The paradox-breaking panRAF plus SRC family kinase inhibitor, CCT3833, is effective in mutant KRAS-driven cancers.

BACKGROUND: KRAS is mutated in ∼90% of pancreatic ductal adenocarcinomas, ∼35% of colorectal cancers and ∼20% of non-small-cell lung cancers. There has been recent progress in targeting G12CKRAS specifically, but therapeutic options for other mutant forms of KRAS are limited, largely because the complexity of downstream signaling and feedback mechanisms mean that targeting individual pathway components is ineffective. DESIGN: The protein kinases RAF and SRC are validated therapeutic targets in KRAS-mutant pancreatic ductal adenocarcinomas, colorectal cancers and non-small-cell lung cancers and we show that both must be inhibited to block growth of these cancers. We describe CCT3833, a new drug that inhibits both RAF and SRC, which may be effective in KRAS-mutant cancers. RESULTS: We show that CCT3833 inhibits RAF and SRC in KRAS-mutant tumors in vitro and in vivo, and that it inhibits tumor growth at well-tolerated doses in mice. CCT3833 has been evaluated in a phase I clinical trial (NCT02437227) and we report here that it significantly prolongs progression-free survival of a patient with a G12VKRAS spindle cell sarcoma who did not respond to a multikinase inhibitor and therefore had limited treatment options. CONCLUSIONS: New drug CCT3833 elicits significant preclinical therapeutic efficacy in KRAS-mutant colorectal, lung and pancreatic tumor xenografts, demonstrating a treatment option for several areas of unmet clinical need. Based on these preclinical data and the phase I clinical unconfirmed response in a patient with KRAS-mutant spindle cell sarcoma, CCT3833 requires further evaluation in patients with other KRAS-mutant cancers.

Aproximación a costos de las lesiones de causa externa / Approach to costs of the injuries of external cause

Informa acerca de la situación de las lesiones de causa externa como reflejo del comportamiento violento y delictivo en Panamá

Characteristics of current international trade of live salmonid eggs.

World trade in live salmonid embryos (eyed eggs) has grown in response to increased global salmon production, particularly in South America, and parallels international trade in farmed salmonid products. Rainbow trout (Oncorhynchus mykiss), Atlantic salmon (Salmo salar) and coho salmon (O. kisutch) are the most commercially important species. In 1992, the Food and Agriculture Organization of the United Nations estimated world production of rainbow trout at 300,000 tonnes, while the production of Atlantic salmon was estimated at 250,000 tonnes and coho salmon at 50,000 tonnes. One can estimate that roughly 3 billion, 150 million and 30 million eggs, respectively, were required to produce this yield. Broodstock are cultivated world-wide, using a wide variety of water sources, including the marine environment, riverine water containing anadromous fish, and ground water free of migrating fish. As many as 70% of all coho eggs are derived from feral fish. Approximately 50% of all commercial salmonid eyed eggs are produced in Europe, and approximately 15% are produced in the state of Washington, United States of America. Conditions which are ideal for commercial salmonid grow-out are not necessarily ideal for the cultivation of salmonid broodstock; this is one reason why international egg trade is necessary. The trend of current salmonid health regulations is towards facilitating egg commerce on a regional level, in an attempt to control disease transmission. Regulations controlling egg importation often include pathogens which are not vertically transmitted. This serves only to increase egg prices, in compensation for the cost of laboratory tests. Genetic improvements have been the cornerstone of increasing commercial production of all agricultural commodities. Fish health regulations are sometimes instituted in an effort to protect the local industry, but in fact they act more often to restrict the flow of genetic material and may actually serve to reduce industry productivity and profitability.

Diagnosis of prostate cancer by transrectal ultrasound.

The comprehensive description of the zonal anatomy of the prostate as developed by McNeal has identified the likely sites of cancer within the gland and provided further understanding of the way in which prostate tumors spread. Two areas where the capsule is deficient have been described: the invaginated extraprostatic space and the apex of the prostate, both of which are easy avenues along which tumor may escape the confines of the prostate. Cancer of the prostate is hypoechoic in comparison with the normal peripheral zone tissue in all cases and can be diagnosed with great accuracy by the use of ultrasound-guided biopsies. The sensitivity of transrectal ultrasound in the diagnosis of prostate cancer is twice that of digital rectal examination. In our clinical study, the overall positive predictive value of a hypoechoic lesion was 41 per cent, and it increased to 61 per cent when combined with the finding of a positive digital rectal examination and to 52 per cent if the prostate-specific antigen level was elevated. Thirty-two per cent of the cancers diagnosed with transrectal ultrasound were not detectable by digital rectal examinations.

