Preclinical assessment of a new magnetic resonance-based technique for determining bone quality by characterization of trabecular microarchitecture.

The utility of HR-CT to study longitudinal changes in bone microarchitecture is limited by subject radiation exposure. Although MR is not subject to this limitation, it is limited both by patient movement that occurs during prolonged scanning at distal sites, and by the signal-to-noise ratio that is achievable for high-resolution images in a reasonable scan time at proximal sites. Recently, a novel MR-based technique, fine structure analysis (FSA) (Chase et al. Localised one-dimensional magnetic resonance spatial frequency spectroscopy. PCT/US2012/068284 2012, James and Chase Magnetic field gradient structure characteristic assessment using one-dimensional (1D) spatial frequency distribution analysis. 7932720 B2, 2011) has been developed which provides both high-resolution and fast scan times, but which generates at a designated set of spatial positions (voxels) a one-dimensional signal of spatial frequencies. Appendix 1 provides a brief introduction to FSA. This article describes an initial exploration of FSA for the rapid, non-invasive characterization of trabecular microarchitecture in a preclinical setting. For L4 vertebrae of sham and ovariectomized (OVX) rats, we compared FSA-generated metrics with those from CT datasets and from CT-derived histomorphometry parameters, trabecular number (Tb.N), bone volume density (BV/TV), trabecular thickness (Tb.Th) and trabecular separation (Tb.Sp). OVX caused a reduction of the higher frequency structures that correspond to a denser trabecular lattice, while increasing the preponderance of lower frequency structures, which correspond to a more open lattice. As one example measure, the centroid of the FSA spectrum (which we refer to as fSAcB) showed strong correlation in the same region with CT-derived histomorphometry values: Tb.Sp: r -0.63, p < 0.001; Tb.N: r 0.71, p < 0.001; BV/TV: r 0.64, p < 0.001, Tb.Th: r 0.44, p < 0.05. Furthermore, we found a 17.5% reduction in fSAcB in OVX rats (p < 0.0001). In a longitudinal study, FSA showed that the age-related increase in higher frequency structures was abolished in OVX rats, being replaced with a 78-194% increase in lower frequency structures (2.4-2.8 objects/mm range), indicating a more sparse trabecular lattice (p < 0.05). The MR-based fine structure analysis enables high-resolution, radiation-free, rapid quantification of bone structures in one dimension (the specific point and direction being chosen by the clinician) of the spine.

'Sink or swim': an evaluation of the clinical characteristics of individuals with high bone mass.

SUMMARY: High bone mineral density on routine dual energy X-ray absorptiometry (DXA) may indicate an underlying skeletal dysplasia. Two hundred fifty-eight individuals with unexplained high bone mass (HBM), 236 relatives (41% with HBM) and 58 spouses were studied. Cases could not float, had mandible enlargement, extra bone, broad frames, larger shoe sizes and increased body mass index (BMI). HBM cases may harbour an underlying genetic disorder. INTRODUCTION: High bone mineral density is a sporadic incidental finding on routine DXA scanning of apparently asymptomatic individuals. Such individuals may have an underlying skeletal dysplasia, as seen in LRP5 mutations. We aimed to characterize unexplained HBM and determine the potential for an underlying skeletal dysplasia. METHODS: Two hundred fifty-eight individuals with unexplained HBM (defined as L1 Z-score ≥ +3.2 plus total hip Z-score ≥ +1.2, or total hip Z-score ≥ +3.2) were recruited from 15 UK centres, by screening 335,115 DXA scans. Unexplained HBM affected 0.181% of DXA scans. Next 236 relatives were recruited of whom 94 (41%) had HBM (defined as L1 Z-score + total hip Z-score ≥ +3.2). Fifty-eight spouses were also recruited together with the unaffected relatives as controls. Phenotypes of cases and controls, obtained from clinical assessment, were compared using random-effects linear and logistic regression models, clustered by family, adjusted for confounders, including age and sex. RESULTS: Individuals with unexplained HBM had an excess of sinking when swimming (7.11 [3.65, 13.84], p < 0.001; adjusted odds ratio with 95% confidence interval shown), mandible enlargement (4.16 [2.34, 7.39], p < 0.001), extra bone at tendon/ligament insertions (2.07 [1.13, 3.78], p = 0.018) and broad frame (3.55 [2.12, 5.95], p < 0.001). HBM cases also had a larger shoe size (mean difference 0.4 [0.1, 0.7] UK sizes, p = 0.009) and increased BMI (mean difference 2.2 [1.3, 3.1] kg/m(2), p < 0.001). CONCLUSION: Individuals with unexplained HBM have an excess of clinical characteristics associated with skeletal dysplasia and their relatives are commonly affected, suggesting many may harbour an underlying genetic disorder affecting bone mass.

