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Background: Brigatinib is a potent ROS1 inhibitor. The existing data on its clinical activity in ROS1-rearranged non-small cell lung cancer (NSCLC) are limited to four cases. Methods: Six patients with ROS1-rearranged advanced NSCLC treated with brigatinib were identified through search of the internal databases of four participating cancer centers. Four additional patients were selected by PubMed and Google Scholar search. The objective response rate (ORR), progression-free survival (PFS) (RECIST v.1.1), duration of treatment (DOT), and safety were assessed. Results: Of eight patients evaluable for response assessment (crizotinib naive-1, crizotinib resistant -7), three patients demonstrated a partial response (ORR-37%). One crizotinib-naive patient had an ongoing response at 21.6 months. Of seven crizotinib-resistant patients, two patients demonstrated a partial response (ORR-29%), and one patient (14%) had stable disease. PFS, available in four crizotinib-resistant patients, was 7.6 + , 2.9, 2.0, and 0.4 months. In crizotinib-resistant patients, DOT was 9.7 + , 7.7 + , 7.6 + , 4.0, 2.0, 1.1, 0.4 months, and was not reported in two patients. Genomic profiling in one responder revealed no ROS1 alteration, suggesting that the response was attributable to "off-target" brigatinib activity. In two patients with progressive disease, genomic profiling demonstrated a cMET exon 14 mutation + KRAS G12A mutation in one case, and a persisting ROS1-CD74 fusion + TP53 K139N, FGFR2 E250G, ATM G2695D, and NF1 R2258Q mutations in the other. No grade 3–5 toxicity was observed. Conclusion: Brigatinib demonstrated modest activity in crizotinib-resistant ROS1-rearranged NSCLC. Its intracranial and systemic activity should be assessed in correlation with the underlying molecular mechanism of crizotinib resistance. Plain Language Summary: Our series is the first to describe brigatinib activity in ROS1-altered NSCLC. In crizotinib-resistant patients, ORR with brigatinib was 29%. PFS with brigatinib was 7.6+, 2.9, 2.0, and 0.4 months. DOT with brigatinib was 9.7+, 7.7+, 7.6+, 4.0, 2.0, 1.1, 0.4 months. The correlation between response and molecular resistance needs further exploration. [ABSTRACT FROM AUTHOR]

Background:Volatile organic compounds (VOCs) are potential biomarkers for cancer detection in breath, but it is unclear if they reflect specific mutations. To test this, we have compared human bronchial epithelial cell (HBEC) cell lines carrying the KRASV12 mutation, knockdown of TP53 or both with parental HBEC cells.Methods:VOC from headspace above cultured cells were collected by passive sampling and analysed by thermal desorption gas chromatography mass spectrometry (TD-GC-MS) or sensor array with discriminant factor analysis (DFA).Results:In TD-GC-MS analysis, individual compounds had limited ability to discriminate between cell lines, but by applying DFA analysis combinations of 20 VOCs successfully discriminated between all cell types (accuracies 80-100%, with leave-one-out cross validation). Sensor array detection DFA demonstrated the ability to discriminate samples based on their cell type for all comparisons with accuracies varying between 77% and 93%.Conclusions:Our results demonstrate that minimal genetic changes in bronchial airway cells lead to detectable differences in levels of specific VOCs identified by TD-GC-MS or of patterns of VOCs identified by sensor array output. From the clinical aspect, these results suggest the possibility of breath analysis for detection of minimal genetic changes for earlier diagnosis or for genetic typing of lung cancers. [ABSTRACT FROM AUTHOR]

