Incidence of medullary thyroid carcinoma and Hirschsprung disease based on the cosmos database.

PURPOSE: Multiple endocrine neoplasia Type 2A (MEN2A) can occur with Hirschsprung disease (HD) due to mutation in the RET proto-oncogene, with the majority developing medullary thyroid carcinoma (MTC). Given the comorbidity, many parents have contacted us to share concerns and unfortunate experiences about the prevalence rates of MEN2A/MTC in patients with HD. The aim is to determine the prevalence rate of patients with HD and MEN2A or medullary thyroid carcinoma, respectively. METHODS: This is a cross-sectional study of the COSMOS database from January 01, 2017, to March 08, 2023. The database was searched for patients diagnosed with MEN2A, MTC, and HD. IRB exemption was provided (COMIRB #23-0526). RESULTS: The database contained 183,993,122 patients from 198 contributing organizations. The prevalence of HD and MEN2A was 0.00002%, and for HD and MTC was 0.000009%. One in 66 patients (1.5%) with MEN2A also had HD. One in 319 patients (0.3%) in the HD group had MEN2A. One in 839 patients (0.1%) within the HD population had MTC. CONCLUSION: The prevalence of MTC and HD or MEN2A and HD in the study population was low. Considering that almost all MEN2A patients have a positive family history, this data does not support the general genetic testing of HD patients.

Bone alkaline phosphatase in rheumatoid arthritis: a longitudinal study.

OBJECTIVE: To determine whether the raised total alkaline phosphatase (TAP) found in patients with active rheumatoid arthritis (RA) is derived primarily from an increase of the bone or liver isoenzyme, and to evaluate the treatment effect of steroids and disease modifying antirheumatic drugs (DMARD) on bone alkaline phosphatase (BAP) in serial analyses. METHODS: 58 patients with RA were treated with the DMARD gold sodium thiomalate (n = 22), D-penicillamine (n = 18), or sulfasalazine (n = 18) over a 24 week period with regular assessment of disease activity and measurement of BAP using a newly developed specific double monoclonal radioimmunometric assay. RESULTS: In the RA group as a whole, BAP correlated with TAP at all time points (e.g., Week 0 rs = 0.50, p < 0.0001). In contrast, no correlation was found between the intraindividual change of BAP and TAP between Weeks 4 and 24. TAP was correlated with disease activity (assessed by plasma viscosity rs = 0.33, p < 0.02 for the whole RA group and rs = 0.48, p < 0.0002 for intraindividual change from Weeks 4 to 24). Similarly, gamma-glutamyltranspeptidase was correlated with disease activity (rs = 0.56, p < 0.0001, and rs = 0.50, p < 0.0001, respectively). In contrast, BAP was not correlated with disease activity. Low dose steroids and the 3 DMARD studied had no significant effect on the time course of BAP. CONCLUSION: In the majority of patients with active RA, any increase of TAP is not mirrored by an increase of BAP. This supports the hypothesis that inflammatory reactions result in an increase in the plasma concentration of the membrane bound enzymes of the hepatobiliary system, including gamma-glutamyltranspeptidase and the liver isoenzyme of alkaline phosphatase, which is likely to be responsible, at least in part, for the increase of TAP. Since BAP is not correlated with disease activity, BAP measurements are not useful in monitoring response to treatment.

Serum hyaluronan concentrations predict survival in patients with chronic renal failure on maintenance haemodialysis.

BACKGROUND: Malnutrition and wasting are common in chronic renal failure and are adverse prognostic features. The underlying mechanisms are complex and not fully understood. Hyaluronan is present in increased concentrations in chronic renal failure and may be associated with adverse features of chronic renal failure. METHODS: We have investigated the relationship of this abnormality to long-term survival. Outcome of 81 patients of median of 5.6 years (3.9-6.8) after measurement of hyaluronan was determined. RESULTS: Survival analysis by the Cox regression model showed that increased concentrations of hyaluronan (P < 0.0001). There was also a weak but significant negative correlation between hyaluronan concentrations and serum albumin concentrations (rs = - 0.27, P = 0.02). CONCLUSIONS: We conclude that serum hyaluronan is a strong independent predictor of long-term survival in CRF may reflect abnormal connective tissue metabolism in this condition.

Bone alkaline phosphatase in rheumatic diseases.