Effects of left ventricular assist device (LVAD) placement on myocardial oxidative stress markers.

PURPOSE: The primary purpose of this study was to examine the changes in myocardial oxidative stress during the support of a left ventricular assist device (LVAD). METHODS: Myocardial tissue was collected from the lower left ventricle of 15 adult subjects with class IV heart failure (HF) during LVAD placement (n=9) or LVAD removal (Post-LVAD; n=6). Each tissue sample was separated into cytosolic and myofibrillar subfractions and analysed for protein content and carbonylation. RESULTS: The myofibrillar proteins in the HF subjects had a significantly lower (p=0.008) level of protein carbonylation when compared to the myofibrillar proteins in Post-LVAD patients at 1.630±0.277 and 3.075±0.413 optical density, respectively. The level of protein carbonylation in myosin and actin were lower in HF (myosin: 1406.22±218.45, actin: 436±79.72 optical density) subjects compared to Post-LVAD (myosin: 2280.5±441.26, actin: 804.67±155.71 optical density) subjects (p=0.035 and p=0.018, respectively). However, once the extent of carbonylation in the myosin and actin bands were normalised to the amount of protein content, all significant difference was lost (HF moysin: 1823.89±413.42, Post-LVAD myosin: 1330.33±297.10 optical density, p=0.199 and HF actin: 3755.78±349.59, Post-LVAD actin: 4402.83±666.51 optical density, p=0.182). There was no significant difference in the cytosolic subfractions before or after normalisation of protein content. CONCLUSION: Carbonylation is elevated in the myocardium of HF and Post-LVAD subjects and it appears that LVAD support does not affect the level of myocardial oxidative stress.

Hyperventilation and hypophosphataemia.

We describe a case where extensive investigations were utilized to identify the aetiology of hypophosphataemia in a patient presenting with non-specific symptoms. The diagnosis of hyperventilation-induced hypophosphataemia was eventually established. Hyperventilation is a relatively common cause of isolated hypophosphataemia, but is easily overlooked as a cause.

What community measurements can be used to predict bone disease in patients with COPD?

BACKGROUND: Osteoporosis is common in patients with COPD. Previously we have reported that loss of fat-free mass (FFM), measured by dual X-ray absorptiometry (DXA) is associated with loss of bone mineral density (BMD). In addition, in patients with a low body mass index (BMI) and a low FFM, all had evidence of bone thinning, 50% having osteopenia and 50% osteoporosis. We explored the utility of different anthropometric measures in detecting osteoporosis in a community-based COPD population. METHODS: Patients with confirmed COPD and not on long-term oral corticosteroids (n=58) performed spirometry. They underwent nutritional assessment by skinfold anthropometry, midarm circumference, calculation of both % ideal body weight (IBW) and BMI. All had DXA assessment of BMD. RESULTS: A total of 58 COPD patients had anthropometric measurements taken, with a mean age of 66.8 (SD 8.7) years, 31 (58%) were male, with a forced expiratory volume in 1s (FEV(1)) of 54.17 (20.18)% predicted. Osteoporosis was present at either the hip or lumbar region in 14 patients (24%). The useful anthropometric measurements identifying those with osteoporosis were both % IBW and BMI. The adjusted odds ratio for %IBW was 0.93 (95% confidence interval (CI) 0.87, 0.99), p=0.016 and for BMI: 0.79 (0.64-0.98), p=0.03. The receiver operating characteristics (ROC) score for both was 0.88, indicating a good fit. CONCLUSION: Osteoporosis is common, even in patients with mild airways obstruction. Nutritional assessment, incorporating a calculation of their BMI or %IBW may confer an additional benefit in detecting those at risk of osteoporosis and guide referral for BMD measurement.

Cost effectiveness analysis of using quantitative ultrasound as a selective pre-screen for bone densitometry.

