Remaining cancer cells within the fibrosis after neo-adjuvant treatment for locally advanced rectal cancer.

AIM: To analyse the incidence and distribution of remaining cancer cells within the fibrosis induced by preoperative chemo-radiotherapy (CRT) for locally advanced rectal cancer. METHODS: The histopathological specimens from 46 patients operated on with extensive surgery for locally advanced rectal cancer after CRT were examined. The extension of fibrosis in relation to the mesorectal fascia (MRF) and the distribution of cancer cells within the fibrosis was examined using routine haematoxylin-eosin staining. In addition, immunohistochemical staining with CK20 was done to examine if cancer cells were missed by routine pathological work up. RESULTS: All specimens showed CRT induced fibrosis. Two specimens showed complete response without viable cancer cells (ypT0). The fibrosis was limited inside the MRF in three cases, adherent to or involved the MRF in ten cases and in 33 cases the fibrosis was obvious outside as well as inside the fascia. Twenty-one cases showed fibrosis on the surgical resection margin, and in 9 of these cancer cells were found on the surgical margin (R1, R2-resection). 37 patients had R0 resections and among those 24 showed fibrosis beyond the MFR and 13 had scattered cancer cells in the fibrosis along or outside the MRF. CONCLUSIONS: The rate of remaining cancer cells within the fibrosis was high in patients with locally advanced rectal cancer treated with CRT. Frequently cancer cells were detected near the border of the fibrosis. A complete resection of the fibrosis is therefore recommended to achieve an R0 resection after neo-adjuvant treatment.

Problems in Interpretation of the short ACTH test: an update and historical notes.

ACTH stimulation test has been used for many years. Some important questions remain unsettled. These are reviewed and discussed in detail. Interpretation of a short ACTH test rests on the fact that a close correlation exists between the responses in plasma cortisol concentrations after administration of ACTH and during insulin induced hypoglycaemia which previously was the standard test. It is generally assumed that the plasma cortisol concentration after ACTH (and insulin) mirrors the response in major stress situations (surgery and critical disease). This notion rests on few observations. Furthermore, extensive changes in protein binding of cortisol occur swiftly during stress. This complicates comparison between cortisol responses to ACTH and to critical disease. Based on published studies it is discussed whether the outcome of an ACTH test is an appropriate indicator of the need for glucocorticosteroid replacement. This issue is of particular importance when deciding if permanent glucocorticosteroid substitution is necessary or not.

Cushing's disease, pseudo-Cushing states and the dexamethasone test: a historical and critical review.

The dexamethasone (DXM) test has been widely used for diagnosing Cushing's disease (CD). The purpose of this paper is to review its diagnostic merit based on calculation of data extracted from earlier publications. Studies presenting individual values for patients with CD and normal subjects were identified through PubMed searches and references in pertinent studies. Calculation of the retrieved data demonstrated huge variation in the relative suppressibility, negative suppression being common. Furthermore, in almost each study retrieved, the pre and post DXM values were closely correlated. Finally, the generally accepted view that DXM causes less suppression in Cushing's disease than in euadrenal controls appears unfounded. A central issue in the definition of so-called "pseudo-Cushing's states" is failure to suppress cortisol secretion with DXM. From analysis of the literature it appears quite possible that this does not reflect a specific endocrine deficit, but a physiological "stress" reaction. The above issues question the diagnostic value of the test, in particular in clinically and biochemically borderline cases.

Long-term ECMO treatment in Jehovah's Witness patient without transfusions.

