Clinical utility of comprehensive circulating tumor DNA genotyping compared with standard of care tissue testing in patients with newly diagnosed metastatic colorectal cancer.

BACKGROUND: Comprehensive biomarker testing is essential in selecting optimal treatment for patients with metastatic colorectal cancer (mCRC); however, incomplete genotyping is widespread, with most patients not receiving testing for all guideline-recommended biomarkers, in part due to reliance on burdensome sequential tissue-based single-biomarker tests with long waiting times or availability of only archival tissue samples. We aimed to demonstrate that liquid biopsy, associated with rapid turnaround time (TAT) and lower patient burden, effectively identifies guideline-recommended biomarkers in mCRC relative to standard of care (SOC) tissue testing. PATIENTS AND METHODS: Prospectively enrolled patients with previously untreated mCRC undergoing physician discretion SOC tissue genotyping submitted pretreatment blood samples for comprehensive circulating tumor DNA (ctDNA) analysis with Guardant360 and targeted RAS and BRAF analysis with OncoBEAM. RESULTS: Among 155 patients, physician discretion SOC tissue genotyping identified a guideline-recommended biomarker in 82 patients, versus 88 identified with comprehensive ctDNA (52.9% versus 56.8%, noninferiority demonstrated down to α = 0.005) and 69 identified with targeted PCR ctDNA analysis (52.9% versus 44.5%, noninferiority rejected at α = 0.05). Utilizing ctDNA in addition to tissue increased patient identification for a guideline-recommended biomarker by 19.5% by rescuing those without tissue results either due to tissue insufficiency, test failure, or false negatives. ctDNA median TAT was significantly faster than tissue testing when the complete process from sample acquisition to results was considered (median 10 versus 27 days, P < 0.0001), resulting in accelerated biomarker discovery, with 52.0% biomarker-positive patients identified by ctDNA versus 10.2% by SOC tissue 10 days after sample collection (P < 0.0001). CONCLUSIONS: Comprehensive ctDNA genotyping accurately identifies guideline-recommended biomarkers in patients with mCRC at a rate at least as high as SOC tissue genotyping, in a much shorter time. Based on these findings, the addition of ctDNA genotyping to clinical practice has significant potential to improve the care of patients with mCRC.

Involvement of K-RAS mutations and amino acid substitutions in the survival of metastatic colorectal cancer patients.

The efficacy of epidermal growth factor-targeting therapies has been found to be limited in tumors with the wild-type K-RAS gene, suggesting a predictive value of K-RAS gene analysis in tumoral response. However, the prognostic value of K-RAS is controversial. This study included patients diagnosed with metastatic colorectal cancer. The presence of K-RAS mutations was analyzed, and the tumors positive for a K-RAS mutation were further analyzed to identify the mutation type. Similarly, the following clinical and pathological variables were also collected. The study was composed of 53.3 % of patients with wild-type K-RAS and 46.7 % of patients with mutated K-RAS (mutated codon 12 was the most frequent). With a mean follow-up of 15 months (range, 1-45), the median survival of patients with wild-type K-RAS was 31.6 months. The median survival was 24.8 months for patients with K-RAS mutated in codon 12 and 17.8 months for patients with mutated codon 13 (p = 0.37). In a univariate analysis, K-RAS was associated with stage IV at diagnosis (p < 0.005). When K-RAS was mutated, a lower overall survival was observed in cases of G → A transition compared with G → T transversion (19.5 vs. 24.2 months, respectively; p = 0.47). When the amino acid change resulted in an acidic substitution, survival was lower, but it increased when the substitution resulted in a polar or nonpolar amino acid (19.5 vs. 23.2 vs. 24.4 months, p = 0.79). The type of K-RAS mutation or amino acid changes may have prognostic implications in metastatic colon cancer patients. Further research is needed in patients treated in prospective controlled trials.

Hemorragia digestiva alta en varón homosexual con infección por el virus de la inmunodeficiencia humana / No disponible

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[Intrascrotal lithiasis: an infrequent finding?]. / Litiasis intraescrotal: un hallazgo infrecuente?