It has been suggested that quantitative ultrasound (QUS) could be used as a selective population pre-screen, to maximise the cost effectiveness of referral for dual energy X-ray absorptiometry (DXA) assessment of bone mineral density (BMD). We set out to examine how such an approach might perform in the assessment of women who were referred by general practitioners for DXA via the open access service in Cardiff. In 115 women aged 40-80 (mean 69) years we used DXA to measure BMD at lumbar spine and hip, and QUS to measure broadband ultrasound attenuation (BUA) in the heel. A bottom-up approach was used to estimate the costs of DXA and QUS. We examined the cost effectiveness of using QUS as a pre-screen, only referring subjects for the more expensive DXA assessment if BUA were less than a pre-determined threshold. The unit costs of pencil-beam DXA and QUS were approximately 44 UK pounds and 16 UK pounds respectively. We identified a BUA threshold of 60 dB/MHz as the most cost effective, and calculated a sensitivity of 81% and specificity of 89% in identifying those subjects whom DXA assessment subsequently identified as having osteoporosis. At the BUA threshold of 60 dB/MHz, pre-screening saved 969 UK pounds at the expense of missing ten women with osteoporosis as diagnosed by DXA. Therefore the cost per additional woman with osteoporosis identified using DXA alone was only 97 UK pounds. QUS assessment does not appear to have a significant cost effective benefit as a pre-screen for DXA in the studied population. A QUS pre-screen would be cost effective only if this investigation could be performed at a substantially lower cost.

Hyperpharmacotherapy in ageing cystic fibrosis patients: The first report of an atypical hip fracture.

Cystic fibrosis (CF) is a common autosomal recessive disorder in Caucasian populations with respiratory, gastrointestinal and endocrine manifestations. Thanks to recent advances in medical therapies and infection control, life expectancy of a patient with CF has significantly increased from less than 5 years in the mid-1900s to almost 50 years nowadays. However, as CF patients are living longer, multimorbidity and Hyperpharmacotherapy are becoming more common. This case illustrates a cascade of problems that ensued from medication side-effects, highlighting the increasing challenge of managing an ageing CF population.

Determinants of remission of Paget's disease of bone.

Bisphosphonates are a safe and effective treatment for Paget's disease of bone, but little information is available about the factors influencing the duration of remission so obtained. We assessed 60 patients with Paget's disease treated with disodium pamidronate (APD). The mean duration of remission was 9.5 months (range 3-25). The major influences were the initial pretreatment alkaline phosphatase (ALP; r = -4.6, p < 0.0001), minimum posttreatment ALP (r = -0.51, p < 0.0001), and the rate of response of bone turnover to the first dose of APD (r = 0.61, p < 0.0001). Multiple linear regression showed that the initial response to treatment was the most significant influence. Also, despite a minimum ALP within the normal range, the duration of remission varied considerably (4-25 months). This may be due to the difficulties in applying a population-based normal range to individuals.

Treatment of Paget's disease with intermittent low-dose infusions of disodium pamidronate (APD).

Disodium pamidronate (APD) is a potent inhibitor of bone resorption, with less risk of defective mineralization than earlier bisphosphonates. We assessed the response to six spaced low-dose intravenous infusions of APD given at intervals of approximately 6 weeks followed by weekly infusions if bone turnover remained abnormal. Three groups of 10 patients were studied, each group receiving infusions of 15, 30, or 45 mg. Hydroxyproline excretion fell by 62% and alkaline phosphatase was reduced by 72%, with no difference between the dose levels. A total of 21 patients (70%) achieved normal levels of bone turnover, indicating that low-dose infusions of APD are a safe and effective treatment for Paget's disease.

Bisphosphonate space measurement in Paget's disease of bone treated with APD.

The bisphosphonate space (BPS) is a quantitative measurement of skeletal uptake of 99mTc-HMDP. We measured BPS in 36 patients with Paget's disease of bone, both before and 6 months after treatment with intravenous APD (disodium pamidronate) infusions. BPS fell after treatment, but proportionally less than serum alkaline phosphatase (ALP) and fasting urinary hydroxyproline/creatinine (HYPRO). There was no dose-response relationship between the dose of APD given and the percentage reduction in ALP and HYPRO at 6 months. Log dose of APD/pretreatment BPS, however, predicted the percentage reduction in ALP and HYPRO very well, and from the respective regression equations it was possible to predict the dose of APD needed to achieve normal values of ALP and HYPRO. In the 10 patients who achieved a normal ALP and 9 patients a normal HYPRO after more than 6 months treatment with APD (range 7-18 months), the predicted dose of APD agreed closely with the actual dose. In conclusion, our data support the idea that log dose APD/pretreatment BPS is a valid predictor of biochemical response in Paget's disease.