life expectancy increases, degenerative lumbar spinal stenosis (DLSS) becomes a common health problem among the elderly. DLSS is usually caused by degenerative changes in bony and/or soft tissue elements. The poor correlation between radiological manifestations and the clinical picture emphasizes the fact that more studies are required to determine the natural course of this syndrome. Our aim was to reveal the association between lower lumbar spine configuration and DLSS. Two groups were studied: the first included 67 individuals with DLSS (mean age 66 ± 10) and the second 100 individuals (mean age 63.4 ± 13) without DLSS-related symptoms. Both groups underwent CT images (Philips Brilliance 64) and the following measurements were performed: a cross-section area of the dural sac, vertebral body dimensions (height, length and width), AP diameter of the bony spinal canal, lumbar lordosis and sacral slope angles. All measurements were taken at L3 to S1. Vertebral body lengths were significantly greater in the DLSS group at all levels compared to the control, whereas anterior vertebral body heights (L3, L4, L5) and middle vertebral heights (L3, L5) were significantly smaller in the LSS group. Lumbar lordosis, sacral slope and bony spinal canal were significantly smaller in the DLSS compared to the control. We conclude that the size and shape of vertebral bodies and canals significantly differed between the study groups. A tentative model is suggested to explain the association between these characteristics and the development of degenerative spinal stenosis. [ABSTRACT FROM AUTHOR]

Although Schmorl's nodes (SNs) are a common phenomenon in the normal adult population, their prevalence is controversial and etiology still debatable. The objective was to establish the spatial distribution of SNs along the spine in order to reveal its pathophysiology. In this study, we examined 240 human skeleton spines (T4-L5) (from the Hamann-Todd Osteological Collection) for the presence and location of SNs. To determine the exact position of SNs, each vertebral body surface was divided into 13 zones and 3 areas (anterior, middle, posterior). Our results show that SNs appeared more frequently in the T7-L1 region. The total number of SNs found in our sample was 511: 193 (37.7%) were located on the superior surface and 318 (62.3%) on the inferior surface of the vertebral body. SNs were more commonly found in the middle part of the vertebral body (63.7%). No association was found between the SNs location along the spine and gender, ethnicity and age. This study suggests that the frequency distribution of SNs varies with vertebra location and surface. The results do not lend support to the traumatic or disease explanation of the phenomenon. SNs occurrences are probably associated with the vertebra development process during early life, the nucleus pulposus pressing the weakest part of the end plate in addition to the various strains on the vertebrae and the intervertebral disc along the spine during spinal movements (especially torsional movements). [ABSTRACT FROM AUTHOR]

MDCT-derived myocardial perfusion has not yet been validated against accepted standards. We developed a technique for quantification of myocardial perfusion from MDCT images and studied its diagnostic value against SPECT myocardial perfusion imaging (MPI). Ninety-eight patients were studied. Abnormal perfusion was detected by comparing normalized segmental x-ray attenuation against values obtained in 20 control subjects. Disagreement with resting MPI was investigated in relationship to MDCT image quality, severity of MPI abnormalities, and stress MPI findings. Resting MPI detected mild or worse abnormalities in 20/78 patients. MDCT detected abnormalities in 15/20 patients (sensitivity of 0.75). Most abnormalities missed by MDCT analysis were graded as mild on MPI. Additional abnormalities found in 16/78 patients were not confirmed on resting MPI (specificity of 0.72). However, 8 of these 16 apparently false positive MDCT perfusion tests had abnormal stress MPI; of these 8 patients, 7 had optimal MDCT image quality, while in 6/8 remaining patients, image quality was suboptimal. When compared with resting MPI, MDCT detected perfusion abnormalities with high accuracy. Moreover, half of MDCT perfusion abnormalities not confirmed by resting MPI were associated with abnormal stress MPI. Importantly, this information can be obtained without additional radiation dose or contrast agent. [ABSTRACT FROM AUTHOR]

To identify the clinical and radiological features distinguishing Mycobacterium simiae respiratory infection from pulmonary tuberculosis, the demographics, underlying conditions, and clinical and radiological findings of 121 consecutive patients with pulmonary tuberculosis and 102 with M. simiae respiratory infection were compared retrospectively. In the M. simiae group, the patients were older (mean age 69 ± 16 years vs. 47 ± 21 years, p = 0.0001), with a female predominance (62% vs. 45%, p = 0.008). Only 4% were of Ethiopian origin compared to 25% of the tuberculosis group ( p = 0.0001). M. simiae infection was associated with significantly higher rates of smoking history, underlying chronic obstructive pulmonary disease, zero human immunodeficiency virus (HIV) infection compared to 10% in the tuberculosis group ( p = 0.001), blunted symptoms, and noncavitary infiltrates in the lower/middle lobes on chest X-ray. HIV-negative patients with M. simiae respiratory infection are distinguishable from patients with pulmonary tuberculosis by several demographic, clinical, and radiological features. These findings have important diagnostic and therapeutic implications. [ABSTRACT FROM AUTHOR]