Transrectal ultrasonography in the evaluation of rectal and extrarectal disease.

Transrectal ultrasonography is a technique that is gaining popularity in the assessment of rectal and extrarectal disease. From April 1987 to May 1989, 53 transrectal sonograms were done to evaluate rectal disease. Twenty-seven of 30 adenocarcinomas have been correctly staged. The operative procedure and the decision to use preoperative radiotherapy have been influenced by the results of these studies. Recurrent tumors and less common anorectal disease have also been evaluated with this technique. When feasible to perform, ultrasonographically guided biopsies yield specimens that can provide added information on which to base a therapeutic approach.

Linear array test tool.

A new linear array test tool is presented. It is easily used to directly measure an image acquisition parameter: the transmit/receive aperture. The aperture measurement gives important information concerning the functioning of the real-time multielement transducer and the equipment's signal-processing hardware and software. A feasibility test of the new test tool demonstrated that it can be easily used by clinical personnel to (1) determine the variation of the transmit/receive aperture with image depth; (2) document the operation of the equipment in each of the operator selectable focusing schemes; (3) perform quick checks of equipment performance when in doubt; and (4) test for and document the existence of nonfunctioning elements in linear, curved linear (convex), and phased arrays.

Transrectal ultrasound in the diagnosis and staging of prostatic carcinoma.

Indications for TRUS are: (a) for diagnosis of nonpalpable cancer, or detection of cancer with greater accuracy than is possible at present; (b) for guidance of transrectal biopsies of hypoechoic lesions for histologic confirmation of cancer; (c) for guidance of staging biopsies to ensure diagnoses of extraprostatic extension; and (d) for staging previously diagnosed prostate cancer.

Hypoechoic lesions of the prostate: clinical relevance of tumor size, digital rectal examination, and prostate-specific antigen.

Two hundred fifty-six patients with hypoechoic lesions of the prostate found at transrectal ultrasound (US) were evaluated with prostate-specific antigen (PSA) study, digital rectal examination (DRE), and US-guided transrectal biopsy. Positive predictive values for cancer were calculated for transrectal US alone and in combination with DRE, PSA study, or both. Results were correlated with lesion size. The positive predictive value for transrectal US alone was 41%; this value increased to 61% if the patient had positive results from DRE, 52% if the PSA level was elevated, and 71% if both the DRE results and PSA level were abnormal. The positive predictive value for transrectal US fell to 24% if results of the DRE were normal, 12% if the PSA level was normal, and 5% if both DRE results and PSA level were normal. No cancers were detected in lesions 1.0 cm or smaller if DRE results and PSA level were normal. DRE and PSA study are valuable complements to abnormal transrectal US examinations. Biopsy of small suspicious lesions may not be indicated if results of both of the studies are normal.

Transrectal biopsy of the prostate guided with transrectal US: longitudinal and multiplanar scanning.

One hundred forty-nine ultrasound (US)-guided transrectal biopsies of the prostate were performed with an 18-gauge needle mounted in a spring-loaded firing device. Two probes were used, one with its sector transducer placed at the tip of the probe and the other with its sector transducer placed at an angle of 45 degrees. All biopsies provided a diagnostic tissue core. Histologic examination of biopsy specimens showed that 78 lesions were cancerous, 17 were dysplastic, and 54 were benign. Two patients developed fever; one of these received oral antibiotics after onset of the fever. Hospitalization was not required for either patient. The authors conclude that US-guided transrectal biopsy is a safe and valuable diagnostic tool.

Transrectal US of the seminal vesicles and ejaculatory ducts: clinical correlation.

Transrectal ultrasonography (US) provides excellent anatomic detail of pathologic changes in the seminal vesicles and ejaculatory ducts. Fifty-two patients with US findings of seminal vesicle dilatation or cysts, ejaculatory duct cysts, or seminal vesicle or ejaculatory duct calculi were given questionnaires concerning a broad spectrum of genito-urinary symptoms. Compared with age-matched controls with normal US findings, patients with calculi in the seminal vesicles or ejaculatory ducts had a significantly increased prevalence of hematospermia and ejaculatory pain (P less than .01), and patients with cystic dilatation of the seminal vesicles were more likely to have perineal pain. Large midline cysts containing calculi or debris were symptomatic and probably represent müllerian duct remnants. Small cysts of the ejaculatory ducts were asymptomatic. Transrectal US may provide clinical insight into the causes of significant genitourinary symptoms that may previously have been ascribed to chronic nonbacterial prostatitis or have been considered to be idiopathic.