Acute changes in calcium homeostasis during treatment of primary hyperparathyroidism with risedronate.

We administered risedronate, a potent oral bisphosphonate, to patients with mild primary hyperparathyroidism in order to 1) determine if we could normalize the serum calcium concentration in the short term, and 2) analyze changes in the homeostatic mechanisms responsible for maintaining hypercalcemia in this patient population. When administered for 7 days, risedronate reduced fasting serum calcium concentrations without significant toxicity in patients with primary hyperparathyroidism. The decrease in serum calcium was accompanied by evidence of inhibition of bone resorption, as assessed by measurement of urinary hydroxyproline, increased serum immunoreactive PTH concentrations, enhanced renal tubular reabsorption of calcium, and a progressive decrease in serum alkaline phosphatase. Serum PTH was partially suppressed by an oral calcium load in untreated patients as well as in patients treated with risedronate. Although patients treated with risedronate had normal fasting serum calcium levels, serum calcium values in these normocalcemic patients were labile after oral ingestion of calcium. After daily calcium intake of 2 g, serum calcium levels in risedronate-treated patients were similar to those in untreated patients with primary hyperparathyroidism, suggesting that there are likely to be fluctuations in serum calcium in risedronate-treated patients with normal fasting serum calcium during postprandial periods. These studies show that risedronate lowers fasting serum calcium during short term treatment. However, further studies are required to determine whether the lability in serum calcium in these patients after an oral calcium load has clinical significance, and whether longer term treatment would maintain serum calcium in the normal range.

Comparison of methods of assessing response of Paget's disease to bisphosphonate therapy.

Bisphosphonates have been shown to be effective in suppressing the elevated bone turnover found in Paget's disease of bone. In theory, the major determinants of post-treatment bone turnover are the initial disease activity and the rate of decline in bone turnover with therapy. In the present study, we examined the rate of decrease of alkaline phosphatase and hydroxyproline (expressed as a half-life) and showed this to be superior to percentage changes in bone turnover as a marker of response. The combination of pre-treatment alkaline phosphatase and the alkaline phosphatase half-life and pre-treatment hydroxyproline and the hydroxyproline half-life were the best models to predict post-treatment bone turnover (multiple r = 0.75, r2 = 0.56, p < 0.0001; and r = 0.71, r2 = 0.51, p < 0.0001, respectively). In addition, measurement of the half-lives of these markers of bone turnover may allow prospective changes to be made during treatment so that maximal disease suppression can be achieved.

The renal response to exogenous parathyroid hormone in treated pseudohypoparathyroidism.

Resistance to the renal actions of parathyroid hormone (PTH) in pseudohypoparathyroidism (PsH) may be improved after treatment with vitamin D or its metabolites, but reports conflict. We have examined the renal response to infusion of 35 micrograms of 1-38 PTH in patients with PsH type I (n = 8) and PsH type II (n = 1) during treatment and related this to prevailing endogenous serum PTH and calcium levels. Nine patients with postsurgical or idiopathic hypoparathyroidism (HP) served as controls. The urinary cAMP increase (delta cAMP) was lower (p < 0.001) in the PsH type I (175 +/- 6.4 nmol/l glomerular filtrate) than in the HP group (3251 +/- 515 nmol/l glomerular filtrate). delta cAMP in the PsH type I subjects was dependent on endogenous PTH concentrations (r = -0.76; p = 0.046) and serum calcium (r = 0.74; p = 0.037). Phosphaturic responses (expressed as % decrease in TmPO4/glomerular filtration rate) were lower (p = 0.013) in the PsH type I (28.8 +/- 3.75) compared with those of the HP patients (43 +/- 3.48). The phosphaturic responses in the PsH type I patients were strongly dependent on endogenous PTH (r = 0.94; p < 0.001) and serum calcium levels (r = 0.94; p < 0.001) so that the responses of subjects with normal or low PTH levels were no different (p = 0.16) from the HP group. Renal handling of calcium and sodium in response to exogenous PTH was identical in patients with PsH (types I and II) and HP. Renal tubular reabsorption during a calcium infusion was normal in all patients with PsH. These results emphasise the importance of the modulatory effects due to associated biochemical abnormalities in PsH on the responses to exogenous PTH. They also confirm that renal handling of calcium and sodium is probably normal in treated PsH.