This retrospective study sought to systematically identify clinical and radiological features differentiating Mycobacterium kansasii from Mycobacterium tuberculosis infection. The sample included matched patients with a culture-positive diagnosis of M. tuberculosis infection ( n = 121) or M. kansasii infection ( n = 62) derived from the databases of two tuberculosis centers. Data on patient background and clinical features were collected, and chest radiographs were analyzed. Sixty percent of the M. kansasii group were native Israelis compared to 15% of the M. tuberculosis group ( p = 0.0001). M. tuberculosis infection was associated with a higher rate of human immunodeficiency virus (HIV) infection ( p = 0.03) and M. kansasii infection with a higher rate of lung disease ( p = 0.0001). M. tuberculosis infection was characterized by a higher likelihood of bilateral disease ( p = 0.005), pleural effusions, and lymphadenopathy ( p = 0.006 and p = 0.001, respectively). There were ten deaths, all in the M. tuberculosis group. On multivariate logistic regression, the presence of chronic obstructive pulmonary disease and associated lung disease were significant predictors of M. kansasii infection. The findings show that there are group differences between the clinical features of the two infections. In the setting of pulmonary mycobacterial infection, the presence of coinfection with HIV, bilateral disease, pleural effusion, and lymphadenopathy make M. kansasii infection very unlikely. [ABSTRACT FROM AUTHOR]

The aim of the present study was to evaluate whether soluble triggering receptor expressed on myeloid cells (sTREM-1) is present in the cerebrospinal fluid (CSF) of patients with acute meningitis and if its presence can predict bacterial infection. We found elevated levels of sTREM-1 in the CSF of seven of the nine (78%) patients with culture-positive specimens and in none of 12 (0%) patients with culture-negative specimens (sensitivity: 78%; specificity: 100%). The area under the receiver operating characteristic curve for sTREM-1 in the CSF as a predictor for bacterial meningitis was 0.889. This suggests that sTREM-1 is upregulated in the CSF of patients with bacterial meningitis with high specificity and that its presence can potentially assist clinicians in the diagnosis of bacterial meningitis. [ABSTRACT FROM AUTHOR]

To evaluate the species distribution and antifungal susceptibility of Candida isolates in a tertiary institution in Israel, all consecutive isolates of Candida spp. recovered from blood during the last 2 years were studied. The isolates were identified by the germ tube test and the API ID 32C test (bioMérieux, Marcy l'Etoile, France). MICs of antifungal agents were determined by the E test. Candida albicans was the most commonly isolated species, accounting for 44% (63/142) of the isolates, followed by Candida tropicalis (25%; 35/142), Candida parapsilosis (20%; 29/142), Candida glabrata (10%; 14/142), and Candida krusei (0.7%; 1/142). All isolates were sensitive to amphotericin B and voriconazole. Resistance to fluconazole (using a high MIC of ≥256 μg/ml) was found in 1.6% of C. albicans isolates, in 3.4% of C. parapsilosis isolates, and in 21.4% of C. glabrata isolates. Resistance to itraconazole was detected in 3.2% of C. albicans isolates, in 2.9% of C. tropicalis isolates, in 3.4% of C. parapsilosis isolates, and in 93% of C. glabrata isolates. Disparities in species distribution and antifungal susceptibility of Candida isolates from the institute studied versus Candida isolates from other centers and countries are described. The findings emphasize the need for continuous surveillance and further clinical investigational studies. [ABSTRACT FROM AUTHOR]