A previously healthy 60-year-old male presented with fever, general pain and a C-reactive protein (CRP) of 160 mg/L. He was prescribed doxycycline. In the emergency room three days later, he was intubated and had a saturation of 70% on 100% oxygen. The chest X-ray showed bilateral lobar pneumonia. Streptococcus pneumonia was later verified. As a Jehovah's Witness, he had refused blood transfusions, but accepted albumin. Two days after admission, veno-venous extracorporeal membrane oxygenation (V-V ECMO) was started and the patient was then transported on ECMO to Stockholm. After two days, echocardiography showed right cardiac failure and the patient had to be converted to veno-arterial ECMO (VV-A ECMO) by cannulation of the left femoral artery. The haemoglobin decreased from 10.0 to 6.0 g/dL. Iron, folic acid, and erythropoietin were administered to stimulate erythropoesis. Romiplostim, to stimulate the production of platelets, was also started immediately. Blood samples were reduced to a minimum. The ECMO circuit was changed twice, using saline for priming, and the blood in the old circuit was then given back to the patient. The haemoglobin concentration varied between 4.5 and 6.0 g/dL during the ECMO treatment and the platelets between 80 and 140 x10(9)/L. After 44 days on ECMO, the patient was weaned off ECMO with 50% oxygen and nitric oxide (NO) at 20ppm in the ventilator. Four days after decannulation, he was transferred to a nearby intensive care unit. Long-term ECMO treatment without transfusion of blood products is possible. Being a Jehovah's Witness should not automatically be a contraindication for ECMO.

Reduction of BDNF expression in Fmr1 knockout mice worsens cognitive deficits but improves hyperactivity and sensorimotor deficits.

Fragile X syndrome (FXS) is a common cause of inherited intellectual disability and a well-characterized form of autism spectrum disorder. As brain-derived neurotrophic factor (BDNF) is implicated in the pathophysiology of FXS we examined the effects of reduced BDNF expression on the behavioral phenotype of an animal model of FXS, Fmr1 knockout (KO) mice, crossed with mice carrying a deletion of one copy of the Bdnf gene (Bdnf(+/-)). Fmr1 KO mice showed age-dependent alterations in hippocampal BDNF expression that declined after the age of 4 months compared to wild-type controls. Mild deficits in water maze learning in Bdnf(+/-) and Fmr1 KO mice were exaggerated and contextual fear learning significantly impaired in double transgenics. Reduced BDNF expression did not alter basal nociceptive responses or central hypersensitivity in Fmr1 KO mice. Paradoxically, the locomotor hyperactivity and deficits in sensorimotor learning and startle responses characteristic of Fmr1 KO mice were ameliorated by reducing BNDF, suggesting changes in simultaneously and in parallel working hippocampus-dependent and striatum-dependent systems. Furthermore, the obesity normally seen in Bdnf(+/-) mice was eliminated by the absence of fragile X mental retardation protein 1 (FMRP). Reduced BDNF decreased the survival of newborn cells in the ventral part of the hippocampus both in the presence and absence of FMRP. Since a short neurite phenotype characteristic of newborn cells lacking FMRP was not found in cells derived from double mutant mice, changes in neuronal maturation likely contributed to the behavioral phenotype. Our results show that the absence of FMRP modifies the diverse effects of BDNF on the FXS phenotype.

Hypothyroidism and thyroid substitution: historical aspects.

The last part of the 19th century was a period of great achievements in medicine and endocrinology. The thyroid gland evolved from being considered a rudimentary structure to an organ related to specific diseases. The singular importance of iodine became acknowledged. Graves-Basedow's disease was described. Surgical treatment evolved with extraordinary speed. Theodor Kocher observed that the clinical picture in patients after total thyroidectomy was similar to the one seen in cretinism. In 1850, the first case of hypothyroidism or myxedema was described. Less than 50 years later, effective treatment was introduced. Another 50 years later, autoimmune thyroiditis was ascertained as the most frequent cause of hypothyroidism (in areas with no iodine deficiency). This paper gives a short survey of the history of hypothyroidism and its treatment.

Structure of delay in carotid surgery--an observational study.