A double monoclonal immunoradiometric assay specific for bone alkaline phosphatase (BAP) was used to determine whether the raised total alkaline phosphatase (TAP) often found in patients with active rheumatoid arthritis (RA) and ankylosing spondylitis (AS) is derived from bone or liver. Fifty-eight patients with RA were compared to 14 with AS and 14 with non-inflammatory rheumatic diseases (NI). None had clinical liver disease and only one had a slightly elevated aspartate transaminase activity. Elevated BAP concentrations were found in seven patients (5 RA, 1 AS, 1 NI), only two of whom also had abnormal TAP. Abnormal TAP activities were found in only three patients (all RA). BAP did not correlate with disease activity in RA or AS. In contrast, TAP correlated with disease activity (assessed by plasma viscosity) in RA (P < 0.002) and gamma-glutamyl transferase (GGT) also correlated with plasma viscosity in RA (P < 0.01). Both TAP and BAP were significantly correlated with GGT in RA (P < 0.001 and P < 0.02, respectively). These findings are discussed, together with possible reasons for the conflicting nature of some of the observations.

Neuron-specific enolase (NSE) in serum. Comparison of monoclonal versus polyclonal assay based on 392 blood samples.

Neuron-specific enolase (NSE) is the best described serum tumor marker for small cell lung cancer (SCLC). Almost all clinical studies carried out so far used assays involving polyclonal antibodies against NSE; the majority of the studies analyzed the samples by a RIA NSE kit. We evaluated a new monoclonal kit and compared it to the polyclonal kit. We analyzed 392 serum samples, 265 from patients with SCLC, 88 from non-small cell lung cancers (NSCLC) and 39 from children with neuroblastomas. We found a good correlation between the results of the two assays. When correlating NSE in SCLC as measured with the two assays with clinical data, we found the same sensitivity, prognostic impact and value in treatment monitoring. We conclude that the "new" monoclonal assay is a fully acceptable alternative to the "old" polyclonal assay.

Bone alkaline phosphatase and prostate-specific antigen in the monitoring of prostate cancer.

A retrospective study has been made on the interrelationship of serum bone alkaline phosphatase (BAP), measured by the Ostase-RIA, and prostate-specific antigen (PSA) in 156 patients with M0 and M1 prostate cancer. BAP is a more sensitive and more specific method of determining osteoblast activity than total alkaline phosphatase (TAP). The main difference between these two assays is seen when the TAP is in the range of normal to twice-normal. BAP shows a low intraindividual variation in M0 disease, and was within normal limits in 18 patients following radical prostatectomy with a PSA < 0.1 ng/ml. A raised BAP was observed in 86.4% of M1 disease at diagnosis before treatment. The change of BAP was concordant with PSA in 69% of 49 cases of M1 disease, although there are marked differences in the rates of change of the two markers. A nadir of PSA < or = 10 ng/ml after androgen blockade in M1 disease was associated with a high probability of a normal BAP.

Neuron-specific enolase.

The clinical value of neuron-specific enolase as a marker is small cell lung cancer, neuroblastoma, melanoma and seminoma has been reviewed. The role of serum and cerebrospinal NSE in benign and malignant disease of the central nervous system is discussed.

Serum neuron-specific enolase (S-NSE) in progressive small-cell lung cancer (SCLC).

Clinical decision making is based on results from qualitative and quantitative information. To provide quantitative data, various laboratory variables are widely used in the clinical evaluation of patients with small-cell lung cancer (SCLC). The tumour marker serum neuron-specific enolase (S-NSE) and the routine laboratory parameter serum lactate dehydrogenase (S-LDH) have been investigated, mostly separately. Few studies have compared their importance in SCLC, especially in progressive disease (PD). The present investigation was undertaken to evaluate S-NSE for diagnostic efficacy in PD and compare it with S-LDH. In 27 patients in a treatment trial of SCLC, regular follow-up laboratory values were prospectively obtained. Chemotherapy was given according to trial protocols, and all clinical evaluation followed the WHO recommendations. At re-evaluation all but three values had normalised (two S-NSE, one S-LDH). S-NSE at progression was increased in 93% of the patients and S-LDH in 59%. The efficacy of S-NSE to discriminate between response and PD was superior to S-LDH (0.92 vs 0.70). There was no additive effect of the two parameters in prediction of PD, and the discriminating power was higher for S-NSE than for S-LDH (P < 0.0008). The disease status-related marker increments in relation to upper reference limits, i.e. the signal-noise relation, were higher for S-NSE than for S-LD. Both of the markers carry information on PD. S-NSE is, however, clearly superior to S-LDH in reflecting disease status during therapy. This prompts us to conclude that S-NSE should replace S-LDH as prognostic factor and disease activity monitor in SCLC.

The role of CA-242 and CEA in surveillance following curative resection for colorectal cancer.