OBJECTIVE: To report on 10 additional cases of intrascrotal calculi and briefly review the literature and pathogenesis of this benign lesion. METHODS: 10 patients that had consulted for diverse testicular conditions were evaluated by ultrasound using the 7.5 MHz probe. RESULTS: All patients were found to have a hydrocele of a larger or smaller volume with a mobile hyperechoic focus that produced acoustic shadows. CONCLUSIONS: The ultrasound finding of intrascrotal calculi is becoming increasingly more frequent. In our view, this is due to the fact that more sonographic studies are currently performed. The possibility to diagnose this condition obviates the need for subsequent explorations or surgery.

New advances in human embryology: morphofunctional relationship between the embryo and the yolk sac.

Organogenesis occurs during the first 8 weeks of human embryonic development; in consequence, early human growth and development take place before and in the absence of fully developed internal organs. During this period, normal development depends on several factors, but two are imperative: nutrition and a functional transport system for the distribution of nutrients and for waste disposal. The yolk sac (YS), a highly differentiated adnexal organ, is known to accomplish this fundamental task during early pregnancy. In this review, we summarize our contribution to the understanding of early human embryology, focusing interest on analysis of the morphofunctional link that is established between the human embryo and the YS during the embryonic period. Embryos were collected from the gestational sac after salpingectomies performed on patients with singleton pregnancies occurring in the fallopian tube. Samples of YS were taken from 20 human embryos at Carnegie stages ranging from 12 to 20. The age of the embryo was estimated from data of the patient's last menstrual history and confirmed from crown-rump length measurements and morphological characteristics of the specimen. The samples were fixed in 3% glutaraldehyde and then postfixed in 2% osmium tetroxide and prepared for light, transmission, and scanning electron microscopy according to conventional techniques. The samples were examined with a Philips 301 EM and an S-4000 Hitachi field emission SEM. The yolk stalk, and the YS wall with its corresponding endodermal, mesenchymal, and mesothelial layers, were analyzed. In accordance with their morphological features, the endodermal cells are equipped with organelles to fulfill several functions that are expressed in absorption from the vitelline cavity via microvilli present into the outer cell surface, in secretion to the extracellular space, and in the synthesis of numerous proteins which are transported by the bloodstream to the embryo. The mesothelial surface is provided with cell-surface differentiation that promotes a protective coat to prevent damage from compression or friction of the YS wall against the amnios, umbilical cord, and chorionic cavity wall during growth. The mesenchyme is the main site for blood vessel formation and gives rise to a network that provides the embryo with nutrients and a means of waste disposal. A critical analysis of the role of the endodermal vesicle in the production of fluid that is accumulated in the YS, and of the role that the vitelline duct play in the exchange function between the YS and intestinal tract, is presented. We have demonstrated that the vitelline duct is not functional after week 5 because of the closure of its lumen. This finding is discussed with reference to the biological meaning of the vitelline duct and its functional period of activity, and its possible role in the physiology of exchange during the embryonic period is assessed.

CT in spontaneous adrenal gland rupture. A case report.

PURPOSE: To report on an exceptional case of spontaneous, idiopathic, unilateral adrenal gland rupture that caused massive retroperitoneal hemorrhage. METHODS AND RESULTS: US and CT were performed in a patient who presented with acute abdominal pain. Urgent adrenalectomy was required to prevent the blood loss from continuing. The CT findings were correlated with the histological findings. CONCLUSION: CT proved to be an accurate imaging modality by which to diagnose adrenal hemorrhage. The absence of irregular tissue enhancement showed that neoplasia was not the underlying cause of the hematoma.

Effects of pindolol and propranolol on blood lipids in hypertensive patients.

Since beta-blockers could affect lipid levels at the therapeutic dose range in hypertensive patients, a parallel 6-month randomized trial with pindolol (PDL) (16 pts.) and propranolol (PPL) (23 pts.) was designed (mean age = 55 + 7.1 years and 57 + 8.0 years; 9 males, 7 females and 15 males, 8 females, respectively). Total cholesterol, LDL and HDL fractions, and triglycerides (TGs) were determined before (washout phase) and during 1, 3, and 6 months of therapy. Patients were instructed to maintain their usual dietary habits. Daily drug doses were adjusted step by step to attain an optimal hypotensive effect (PDL 15-45 mg, PPL 180-240 mg). In the PPL-treated group, total cholesterol and LDL did not change significantly, HDL decreased (from 45.2 to 40.5 mg/dl, p less than 0.05) and TG increased (from 133 to 169 mg/dl, p less than 0.05). In the PDL group total cholesterol and LDL did not change either, but HDL increased (35.9 to 44.7 mg/dl, p less than 0.01) and TGs, were reduced (from 169 to 131 mg/dl, p less than 0.05). No dose-effect relationship was recorded. It is concluded that pindolol does not negatively influence HDL nor the TG blood lipid profile as does PPL. Accordingly, pindolol might be preferred to propranolol in the treatment of hypertensive patients with an unfavorable lipid profile, but this assumption remains to be proven in larger, prospective, long-term followup trials.

