Lung cancer remains the leading cause of cancer death globally. More than 50% of new cases are diagnosed in an advanced or metastatic stage, thus contributing to the poor survival of such patients. ...Mutations in the KRAS (Kirsten rat sarcoma virus) gene occur in nearly a third of lung adenocarcinoma and have for decades been deemed an ‘undruggable’ target. Yet, in recent years, a growing number of small molecules, such as the GTPase inhibitors, has been investigated in clinical trials of lung cancer patients harboring KRAS mutations, yielding promising results with improved outcomes. Currently, there are only two approved targeted therapies (adagrasib and sotorasib) for advanced or metastatic KRAS -mutated NSCLC from the second-line setting onwards. In this narrative review, we will focus on KRAS , its molecular basis, the role of its co-mutations, clinical evidence for its inhibition, putative mutation to resistance, and future strategies to overcome resistance to KRAS inhibition.
Anti-glomerular basement membrane (anti-GBM) disease is an acute and life-threatening systemic autoimmune disorder. The coexistence of circulating anti-neutrophil cytoplasmic antibodies (ANCA) and ...anti-GBM disease, the so-called double-positive disease (DPD), is exceptionally rare. We report a unique case of DPD manifesting as pulmonary-renal syndrome (PRS) in a 46-year-old woman who first presented with clinical and radiological suspicion of pneumonia. Chest computed tomography scan later revealed bilateral alveolar hemorrhage. Kidney biopsy showed necrotizing crescentic (100% glomeruli) glomerulonephritis. On immunofluorescence microscopy, glomeruli were global linear positive for IgG, confirming anti-GBM disease. Double positivity was detected for circulating anti-myeloperoxidase ANCA (p-ANCA) and anti-GBM antibodies. Acute renal failure evolved rapidly. Therapeutic plasma exchange (TPE) and hemodialysis (HD) were initiated early in combination with intravenous pulse corticosteroid therapy followed by oral methylprednisolone and cyclophosphamide. Pulmonary hemorrhage resolved, but renal function could not be preserved. The patient remains HD dependent. This case report highlights that pulmonary symptomatology may be the leading clinical presentation of PRS, with initially normal renal function at DPD onset. Early recognition and diagnosis are therefore crucial to timely clinical intervention. The role of prompt kidney biopsy and initiation of TPE and HD in PRS must not be underestimated.
- Tigecycline susceptibility testing (TST) presents a tremendous challenge for clinical microbiologists. Previous studies have shown that the Epsilometer test (E-test) and Vitek 2 automated system ...significantly overestimate the minimum inhibitory concentrations for tigecycline resistance compared to the broth microdilution method (BMM). This leads to very major errors or false susceptibility (i.e. the isolate is called susceptible when it is actually resistant). The aim of this study was to compare E-test against BMM for TST in carbapenem-resistant and carbapenem-susceptible
and to analyze changes in tigecycline susceptibility between two time periods (2009-2012 and 2013-2014), with BMM as the gold standard. Using the EUCAST criteria, the rate of resistance to tigecycline for the OXA-23 MBL-positive, OXA-23 MBL-negative and carbapenemase-negative strains for BMM was 54.5% (6/11), 29.4% (5/17) and 2.7% (1/37), respectively; the OXA-24/40 and OXA-58 producing organisms did not exhibit any resistance. With E-test, all OXA-23 MBL-positive organisms (11/11), 23.5% (4/17) of OXA-23 MBL-negative, and 4.1% of OXA-24/40 (3/74) strains displayed tigecycline resistance; there were no resistant strains among the OXA-58 and carbapenemase-negative isolates. Resistance emerged in the bacterial isolates from 2013 to 2014. Although tigecycline does not display cross-resistance, the highest rates of resistant
isolates were observed among those producing VIM MBL, regardless of the testing method. These findings suggest that the commercial E-test does not provide reliable results for TST of
. Further confirmation with the dilution method should be recommended, particularly in cases of serious infections.
Phenotypic detection of metallo-β-lactamases (MBLs) in
is a serious challenge to clinical microbiologists. MBLs are inhibited by metal chelators such as ethylenediaminetetraacetic acid) (EDTA). ...Production of MBLs cannot be recognized based on resistance phenotype. Therefore, phenotypic tests using EDTA are recommended. The aim of this study was to investigate the sensitivity and specificity of inhibitor based tests (EDTA) for detection of MBL. A total of 172
strains (123 carbapenemase positive and 49 carbapenemase negative) were analyzed. Phenotypic detection of MBLs was performed by the combined disk test with EDTA (CDT-EDTA) and EPI-dilution test (EPI-DT). Both tests were positive in all 11 isolates possessing VIM-1 MBL, showing 100% sensitivity. However, false positive results were observed in strains with class D carbapenemases using both tests, i.e. all OXA-23 and OXA-24/40 producing organisms and most OXA-58 positive strains (77% with CDT-EDTA
. 65% with EPI-DT). False positive results can occur because oxacillinases are converted to a less active state in the presence of EDTA, leading to augmentation of the inhibition zone around the carbapenem disk or reduction of carbapenem minimum inhibitory concentrations. This study showed high sensitivity but low specificity of phenotypic methods in the detection of MBLs.