This study was undertaken to evaluate the role of a new tumour marker, CA-242, alone or in combination with CEA in the practical management of colorectal cancer patients after potentially curative resection. A cohort of 149 patients who had undergone 'curative' surgery was followed up according to an intensive protocol in order to detect recurrent disease. Over a median tumour marker follow-up period of 24 months there were 25 recurrences in 24 patients. Both CEA and CA-242 alone detected half the local recurrences. The sensitivity of CEA was 84% for distant or mixed recurrence compared with 64% for CA-242. An abnormality of either CEA or CA-242 enabled detection of five out of six local recurrences and 17 out of 19 distant or mixed recurrences with a median lead time of 5 months for each marker. Both markers were elevated concurrently in only one local and 11 distant recurrences. While CA-242 alone is not superior to CEA, their combined use (either abnormal) has a high sensitivity (88%), specificity (78%) and negative predictive value (97%); this may be useful in reducing unnecessary investigations in follow-up programmes and as a guide to the initiation of further treatment for recurrent disease.

Commercial assays for serum osteocalcin give clinically discordant results.

Serum samples from 9 healthy controls and from subjects with primary hyperparathyroidism (n = 5), Paget disease (n = 3), pregnancy (n = 5), glucocorticoid therapy (n = 5), postmenopausal osteoporosis (n = 10), and renal failure (n = 10) were used to assess the clinical agreement among eight commercially available assay kits for osteocalcin (OC). These kits differ in their assay configurations (six radioimmunoassays, two immunoradiometric assays), standards (five bovine, three human), and antibodies (six polyclonal, two monoclonal). Individual results were divided by the mean OC of the control subjects for each assay and expressed as percentage deviations. The expected wide variation in absolute OC concentrations between kits was only partially reduced by this transformation. Agreement was equally poor when absolute OC concentrations were compared with the reference ranges quoted by the manufacturers. The discordance was particularly marked in renal failure, presumably because of immunoreactive fragments, and in osteoporosis. Systematic differences could not be attributed to assay format, species source of standard, or antibody specificity. We conclude that results cannot be compared between assays even when normalized against healthy subjects, and that standardization is needed.

Tumor markers. Consensus Conference on Diagnosis and Prognostic Parameters in Localized Prostate Cancer. Stockholm, Sweden, May 12-13, 1993.

This chapter mainly deals with biochemical aspects on prostate specific antigen (PSA) and its clinical value. To a limited extent, also other tumor markers, which might be of importance in the evaluation of patients with prostate cancer are discussed. In serum, PSA exists in a free form or bound to antichymotrypsin. Interestingly, only 10% of PSA secreted from cancer cells seems to exist in a free form, as compared to 30% of PSA secreted from cells in benign prostatic hyperplasia (BPH). PSA seems to be closely, but not absolutely, related to tumor grade and stage. The mean value of PSA in patients with tumors dominated by Gleason grades 3 or below, was 10 ng/ml, compared to 29 ng/ml in those with higher grades. Patients with PSA values of 50 ng/ml or above almost exclusively had tumor of Gleason grades 4 or 5, and this limit usually reflected a generalized disease. Patients with PSA-values below 10 ng/ml almost exclusively had tumors confined to the prostate gland. In countries where screening for prostate cancer is believed in, it is important to understand that normal cut-off values are related to patient's age. The upper normal limit of males below 50 years of age should be set at 2.5 ng/ml, as compared to 6.5 ng/ml for men over 70 years of age. To improve the value of PSA determination and for scientific purposes, the standardization of the assay is urgently needed and under way. Prostate acid phosphatase (PAP) has in most centres been replaced by PSA. An elevated PAP value, as measured by the enzymatic method, invariably indicates a generalized disease and could thus be used as a complementary informative assay to PSA. Other markers have been used mainly to achieve additional prognostic information. In a multivariate analysis, the non-specific tumor marker neopterin, which reflects the host response to tumor antigens, was closely related to short-term prognosis. Neopterin was followed by thymidine kinase, a protein reflecting the cell turn-over and tumor grade. Also PSA at diagnosis seemed to add some prognostic information, whereas other markers did not.

Clinical evaluation of serum tissue polypeptide-specific antigen (TPS) in non-small cell lung cancer.