Prostate cancer: comparison of transrectal US and digital rectal examination for screening.

The authors examined 784 self-referred men over age 60 years to compare clinical usefulness of transrectal ultrasound (US) and digital rectal examination in a screening program for prostate cancer. Biopsy was performed in 77 cases, 83% (64 of 77) for abnormalities detected with transrectal US and 38% (29 of 77) because of findings at digital examination. Twenty-two cancers were detected, 20 with transrectal US and ten at digital examination. Overall detection rate for prostate cancer with transrectal US was two times higher than that with digital examination (2.6% vs 1.3%). Sensitivity, specificity, and negative predictive value for transrectal US and digital examination were calculated for a range of prevalences (0.028-0.1543). Sensitivity was two times higher for transrectal US than for digital examination. Transrectal US demonstrated 100% (17 of 17) of tumors with the most favorable prognosis (less than or equal to 1.5 cm in diameter) compared with 41% (seven of 17) for digital examination. The authors conclude that transrectal US is more sensitive than digital examination in the detection of prostate cancer, and they advocate broader implementation and evaluation of transrectal US as a tool for early detection.

Obstetric ultrasound training for family physicians. Results from a multi-site study.

A practical program to train family physicians in obstetric ultrasound was tested with 13 family physicians. Each physician completed 6.5 days of course work and ultrasound laboratory apprenticeship prior to beginning a clinical preceptorship of approximately 14 months' duration. During the clinical preceptorship the physicians performed ultrasound studies in their own offices. All studies were reviewed by a local consultant radiologist utilizing examination data sheets and videotapes. At the conclusion of the training program, the physicians took a combined practical and written proficiency examination administered by an independent sonographer. Eight physicians completed the training, performing during the preceptorship an average of 78 examinations. The rated performance of the physicians improved markedly over the course of the preceptorship. During the last segment of the preceptorship the radiologist preceptors rated 94 percent of the ultrasound studies as acceptable, compared with 79 percent rated acceptable at the beginning of the preceptorship. Seven of the eight physicians completing the protocol took the proficiency examination: all passed. This study can provide a blueprint for an individual family physician to design his own training, or it can guide an academic department of family medicine in developing and evaluating ultrasound training programs for residents and practicing physicians.

The use of transrectal ultrasound in the diagnosis, guided biopsy, staging and screening of prostate cancer.

In the authors' experience, transrectal sonography has the ability not only to stage prostatic cancer accurately, but also to detect such lesions before they become palpable.

Needle aspiration and core biopsy of prostate cancer: comparative evaluation with biplanar transrectal US guidance.

Biplanar, transrectal ultrasound (US) guidance of needles was used in the transperineal biopsy of possibly malignant prostatic lesions in 80 patients (83 biopsies). A 22-gauge cytologic needle was used to locate and fixate the lesion, and aspiration specimens for cytologic and histologic evaluation were obtained (with 22- and 14-gauge needles, respectively). Twenty-one 19-gauge needle core biopsies were also performed. Forty-nine patients (61%) had histologically prove adenocarcinoma. The rate of cancer diagnosis was 53% with cytologic evaluation and 54% with histologic evaluation (combined yield, 61%). This included 34% of cancers less than 1.0 cm in diameter and 56% of those 1.0-1.5 cm. Thirteen of 23 (57%) of these lesions were nonpalpable or equivocal on digital rectal examination. These results suggest that transrectal US guidance of thin-needle biopsies is useful in diagnosing early prostate cancer.

Prostatic evaluation by transrectal sonography: criteria for diagnosis of early carcinoma.

Over a 7-month period, from a total of 417 transrectal ultrasound (US) studies, 45 transperineal biopsies of the prostate were performed in the radiology department. Transrectal US guidance and local anesthesia were used. Twenty-two of 32 hypoechoic lesions, located within the peripheral zone tissue of the gland, were proved by histologic study to be cancerous. Hyperechoic lesions were all histologically benign hyperplasias. The patients experienced no major complications necessitating hospitalization or increased length of hospital stay as a result of the procedure.