The National Committee for Clinical Laboratory Standards (NCCLS) recommendations for screening and confirming the production of extended-spectrum beta-lactamases (ESBLs) were evaluated in 115 isolates ofEscherichia coliand 157 isolates ofKlebsiellaspp. from Israeli patients with bacteremia. All isolates were screened using cefotaxime, ceftazidime, and cefpodoxime discs. Confirmatory tests using pairs of discs containing ceftazidime, cefotaxime, or cefpodoxime in which clavulanic acid was added to one of the discs in each pair [inhibitor-potentiated disc diffusion test (IPDDT)] and two double-sidedEtest strips containing ceftazidime or cefotaxime with and without clavulanic acid were performed on all isolates regardless of the results of screening tests. Isolates that tested positive by one or more confirmatory tests were considered ESBL producers. Overall, 69 (25.4%) strains were found to be ESBL producers. The sensitivity of the NCCLS screening criteria ranged between 98.6% for cefotaxime and 92.8% for ceftazidime, and the specificity ranged between 100% for cefotaxime and cefpodoxime and 99.0% for ceftazidime. The sensitivity of the confirmatory tests ranged between 97.1% for the cefotaximeEtest and only 75.4% for the ceftazidime IPDDT discs. All 64 isolates that fell in the intermediate and resistant categories for cefotaxime, as well as all 41 in the same categories for ceftazidime and 68 of 69 in these categories for cefpodoxime, were confirmed as ESBL producers. The use of multiple antimicrobial discs for screening isolates and combinations of IPPDT discs is needed to improve the sensitivity of confirmatory testing. It is recommended that isolates falling in the intermediate and resistant categories in disc diffusion testing be reported as ESBL producers. The use of confirmatory tests should be limited to organisms with inhibition zone diameters ranging between the NCCLS recommendations for ESBL screening and the intermediate category breakpoints. [ABSTRACT FROM AUTHOR]

The annual incidence of gonorrhea in Israel has sharply increased during the past 2 years. At the end of 1999, high-level ciprofloxacin-resistant strains of Neisseria gonorrhoeae (MIC90, ≥32 mcg/ml) also exhibiting decreased susceptibility to penicillin and tetracycline were isolated for the first time in southern Israel, as well as in other regions of the country. The incidence of male gonococcal urethritis in the south increased in a 1.5-year period from 3/100,000 to 12/100,000 (P<0.05) in correlation with increased isolation of ciprofloxacin-resistant organisms. A marked increase in the incidence of gonorrhea was also encountered in Jerusalem, where ciprofloxacin resistance affected 54.5% of the isolates in 2000. Pulsed-field gel electrophoresis typing of gonococci from different areas of Israel indicated that all of the ciprofloxacin-resistant isolates belonged to identical or related strains. Since fluoroquinolone-resistant gonococci may emerge and disseminate extensively over a short period of time, continuous surveillance of antibiotic susceptibility among gonococcal isolates should be performed to guide empiric therapy. [ABSTRACT FROM AUTHOR]

The performance of a novel dipslide (DipStreak; Novamed, Israel) consisting of chromogenic agar (Uriselect 3; Sanofi Pasteur, France) and blood agar media was evaluated prospectively and compared to that of conventional urine culture for the diagnosis of urinary tract infection. A total of 1070 clean-catch urine specimens obtained from 251 hospitalized patients and 819 outpatients were processed. The overall performance of the DipStreak was as follows: sensitivity, 95.7%; specificity, 99.2%; agreement, 89.8%; accuracy, 98%; positive predictive value, 98.5%; and negative predictive value, 97.7%. A total of 270 urine specimens were positive by both DipStreak and conventional culture. The chromogenic agar allowed rapid identification of organisms in 211 (78.1%) cultures, while isolates in the other 59 (21.9%) cultures remained unidentified. The results indicate that the DipStreak device coupled with the Uriselect 3 agar represents a convenient and accurate method for inoculation of urine specimens, quantitation of bacteria, diagnosis of significant bacteriuria, and presumptive identification of isolates. [ABSTRACT FROM AUTHOR]