OBJECTIVES AND DESIGN: Undelayed investigation and surgical treatment of symptomatic carotid artery stenosis are recommended as per guidelines on stroke prevention. We evaluated patient referral pathways and delays from symptom to surgery in Helsinki University Central Hospital (HUCH) region. MATERIALS AND METHODS: One hundred consecutive symptomatic patients scheduled for carotid endarterectomy (CEA) between August 2007 and September 2008 were identified and the delay between ischaemic index symptom and CEA was analysed. RESULTS: The median time from the index symptom to surgery was 47 days (range: 3-688 days). The longest delay was surgery related with a median of 25 days (range: 2-202 days) from the consultation of the vascular surgeon to the operation. Only 11% of the patients were operated within the recommended 2 weeks' time. It was more likely that CEA was performed within 2 weeks if an emergent consultation to Meilahti Hospital neurologist on call did take place (odds ratio (OR) 12.6, 95% confidence interval (CI) 1.5-104, p = 0.019). CONCLUSION: Delays from symptom to surgery were generally too long and the in-hospital door-to-knife time (DKT) was long mostly due to waiting for the operation theatre. The investigation of all stroke, amaurosis fugax and transient ischaemic attack patients should be performed on an emergency basis and most optimally centralised to hospitals were carotid surgery is performed.

Incidence of craniopharyngioma in Denmark (n = 189) and estimated world incidence of craniopharyngioma in children and adults.

We studied the incidence of craniopharyngioma in Denmark during the period 1985-2004 and estimated worldwide incidence rates (IR) of craniopharyngioma based on a literature review. Craniopharyngioma patients diagnosed during the period 1985-2004 were identified from the Danish National Patient Registry, the Danish Cancer Registry and regional registries. Medical records were reviewed. Danish population data were obtained from Statistics Denmark. European and World population data were obtained from EU and WHO homepages. Prior studies providing data on craniopharyngioma IRs were identified via PubMed and, if appropriate, were included in a weighted analysis estimating overall and children's IRs of craniopharyngioma. IRs are given as new cases per million per year. We identified 189 patients with new verified (162) or probable craniopharyngioma. The overall WHO World-standardised incidence rate was 1.86 (1.60-2.14) for all ages and 2.14 (1.53-2.92) for children (age <15 years). Peak incidence rates were observed in age groups 5-9 and 40-44 years. Fifteen prior studies (including 1,232 craniopharyngioma cases) were identified. Seven and 11 studies, respectively, were eligible for weighted all-ages and childhood population IR analyses, yielding summary IRs of 1.34 (1.24-1.46) (all ages) and 1.44 (1.33-1.56) (children). We have provided a detailed survey of the incidence of craniopharyngioma in Denmark during a recent 20-year period. Overall IR of craniopharyngioma in Denmark was 1.86 (1.60-2.14) as compared to 2.14 (1.53-2.92) among children. Weighted estimates of craniopharyngioma world IRs were 1.34 (1.24-1.46) in all ages and 1.44 (1.33-1.56) among children.

A role for BDNF/TrkB signaling in behavioral and physiological consequences of social defeat stress.

Accumulating evidences underlie the importance of the interplay between environmental and genetic factors in contributing to the risk to develop mental illness. Brain-derived neurotrophic factor (BDNF) and its Tyrosine receptor kinase B (TrkB) receptor play a fundamental contribution to brain development and plastic adaptations to life events. In the present study, the potential for the BDNF/TrkB contribution in increasing vulnerability to negative social experiences was assessed by subjecting TrkB.T1 overexpressing mice to a chronic social defeat model. TrkB.T1 mice overexpress the dominant-negative truncated splice variant of TrkB receptor leading to decreased BDNF signaling. After repeated social defeat, mice were assessed in a longitudinal study for behavioral, physiological, endocrine and immune responses potentially related to psychiatric endophenotypes. TrkB.T1 overexpression corresponded to smaller changes in metabolic parameters such as body weight, food intake, feed efficiency and peripheral ghrelin levels compared with wild-type (wt) littermates following social defeat. Interestingly, 4 weeks after the last defeat, TrkB.T1 overexpressing mice exhibited more consistent social avoidance effects than what observed in wt subjects. Finally, previously unreported effects of TrkB mutations could be observed on lymphoid organ weight and on peripheral immune biomarker levels, such as interleukin-1α and regulated on activation, normal, T-cell expressed, and secreted (RANTES), thus suggesting a systemic role of BDNF signaling in immune function. In conclusion, the present data support a contribution of TrkB to stress vulnerability that, given the established role of TrkB in the response to antidepressant treatment, calls for further studies addressing the link between stress susceptibility and variability in drug efficacy.