M3 is an epitope of the tissue polypeptide antigen detectable in the serum by immunoradiometric assay. This epitope is referred to as tissue polypeptide-specific antigen (TPS). We examined the pretreatment TPS level of 160 non-small cell lung cancer (NSCLC) patients and 71 patients who suffered from non-malignant pulmonary diseases. The upper limit of normal values was 140 U/l. Using this cutoff, the sensitivity and specificity were 36 and 90%, respectively. The TPS was significantly higher in NSCLC patients with an advanced stage, a mediastinal lymph node involvement or a poor performance status. This level was significantly higher in the group of patients for whom the disease proved to progress during chemotherapy. In univariate analysis, patients with a high TPS level proved to have a shorter survival than patients with a TPS < or = 140 U/l. In Cox's model analysis, performance status, stage of the disease and serum TPS were the only significant prognostic variables. The low sensitivity of TPS precludes its use for diagnosis. However, the pretreatment TPS level adds information to the management of NSCLC inasmuch as it predicts a low sensitivity to chemotherapy and a poor prognosis.

Clinical evaluation of serum tumour marker CA 242 in non-small cell lung cancer.

CA 242, a novel tumour carbohydrate antigen present in serum (upper limit of normal values: 20.0 U ml-1), has been measured in a group of 102 pathologically confirmed non-small cell lung cancer patients. The aim of the present prospective study was to identify any relationship between pre-treatment serum CA 242 level and different features of lung cancer including prognosis. Serum CA 242 was measured using the delayed europium lanthanide fluoroimmunometric assay. Sensitivity and specificity were 28.5% and 95.6% respectively. Its level was significantly lower in squamous cell carcinoma in comparison with non-squamous histologies (adenocarcinoma and large cell carcinoma). The CA 242 level was higher in metastatic disease (median: 15.3 U ml-1) in comparison with non-metastatic (median: 7.9 U ml-1; Mann Whitney U test; P < 0.003), and increased significantly from stage I to stage IV. In 50 patients who underwent chemotherapy, the serum CA 242 level was higher in non-responder patients when compared with responders (median: 16.8 U ml-1 and 9.5 U ml-1 respectively; Mann Whitney; P < 0.02). Univariate analysis of the entire population showed serum CA 242 levels were not related to survival. However, patients with unresectable non-small cell lung cancer and elevated CA 242 level proved to have a significantly shorter survival than those with a CA 242 < 20 U ml-1. In Cox's model analysis, stage of the disease and performance status were the only significant determinants of survival. We conclude that a high level of serum CA 242 (1) is significantly related to the stage of disease, (2) predictive of no response to chemotherapy but seems to add weak prognostic information to stage of disease and performance status, the main prognostic determinants of non-small cell lung cancer.

The use of tumour markers CEA, CA-195 and CA-242 in evaluating the response to chemotherapy in patients with advanced colorectal cancer.

Tumour markers CEA, CA-195 and CA-242 were measured in 33 patients undergoing chemotherapy for advanced colorectal cancer. The aim was to determine whether they could be used to accurately monitor the course of the disease, and reduce the need for imaging. Treatment with a 5-fluorouracil based regimen resulted in a partial response in nine patients (27%), whereas the remainder either had disease stabilisation or suffered from progression. Before treatment the CEA was elevated in 85% of patients and the CA-195 and CA-242 in 78%. All three markers were elevated in 70% and at least one elevated in 93%. CA-195 and CA-242 appeared to be co-expressed, by contrast with the CEA. When compared to the results of serial CT scanning the CEA correlated best with the course of the disease, the positive predictive value being 54% for a partial response, 77% for minor and partial responses combined and 100% for progressive disease. The corresponding values for CA-195 were 46%, 62% and 100% respectively and for CA-242, 50%, 67% and 100% respectively. Thus, although falling levels of markers overestimate the number of responses demonstrated by imaging, rising tumour markers invariably herald progressive disease. This was often evident up to 16 weeks before progression was observed on scanning. CEA is the most useful of the three markers in the monitoring of patients being treated for advanced colorectal cancer, but other markers may prove valuable if the CEA is normal. The use of tumour markers should reduce the need for regular scanning.

Hyaluronic acid metabolism and its clinical significance in patients treated by continuous ambulatory peritoneal dialysis.

Musculoskeletal syndromes are common in patients treated by dialysis for end-stage renal failure and abnormal connective tissue metabolism has been implicated. Hyaluronic acid is a major component of connective tissue ground substance. Serum, dialysate, and 24-h urine hyaluronic acid was therefore measured in 43 patients treated by CAPD to determine hyaluronic acid metabolism and to relate these variables to morbidity and mortality over an 18-month period. Serum hyaluronic acid was elevated in 71% patients, being correlated with patient age, length of time on dialysis, and weight loss over the preceding 6 months. Small quantities of predominantly low-molecular-weight hyaluronic acid were lost in the urine, whereas much larger amounts of mixed-molecular-weight hyaluronic acid were excreted in peritoneal dialysate. Dialysate hyaluronic acid exceeded serum hyaluronic acid. Baseline serum hyaluronic acid was closely correlated with morbidity and mortality over the following 18 months. Serum hyaluronic acid is an accurate predictor of mortality and morbidity over an 18-month period in patients treated by CAPD. Large quantities of hyaluronic acid are excreted in peritoneal dialysate, which in part represents local hyaluronic acid production.