Comparison of low-dose intramuscular and intravenous salcatonin in the treatment of primary hyperparathyroidism.

The treatment of hypercalcaemia with low-dose salcatonin (100 U/d), administered either as a single intramuscular bolus or as a continuous intravenous infusion for five days, was examined in two groups of 10 patients with primary hyperparathyroidism, in a randomized open parallel study. Both the peak (0.31 +/- 0.035 mmol/L v 0.13 +/- 0.034 mmol/L) and overall (0.073 +/- 0.016 mmol/L v 0.018 +/- 0.016 mmol/L) hypocalcaemic responses were greater in the infusion group. The peak reduction in serum calcium occurred on day 2 of treatment after which there was a progressive attenuation of response. All the differences between the two methods of administration wer due to renal rather than bony effects of salcatonin. Possible causes of progressive resistance to treatment included reductions in sodium excretion and serum phosphate. It is concluded that low-dose salcatonin administered as a continuous infusion was more effective than the same dose given as a bolus. The kidney played a pivotal role both in the cause of the hypercalcaemia and in the response to treatment, including the rapid development of resistance which limits the use of salmon calcitonin in primary hyperparathyroidism to short-term reduction of serum calcium.

The role of surgical resection of liver metastases in colorectal carcinoma.

While hepatic resection of colorectal carcinoma, metastatic to the liver, is a suitable and effective treatment, it nevertheless remains applicable only to a highly selective group of patients. Even within this highly selective group of patients only a minority will survive 5 years disease-free indicating the increased sophistication needed to understand the biological factors that control outcome. It is clear that the good results come from biological suitability and not temporal acceleration of the detection process. Appropriate patients after careful selection and sophisticated diagnostic studies should be subjected to exploration and attempted hepatic resection. A preliminary prognostic scoring system has been presented to illustrate the usefulness of this approach.

Locally advanced rectal carcinoma: pelvic control and morbidity following preoperative radiation therapy, resection, and intraoperative radiation therapy.

PURPOSE: To determine the impact of intraoperative radiation therapy (IORT) combined with preoperative external beam irradiation and surgical resection in patients with locally advanced, unresectable rectal carcinoma. METHODS AND MATERIALS: Between 1982 and 1993, 40 patients with locally advanced colorectal cancer unresectable at initial presentation were treated with preoperative external beam radiation therapy (median dose 50.4 Gy). Thirty patients received concurrent 5-fluorouracil. Twenty-seven patients had primary tumors and 13 had recurrent disease; 1 patient had a solitary hepatic metastasis at the time of surgery. Four to 6 weeks after radiation, surgical resection was undertaken, and if microscopic or gross residual disease was encountered, IORT was delivered to the tumor bed. Patients with an unevaluable or high-risk margin were also considered for IORT. IORT was delivered through a dedicated 300-kVp orthovoltage unit. The median dose of IORT was 12.5 Gy (range 8-20). The dose was typically prescribed to a depth of 1-2 cm. The median follow-up was 33 months (range 5-100). RESULTS: Thirty-three patients were able to undergo a curative resection (83%). Five patients had gross residual disease despite aggressive surgery. Seven patients did not receive IORT: six because of clear margins, and one with gross disease that could not be treated for technical reasons. The remainder of the patients (26) received IORT to the site of pelvic adherence. The crude local control rates for patients following complete resection with negative margins were 92% for patients treated with IORT and 33% for patients without IORT. IORT was ineffective for gross residual disease. Pelvic control was none of four in this setting. The crude local control rate of patients with primary cancer was 73% (16 of 22), as opposed to 27% (3 of 11) for these with recurrent cancer. The 5-year actuarial overall survival and local control rates for patients undergoing gross complete resection and IORT were 64% and 75%, respectively. Seventeen of the 26 patients (65%) who received IORT experienced pelvic complications, as opposed to two patients (28%) who did not receive IORT. The incidence of complications was similar in the patients with primary versus recurrent disease. All cases were successfully treated with the placement of a posterior thigh myocutaneous flap. Of note, no pelvic osteoradionecrosis was seen in this series. CONCLUSION: Patients with locally advanced carcinoma of the rectum were aggressively treated with combined modality therapy consisting of preoperative external beam radiotherapy, surgery, and IORT. The pelvic control rate was 82% for patients with minimal residual disease. IORT failed to control gross residual disease. The incidence of pelvic wound healing problems was 65% in this series; however, a reconstructive procedure which replaced irradiated tissue with a vascularized myocutaneous flap was successful in treating this complication. We believe that IORT has therapeutic merit in the treatment of locally advanced rectal cancer, particularly in the setting of minimal residual disease.

