphetamine structure.

The cost of burn care and the federal government's response in the 1990s.

This article attempts to predict the federal government's response to the cost of burn care in the 1990s by examining the explosive growth of health care costs in the 1980s and the impact that this had on hospitals with burn centers. The Prospective Payment System (PPS) was enacted in 1983, which limited the government's liability to hospitals by effectively capping the amount of federal dollars in the system. The inequities of the classification of burn patients by the PPS is discussed and a proposal for modification is outlined.

Treatment of toxic epidermal necrolysis by burn units: another market or another threat?

A survey of burn care facilities in the United States has provided information regarding the treatment of toxic epidermal necrolysis and related diseases in burn units. The survey suggests that a disproportionate share (12% to 15%) of the projected number of cases of toxic epidermal necrolysis that occur annually are being transferred to the 2% of United States hospitals that have burn units. Because of the potential for a complex hospital course and extended length of stay, treatment of these patients in a prospective payment system poses a significant fiscal threat to hospitals with burn units.

Iron fortification of infant foods. A decade of change.

A survey of iron-fortified commercial foods commonly marketed for consumption by infants was conducted in 1972 and again in 1982. Positive changes had occurred in infant formulas and cereals during that decade, in availability of fortifying iron, level of fortification, and label information. Miscellaneous iron-containing products, cookies, and crackers were unreliable sources of dietary iron in both 1972 and 1982. Availability of fortifying iron in regular cereals had improved by 1982, though 10 percent lacked the label information. Fortified infant formulas and cereals contribute iron of high bioavailability to the typical infant diet in amounts equal to the USRDA. Food manufacturers need to continue to apply knowledge gained through research to sustain the lessened but still highly prevalent incidence of anemia in 1-2-year old children.