The aim of this study was to describe antibiotic resistance rates of enterotoxigenic Escherichia coli in Israel in order to facilitate the empirical choice of antibiotic treatment or prophylaxis for traveler's diarrhea and infantile diarrhea in our region. A total of 281 enterotoxigenic Escherichia coli isolates were tested: 144 from Bedouin infants and 137 from Israeli soldiers. Antibiotic-resistant isolates were prevalent in both groups, but higher resistance rates were found in the pediatric group. Strains producing heat-labile toxin showed higher resistance rates than strains producing heat-stable toxin. The results obtained in Israel preclude the use of many commonly used antibiotics for the treatment of traveler's diarrhea. Quinolones, however, are still effective. [ABSTRACT FROM AUTHOR]

In order to monitor changes in the frequency and antimicrobial resistance of urinary pathogens over several years, urinary cultures received from outpatient clinics and from a hospital during a period of one month each in 1991 and 1995 were analyzed at a clinical microbiology laboratory. In 1991 and 1995, 1366 and 1534 significant monomicrobic cultures respectively were reviewed. The frequency of Escherichia coli dropped significantly in the outpatient clinics from 70.5% to 61.2% (p<0.0001). The frequency of Proteus mirabilis, Morganella morganii, Pseudomonas aeruginosa and other gram-negative bacteria also decreased, but the frequency of Klebsiella spp. and Enterobacter spp. increased from 2.6% to 5.8% (p<0.0001). In the hospital, the frequency of Enterobacter spp. (p<0.04), Escherichia coli and Morganella morganii declined from 1991 to 1995, whereas the frequency of Pseudomonas aeruginosa (p=0.001), Acinetobacter spp. (p<0.05), Klebsiella spp., Proteus mirabilis and other gram-negative rods increased considerably. The frequency of gram-positive aerobic bacteria rose markedly in outpatient specimens from 6.1% to 13.5% (p<0.0001), while a decline from 14.4% to 9.3% was noted in hospital specimens (p<0.02). A significant rise in the resistance of Escherichia coli to gentamicin and ciprofloxacin (p<0.0001) was detected in outpatient isoates. In the hospital, gram-negative urinary pathogens demonstrated increased resistance to ampicillin (p=0.042), cefuroxime (p=0.005), gentamicin (p=0.002) and ciprofloxacin (p<0.0001) during the study period. The changing etiology of urinary tract infections and the increasing resistance of organisms indicate that periodic monitoring and possibly also modification of empirical therapy are required. [ABSTRACT FROM AUTHOR]

A mixed culture of oropharyngeal swabs, nasopharyngeal swabs and nasopharyngeal washings, taken from 400 patients, was compared to separate cultures of the same samples. The mixed culture identified Streptococcus pneumoniae in 37 of 40 (93%) patients with positive samples, Hemophilus influenzae in 28 of 29 (97%), and Moraxella catarrhalis in 94 of 94 (100%). These sensitivity rates clearly justify the use of mixed cultures instead of separate cultures for clinical and epidemiological purposes. The reduction in costs stemming from the use of mixed cultures may have a decisive influence when considering this test for extensive clinical and epidemiological purposes. [ABSTRACT FROM AUTHOR]

The article presents a comparative study of the link between age and clinical features and outcome of infective endocarditis in children, young adults and elderly patients. Results revealed that age is not a major determinant in the clinical manifestation and disease prognosis. It was found that hypoalbuminemia and hyperbilirubinemia contribute to the outcome of IE.

: Brucellosis is an important cause of paediatric septic arthritis in endemic areas. Because the Gram stain is frequently negative and culture results are unavailable at the time of the patient’s admission, the diagnosis of brucellar arthritis is usually entertained on the bases of epidemiological considerations and cytological examination of the synovial fluid aspirate. The aim of this study was to assess the sensitivity of a synovial fluid leukocyte count >50 000 WBC/mm3 for detecting culture-proven brucellar arthritis in children. The medical records of all children with brucellar arthritis diagnosed since 1994 in a hospital serving an endemic area for brucellosis in southern Israel were reviewed. Nine patients (six males and three females), aged 3–14 years, were identified. A single joint was affected in all patients. The median leukocyte count in the synovial fluid was 9500 WBC/mm3 (range 300–61 500 WBC/mm3), and in eight of the nine patients it was less than 50 000 WBC/mm3. Brucella melitensis was recovered from the synovial fluid culture in all patients. The diagnosis of brucellar septic arthritis cannot be excluded on the basis of a low leukocyte count in the joint aspirate. A high index of suspicion and use of modern culture techniques are recommended to improve the diagnosis of brucellar arthritis. [ABSTRACT FROM AUTHOR]