Craniopharyngioma: historical notes.

For centuries tumors have been described which today with some confidence can be diagnosed as craniopharyngiomas. It was not until 1904 Erdheim described what he called 'hypophysial duct tumors', and which Cushing later gave the name craniopharyngioma. The first operation for this neoplasm took place in 1909. It soon became evident that the outcome of surgery was rather dismal with high mortality and morbidity rates-even after corticosteroid therapy became available around 1950. Radiotherapy was introduced and later refined as radiosurgery. This paper presents a short survey of the accumulation of knowledge of craniopharyngiomas.

Pituitary-gonadal axis: historical notes.

Though it was appreciated at a very early time that removal of gonads had evident consequences, the anatomy and function of the gonads were essentially unknown in the Antiquity. It was not until around 1600 that men like Vesalius, de Graaf and Leeuwenhoek initiated rational studies on the structure and function of the gonads. The close relationship between gonads and hypothalamus/pituitary was recognized less than 100 years ago. The last pituitary hormone with gonadotroph effect was discovered a generation ago. This paper briefly describes some major points in the development of our knowledge of the pituitary-gonadal function. Considering the huge number of studies involved, this review reflects but a tiny fraction of the work laid down over millennia within this field.

Excess mortality in women with pituitary disease: a meta-analysis.

BACKGROUND: Increased mortality has been reported in patients with pituitary disease, with some studies showing higher standard mortality rates (SMR) in women than in men. OBJECTIVE: To assess overall SMR for men and women with benign pituitary disease without excessive ATCH or GH secretion and to investigate associations between SMR and time period of diagnosis. DESIGN: From searches in PubMed, Embase and Web of Science databases, and reference lists of major reviews and original articles, we included original studies providing SMR values and 95% confidence intervals (CI) for men and women separately. Thirty articles were studied in detail. Six studies were eligible for the meta-analysis of sex-specific mortality, and seven for the analysis of association between SMR and diagnosis period. RESULTS: Individual studies (total 5412 patients) reported total SMR values (men and women together) ranging from 1.21 to 3.80. SMR varied from 0.98 to 3.36 in men and from 2.11 to 4.54 in women. Weighted SMR values were significantly higher in women (2.80; CI 2.59-3.02) than in men (2.06; CI 1.94-2 20) (P < 0.0001). SMR was negatively correlated with first year of diagnosis in individual studies (partial correlation analysis controlling for sex, P = 0.017), and approached normal in recent studies in men but not in women. CONCLUSIONS: In our meta-analysis of patients with pituitary disease without ACTH or GH excess, SMR was significantly higher in women than in men. SMR reached normal levels in men treated in recent decades, but remained elevated in women.

Hypopituitarism and mortality in pituitary adenoma.

BACKGROUND AND OBJECTIVE: Previous studies on hypopituitarism and mortality have concluded that insufficient pituitary function is associated with decreased survival. For several reasons the results are difficult to compare - particularly because definitions and treatment of hypopituitarism have varied and various underlying disorders have been included. The purpose was to assess the relationship between mortality and pituitary function. PATIENTS AND DESIGN: One hundred and sixty consecutive patients (99 men and 61 women) with functionless, suprasellar pituitary adenoma. All were operated on transsphenoidally during the period 1985-1996. Additional radiotherapy was given to 29 patients. Mortality was calculated 12.4 years (median, range 8.1-19.9) after operation. Postoperative hormonal deficits were treated in most, though GH substitution was given only to a minority of patients. RESULTS: Postoperatively 30% of the patients had normal pituitary function (normal adrenocortical, thyroid and gonadal function), 26% were panhypopituitary and 36% had partial pituitary insufficiency. Forty-one patients had died (34.7 expected) yielding a standard mortality ratio (SMR) of 1.18 (95% confidence limits (CI) 0.87-1.60). SMR was significantly increased in women (1.97, CI 1.20-3.21) but not in men (0.83, CI 0.55-1.26). SMR in patients with normal pituitary function, panhypopituitarism and partial insufficiency were not different from that in the general population. SMR in hypopituitary women was substantially higher than in men with pituitary insufficiency. Treatment with growth hormone in GH-deficient patients did not influence survival. CONCLUSION: Pituitary surgery for nonfunctioning adenoma and subsequent pituitary insufficiency had no effect on mortality in men, but was associated with significantly increased mortality in women. Suboptimal hormonal substitution in women may play a role.