Effect of resident call status on ABSITE performance. American Board of Surgery In-Training Examination.

BACKGROUND: Long work hours that result in fatigue may adversely affect cognitive function. Chronically sleep-deprived surgical residents fear that being on call the night before sitting for a standardized test puts them at a potential disadvantage. We examined American Board of Surgery In-Training Examination (ABSITE) scores to assess the effect of call status on exam performance. METHODS: Results of the 1994 ABSITE for 424 residents in 15 New England general surgery programs were collected. We compared standard scores of residents for the total test, clinical management, and basic science components with resident call status (on/off) for the night before the exam. RESULTS: Differences were apparent in total test scores (mean: off, 496.1; on, 466.0; P <.03) and clinical management scores (mean: off, 504.3; on, 470.6; P <.02) (t test, Mann-Whitney U test). Multivariate analyses revealed that differences in postgraduate year level and training track were significant contributors to differences in scores in all test components (analysis of covariance). Call status was not a significant factor in score variation after adjusting for these 2 factors. CONCLUSIONS: Differences in ABSITE scores of residents were related to postgraduate year level and training track. Call status had no significant effect on ABSITE performance.

Intraoperative radiation therapy for biliary tract carcinoma: results of a 5-year experience.

The results of a 5-year experience with use of intraoperative radiation therapy (IORT) in the management of locally advanced bile duct carcinoma are presented. Fifteen patients received IORT doses between 5 and 20 Gy for localized disease, which was either primary and resected with microscopic residual (2 patients), primary and unresected (10 patients), or recurrent (3 patients). Thirteen patients also received postoperative radiation therapy. The median survival of the 12 patients with primary disease was 14 months, with disease controlled in the porta hepatis in 5 of 10 evaluable patients. The three patients with recurrent disease survived 2, 9, and 11 months. There were two operative deaths, for an operative mortality of 13%. Acute and chronic complications are reviewed. Cholangitis is the most frequent in both categories. This aggressive approach in the therapy for advanced disease has an acceptable level of morbidity and may warrant the use of IORT as part of the management of biliary tract cancer.

Investigation of factors determining the optimal glucose infusion rate in total parenteral nutrition.

We have used the primed constant infusion of U-13C-glucose to study glucose metabolism during conventional total parenteral nutrition (TPN) in five postoperative surgical patients. Glucose production from nonrecycled carbon sources was suppressed to 17% of the basal level at the lowest rate of glucose infusion tested (4 mg/kg x min). Subsequent increases in glucose infusion rate had minimal effect in further suppressing glucose production. Additional nitrogen-sparing effects of glucose when glucose is infused at rates in excess of 4 mg/kg x min must therefore be derived from oxidation of the infused glucose. An increase in the infusion rate from 4 mg/kg x min to 7 mg/kg x min was associated with an increased rate of glucose oxidation, but a further increase in glucose infusion rate (9 mg/kg x min) was without significant effect on glucose oxidation. As the rate of TPN administration (glucose and amino acids) increased, both metabolic rate and RQ rose significantly. Our calculations indicate that the high RQ's observed during the highest glucose infusion rate (X = 1.13) could be attributed to the synthesis of fat from infused glucose, and that about 30% of the increase in VO2 above the basal level could also be attributed to fat synthesis. The progressive increase in the ability to clear glucose from the blood that occurred as TPN progressed was not due to an increase in the rate of oxidation of glucose; we found no correlation between glucose clearance and glucose oxidation.

Continuing trends in the prevalence of right-sided lesions among colorectal carcinomas.

The shift of colorectal carcinoma location toward the proximal colon has been reported. This study documents that this statistically significant trend has continued through 1992. An increase in transverse and descending colon cancers is now apparent also. Only 59% of all large-bowel cancers occurred distal to the descending colon between 1978 and 1992. Both right-sided and distal large-bowel cancers have significantly decreased in size, yet the incidence and frequency of lymph node metastases have not changed over a 65-year interval (from 1928 to 1992). This constant proportion of lymph node metastases may suggest distinct biological subsets of cancers (lymph node avid vs lymph node avoidance). The progression from small size with fewer metastases to large size with more lymph node metastases occurs only in some of the smallest distal colorectal cancers.