A prospective surveillance was conducted to monitor the prevalence and dynamics of antimicrobial resistance among enterococci isolated from blood cultures in southern Israel. A total of 242 organisms isolated between 1993 and 1996 were studied. The prevalence of Enterococcus faecalis significantly decreased during the study period, whereas that of Enterococcus faecium doubled. Antimicrobial drug resistance increased steadily among Enterococcus faecium isolates: resistance to ampicillin increased from 19% in 1993–1994 to 53% in 1995, and to 67% in 1996 (p = 0.005); during the same period, resistance to vancomycin increased from 0% to 20%, and to 50% (p = 0.002), and combined resistance to ampicillin and vancomycin and high-level resistance to gentamicin from 0% to 20% and to 38% (p < 0.02). [ABSTRACT FROM AUTHOR]

Long-term prostaglandin (PG) therapy has recently been associated with gastric mucosal hyperplasia. We reviewed the clinical and radiologic (especially sonographic) records of eight patients with complex congenital heart disease who were on PG therapy. Feeding problems, vomiting, and abdominal distension were present in six patients. Barium meal revealed antral narrowing in three patients, suggestive of hypertrophic pyloric stenosis in two. Sonography showed a variable degree of increased gastric mucosal lobulation often accompanied by a marked polypoid or lobular appearance. Cortical hyperostosis related to PG therapy was seen in three patients. PG-associated gastric mucosal hyperplasia can cause feeding problems and pronounced gastric lobulation. [ABSTRACT FROM AUTHOR]

Enterococcus hirae, member of the Enterococcus genus known to cause infection in animals, is rarely encountered in clinical practice. There are no published reports describing clinical features of Enterococcus hirae infection in humans. A case of Enterococcus hirae septicemia in a 49-year-old patient with end-stage renal disease undergoing hemodialysis is reported here. A review of the available literature regarding the clinical spectrum of Enterococcus hirae infection in humans and the antimicrobial susceptibility of Enterococcus hirae is also included. [ABSTRACT FROM AUTHOR]

Personalized medicine has revolutionized approaches to treatment in the field of lung cancer by enabling therapies to be specific to each patient. However, physicians encounter an immense number of challenges in providing the optimal treatment regimen for the individual given the sheer complexity of clinical aspects such as tumor molecular profile, tumor microenvironment, expected adverse events, acquired or inherent resistance mechanisms, the development of brain metastases, the limited availability of biomarkers and the choice of combination therapy. The integration of innovative next-generation technologies such as deep learning-a subset of machine learning-and radiomics has the potential to transform the field by supporting clinical decision making in cancer treatment and the delivery of precision therapies while integrating numerous clinical considerations. In this review, we present a brief explanation of the available technologies, the benefits of using these technologies in predicting immunotherapy response in lung cancer, and the expected future challenges in the context of precision medicine., (© 2023. The Author(s).)

Deficits in cognitive control-that is, in the ability to withhold a default pre-potent response in favour of a more adaptive choice-are common in depression, anxiety, addiction and other mental disorders. Here we report proof-of-concept evidence that, in participants undergoing intracranial epilepsy monitoring, closed-loop direct stimulation of the internal capsule or striatum, especially the dorsal sites, enhances the participants' cognitive control during a conflict task. We also show that closed-loop stimulation upon the detection of lapses in cognitive control produced larger behavioural changes than open-loop stimulation, and that task performance for single trials can be directly decoded from the activity of a small number of electrodes via neural features that are compatible with existing closed-loop brain implants. Closed-loop enhancement of cognitive control might remediate underlying cognitive deficits and aid the treatment of severe mental disorders., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)