The prognostic value of the tumour markers CA 195 and CEA in patients with adenocarcinoma of the pancreas.

The serum levels of CA 195 were determined in 52 patients with histologically proven pancreatic carcinoma and compared with carcino-embryonic antigen (CEA), serum bilirubin and albumin. CA 195 levels were raised above the upper limit of 20 U/ml in 42 cases, giving a sensitivity of 80% for the detection of pancreatic carcinoma, whereas CEA was raised in only 55%. The levels of CA 195 and CEA were significantly higher in patients with metastatic disease, but potentially curable cases were not discriminated. Bilirubin and albumin levels were not significantly related to either the presence of metastases or the levels of the tumour markers. At the time of initial presentation, levels of both tumour markers correlated with the eventual duration of survival, but bilirubin and albumin did not. Significant increases in CEA and CA 195 were found in sequential blood samples, as the disease progressed. Neither CA 195 nor CEA was of sufficient sensitivity to be of value for screening, but both give an indication of the presence of metastases and of the subsequent duration of survival. CA 195 appeared to be more sensitive and might help to assess progress of the disease.

Serum neuron specific enolase (NSE) is a determinant of response duration in small cell lung cancer (SCLC).

Seventy-two consecutive patients were eligible for a study of clinical determinants of response and response duration in small cell lung cancer (SCLC). Pretreatment values of routine laboratory parameters, and three tumour markers: neuron specific enolase (NSE), carcinoembryonic antigen (CEA), and acidic glycoprotein (AGP) were measured. Descriptive clinical variables as performance status (PS), extent of disease, age and sex were also included in the study. All variables were analysed for influence on the type and duration of response. The complete remission probability was only related to pretreatment extent of disease. In a multivariate analysis (Cox) of response duration, only NSE and type of response had significant influence. Consequently, measurements of NSE before therapy will be useful in future clinical trials on SCLC especially in situations, where responding patients are submitted to specific treatment strategies.

Tumor markers in prostate cancer.

Prostatic specific antigen (PSA) is a tissue specific marker that is now the most widely used biochemical test for the assessment and follow-up of prostate cancer. The levels of PSA rise with tumor stage, but there is considerable overlap of their distribution between stages. PSA measurement now forms a part of the workup of a suspected carcinoma of the prostate, with a level of more than 4 ng/ml being an indication for further investigation. The sensitivity of PSA makes it an essential test for the postoperative assessment of radical prostatectomy and curative radiation therapy. The rates of change of PSA levels in locally advanced and metastatic disease treated by hormone manipulation can provide prognostic information. Low levels of PSA (less than 10 ng/ml) 6 months after treatment are a sign that the response will be prolonged. However, the sensitivity of PSA often results in a rising level preceding clinical evidence of progression by several months and is not necessarily an indication to change treatment. Alkaline phosphatase and prostatic acid phosphatase provide a less sensitive test for the bone response to skeletal metastases and tumor activity in advanced disease, respectively.

Serum bone alkaline phosphatase and CA 549 in breast cancer with bone metastases.

A monoclonal radioimmunometric assay for bone alkaline phosphatase (BAP) developed by Hybritech, USA, with an upper limit of normal of 40 U/l, was examined in 125 patients with breast cancer. Eleven patients who remained tumour free for 5-6 years had small intra-individual variations of BAP. The median value in 33 patients with multiple bone metastases of 60 U/l was elevated when compared with that in 40 patients with no evidence of metastases (22 U/l) and 34 U/l in 16 with limited bone disease (1-2 hot spots). By contrast, only 2 out of 25 patients with extensive local recurrence, lung, or hepatic metastases, without bone involvement showed an increase of BAP (< 200 U/l). The BAP levels were compared to total alkaline phosphatase (TAP), the breast cancer marker CA 549 (HybriBREScan). Longitudinal studies of 15 patients with bony metastases showed that TAP and BAP were well correlated only when the TAP was elevated; CA 549 and BAP could vary independently. The main use of BAP in patients with bone metastases appears to be an aid to the monitoring of treatment; however, it is not significantly raised in limited bone metastases.