Growth hormone: historical notes.

A brief review of important contributions to our present knowledge of growth hormone is given. In 1887 it had been noted that a pituitary tumor was present in most patients with acromegaly. Even at the beginning of the 20. Century relationship between growth disorders and the pituitary was contested. From 1908 pituitary surgery became established treatment in GH hypersecretion. In 1922 it was demonstrated that injection of pituitary extract to animals caused excessive growth and soon after the opposite: removal of the pituitary caused growth retardation. A huge number of studies on the effects of GH were subsequently reported as were trials with GH treatment. They were impeded by failure to recognize the impact of species specificity of GH. After this issue was clarified in 1957, treatment with human growth hormone proved effective. In 1985 it was realized that Creutzfeldt-Jakob's disease might be transmitted through human growth hormone. At this time recombinant GH had become available. In 1971 the structure of human GH was established. In the same period both GH releasing and inhibiting hormones were identified and an analogue of somatostatin had evolved into the first effective pharmacological treatment for acromegaly.

Frequent occurrence of pituitary apoplexy in patients with non-functioning pituitary adenoma.

BACKGROUND AND OBJECTIVE: There is agreement in the literature that pituitary apoplexy is a rare disorder. As our experience differs from this view, we analysed the incidence in patients operated on for a nonfunctioning pituitary adenoma. PATIENTS AND DESIGN: One hundred ninety-two consecutive patients with a suprasellar, clinically inactive adenoma operated on during the period 1985-1996 were retrospectively reviewed. A diagnosis of pituitary apoplexy was made from relevant neurological symptoms together with pertinent findings at operation. RESULTS: Pituitary apoplexy occurred in 41 patients (21%), in 23 patients within 12 days prior to the operation. The male/female ratio was 1.9. Median follow-up time was 13.7 years (range 8.9-19.9). During this period, 12 patients had died, yielding a standard mortality ratio of 1.09 (95% CI 0.62-1.92), similar to that in the patients who had not sustained pituitary apoplexy. Postoperatively, 24% of the patients had normal pituitary function, 38% were panhypopituitary and partial pituitary insufficiency was present in 38%. Subnormal GH secretion was present in virtually all patients tested. Two patients died within 60 days of surgery and in two no or incomplete data were available, although they most likely were panhypopituitary. CONCLUSION: Most of our findings add little to what is known about pituitary apoplexy. On one point, however, they are contrary to previously presented data. We found a much higher incidence of pituitary apoplexy despite rather rigorous criteria for the diagnosis. The outcome as regards survival and endocrine function was not different from that in patients with a nonfunctioning adenoma who did not suffer pituitary apoplexy.

Radiofrequency ablation in the liver close to the bile ducts: can intraductal cooling offer protection?

BACKGROUND: One complication of radiofrequency ablation (RFA) of the liver is biliary duct damage. Intraductal cooling (IDC) has been proposed as a means of protection. METHODS: In the first experiment, designed to evaluate the influence of IDC on the RFA procedure per se and on lesion formation, lesions were created in vivo in pig liver with and without IDC. The RFA needle was placed with a 1.5-cm safety margin from the bile ducts. In the second experiment, designed to evaluate the potential protective effects of IDC, lesions were created close to a bile duct with and without IDC. RESULTS: With the safety margin, the RFA parameters and lesion size were not negatively affected by IDC. Microscopic examination revealed that IDC had a protective effect in most of the lesions created close to a bile duct. CONCLUSIONS: The IDC procedure was feasible and had no negative effect on the RFA procedure or the lesions. However, the protective effect of IDC was not statistically significant (p = 0.12).

Prognostic value of preoperative magnetic resonance imaging of the pelvis in rectal cancer.