Glucose tolerance and the insulin response in recently drinking alcoholic patients: possible effects of withdrawal.

To investigate possible effects of withdrawal on carbohydrate metabolism in chronic alcoholic patients, intravenous glucose tolerance tests were performed in three periods in 11 alcoholic patients: early abstinence (less than three days), early abstinence plus ethanol (1 g/kg/BW IV), and late abstinence (three weeks later). According to liver biopsy results and laboratory tests, patients were classified as a group with liver damage (four cases) and a group without it (seven cases). In the group without damage, glucose tolerance expressed as K% and compared to a control group, was significantly decreased in early and late abstinence but not after the infusion of ethanol. Cases with damage also had glucose intolerance at admission. Plasma insulin levels after the glucose load were significantly lower at ten and 30 minutes in the group without damage, in early or late abstinence. They were normal in the presence of ethanol. Patients with liver damage presented higher basal and postglucose plasma insulin concentrations. It was concluded that glucose intolerance in alcoholic patients is a common finding that occurs in the presence or absence of liver damage. In cases with liver damage it seems to be due to peripheral insulin resistance. In those without damage it is related to low peripherovenous insulin levels.

Nutritional status of alcoholic patients: it's possible relationship to alcoholic liver damage.

This study was performed to look for a possible relationship between the nutritional status and the presence of liver damage in alcoholic patients. One hundred chronic alcoholics admitted for treatment to the Alcoholism Ward, without clinical signs of liver failure, were studied. In 84, anthropometric nutritional indexes, liver function tests, and a liver biopsy were performed; in 69 patients a dietary survey was obtained. A dietary imbalance was observed in the total group; 65% of ingested calories were derived from ethanol. The intake of proteins, vitamins, and minerals was below the RDA, NAS/USA, and no differences were found between patients with and without liver damage. Neither were significant differences in daily alcohol calories or total ethanol dose found between both groups of patients. Mean anthropometric values were within 80 to 100% of commonly used standards. However, patients with alcoholic hepatitis and/or cirrhosis had a significantly higher percentage of ideal body weight, compared to alcoholics with normal livers or less severe histological alterations (109.7 +/- 20.3 versus 95.6 +/- 12.5, SD, p less than 0.005). A similar difference was observed in arm muscle areas. These findings show that overweight is associated with liver alterations in the alcoholic and should be investigated as a risk factor to develop liver damage.

Possible relationship between the rate of ethanol metabolism and the severity of hepatic damage in chronic alcoholics.

The rate of ethanol metabolism (EMR) was determined in alcoholic patients with or without hepatic necrosis, steatosis, and/or cirrhosis. Fifty six cases were studied after 9-25 days of abstinence (mean 15 days). A significant increase in EMR (P less than 0.01) was found in alcoholics with hepatic necrosis (265 +/- 20.5 mg/kg/hr) compared with alcoholics with normal liver histology (154 +/- 17) and nonalcoholic controls (159 +/- 15). In alcoholics with liver steatosis but without necrosis a lesser increase in EMR (207 +/- 20, P less than 0.05 was also observed. Patients with slight fibrosis but without other abnormalities in their liver biopsies and cirrhotics with overt liver failure (jaundice, ascites) showed EMR similar to controls.

Serum immunoglobulin A changes in alcoholic patients.

1. Serum concentrations of immunoglobins IgA and IgG were determined in: Alcoholic men without liver damage (normal laboratory tests and only slight abnormalities in liver biopsy). 2. Patients at different stages of alcoholic liver disease. 3. Non alcoholic patients with liver disease. The serum IgA concentration was increased in all groups of alcoholics and this increase was related to the severity of liver damage. It was also raised in non alcoholic patients but both the degree of increase and the IgA/IgG ratio could be used to differentiate them. The increase in the serum IgA concentration in alcoholics without liver damage has not previously been proved and the reasons put forward for it in alcoholics are not valid for this group.