BACKGROUND: Despite radiotherapy and improved surgical techniques, local recurrence rates after treatment of rectal cancer still vary between 3 and 30 per cent. Tumour involvement of the circumferential resection margin (CRM) predicts a high risk of local recurrence. Magnetic resonance imaging (MRI) allows accurate description of the tumour and its spread within the mesorectum. The aim of this study was to assess the prognostic impact of an involved CRM identified at preoperative MRI in patients with rectal cancer. METHODS: Preoperative MRI was performed in 115 patients with rectal cancer between 1995 and 1999. The images were evaluated retrospectively. The shortest distance from the tumour to the CRM was measured, correlated with patient outcome and compared with histopathological findings. RESULTS: The risk of any recurrence in patients with or without a tumour-involved margin on MRI was nine of 29 and nine of 57 respectively (P = 0.036). Overall survival at 5 years was 43 and 77 per cent (P = 0.012) respectively. Twenty-four of 30 patients who had an involved CRM on histopathology were correctly identified by MRI. CONCLUSION: Patients with a potentially involved CRM identified by MRI had a significantly higher risk of recurrence and cancer-related death. Preoperative MRI may be of prognostic value in rectal cancer and may be used to select patients for neoadjuvant radiochemotherapy and/or more radical surgery.

Changing pattern of paediatric inflammatory bowel disease in northern Stockholm 1990-2001.

BACKGROUND: An increased incidence of paediatric Crohn's disease was reported recently by our group. AIMS: To assess the incidence and characteristics of inflammatory bowel disease (IBD) in northern Stockholm between 1990 and 2001. METHODS: All records of individuals 0-15 years of age with suspected IBD in the population based catchment area of 180000 individuals were scrutinised using defined diagnostic criteria. Patient files were searched for relatives with IBD, and for concomitant autoimmune diseases. RESULTS: A total of 152 children were diagnosed with IBD, corresponding to an overall incidence (per 100000) of IBD of 7.4. The incidence of Crohn's disease (CD) was 4.9, ulcerative colitis (UC) 2.2, and indeterminate colitis 0.2. Between 1990 and 2001, there was a marked increase in the incidence of CD while the incidence of UC was almost unchanged, leading to a net increase in the overall occurrence of IBD. There was a male dominance of CD. Fourteen per cent and 11% of patients with CD and UC, respectively, had a first or second degree relative with IBD. Eighteen per cent and 10% of patients with CD and UC, respectively, had a concomitant autoimmune disease. Ten patients with CD (10%) underwent surgery. CONCLUSIONS: The incidence of CD has increased in northern Stockholm. The current incidence is higher than that reported from other areas. Our results suggest a shift in presentation and diagnosis from UC towards CD, but also a net increase in IBD. Concomitant autoimmune disorders and family history are common in paediatric IBD.

Cryptal lymphocytic coloproctitis: a new phenotype of lymphocytic colitis?

BACKGROUND/AIMS: Lymphocytic colitis is a clinicopathological entity characterised by protracted watery diarrhoea and an increased number of intraepithelial lymphocytes (IELs) in the surface epithelium of the colonic mucosa. This report describes two patients with symptoms similar to those of lymphocytic colitis and an increased number of IELs, but within the cryptal epithelium. METHODS: The numbers of IELs were assessed in colorectal biopsies from the two patients. Sections were stained immunohistochemically for CD3, CD8, CD20, and TIA1. RESULTS: The colorectal biopsies had an abnormally high number of IELs in the epithelium of the crypts but not in the surface epithelium. The IELs in the crypts were CD3+++, CD8+, TIA1+, and CD20-. CONCLUSIONS: The histological diagnosis in these two patients was cryptal lymphocytic coloproctitis. Patients with similar symptoms and an increased number of IELs in the surface epithelium are now filed at this department as having surface lymphocytic coloproctitis. Immunohistochemistry showed that the cryptal IELs were cytotoxic suppressor T cells. Interestingly, a case of cryptal lymphocytic colitis was recently recorded in a non-human primate dying after years of protracted chronic diarrhoea. It is possible that antigens present in the lumen of the crypts elicit a lymphocytic reaction within the cryptal cells.