Lung cancer is the leading cause of malignant pleural effusion (MPE). Management of MPEs remains a clinical challenge due to recurrence and poor quality of life. An ideal sclerosing agent has yet to ...be found. The aim of this cohort pilot study was to evaluate the role of mitoxantrone pleurodesis (MP) as an alternative to talc sclerotherapy for managing MPEs in lung cancer patients.
A retrospective chart review was conducted on consecutively admitted patients with MPE to the Department of Post-Intensive Care at the Clinic for Respiratory Diseases "Jordanovac", University Hospital Centre Zagreb, in Croatia.
Of 34 patients with MPE, twenty-one (64.8±9.46 years; 47-84 years) with primary lung carcinoma who received MP (30 mg of mitoxantrone) between December 2003 and February 2009 were included in this study. Chest radiographs taken prior to sclerotherapy and at 1-, 2-, and 3-month follow-up were compared. At the post-sclerotherapy evaluation periods, overall success (OS) rates of MP were 88.2% 17.6%, complete response (CR); 70.6%, partial response (PR), 53.9% (7.7% CR; 46.2% PR), and 45.5% (PR), respectively. Kaplan-Meier median survival from MP until death was 5.2 months, while that from diagnosis of primary lung cancer was 12.3 months.
MP may be a safe and effective method of managing MPE due to lung cancer. Future randomized controlled studies comparing mitoxantrone and talc pleurodesis in lung cancer patients are warranted to elucidate whether a significant difference exists between these agents. Factors affecting success, survival probability, and quality of life also require further investigation.
Anti-glomerular basement membrane (anti-GBM) disease is an acute and life-threatening systemic autoimmune disorder. The coexistence of circulating anti-neutrophil cytoplasmic antibodies (ANCA) and ...anti-GBM disease, the so-called double-positive disease (DPD), is exceptionally rare. We report a unique case of DPD manifesting as pulmonary-renal syndrome (PRS) in a 46-year-old woman who first presented with clinical and radiological suspicion of pneumonia. Chest computed tomography scan later revealed bilateral alveolar hemorrhage. Kidney biopsy showed necrotizing crescentic (100% glomeruli) glomerulonephritis. On immunofluorescence microscopy, glomeruli were global linear positive for IgG, confirming anti-GBM disease. Double positivity was detected for circulating anti-myeloperoxidase ANCA (p-ANCA) and anti-GBM antibodies. Acute renal failure evolved rapidly. Therapeutic plasma exchange (TPE) and hemodialysis (HD) were initiated early in combination with intravenous pulse corticosteroid therapy followed by oral methylpred-nisolone and cyclophosphamide. Pulmonary hemorrhage resolved, but renal function could not be preserved. The patient remains HD dependent. This case report highlights that pulmonary symptomatology may be the leading clinical presentation of PRS, with initially normal renal function at DPD onset. Early recognition and diagnosis are therefore crucial to timely clinical intervention. The role of prompt kidney biopsy and initiation of TPE and HD in PRS must not be underestimated. Key words: anti-glomerular basement membrane (anti-GBM) disease, Goodpasture's syndrome, p-AN-CA (anti-neutrophil cytoplasmic antibodies), pulmonary-renal syndrome, rapidly progressive glomerulonephritis with pulmonary hemorrhage Bolest protiv glomerularne bazalne membrane (anti-GBM) je akutna i po zivot opasna sistemska autoimuna bolest. Pojava cirkulirajucih antitijela na citoplazmu granulocita (engl. anti-neutrophil cytoplasmic antibody, ANCA) u bolesnika sa anti-GBM glomerulonefritisom, tako zvana dvostruko pozitivna bolest (engl. double-positive disease, DPD), je vrlo rijetka. Prikazujemo 46 godisnju bolesnicu u koje je prvo klinicki i radioloski postavljena sumnja na upalu pluca, a koja se kasnije manifestirala sa pulmo-renalnim sindromom (PRS) odnosno DPD. Kompjutorskom tomografijom pluca dokazano je alveolarno krvarenje. Biopsijom bubrega dokazan je nekrotizirajuci glomerulonefritis (100 % glomerula). Imunoflorescencija je pokazala pozitivne linearne IgG depozite, sto odgovara anti-GBM glomerulonefritisu. U bolesnice su dokazana antitijela na mijeloperoksidazu p-ANCA i antitijela na glomerularnu bazalnu membranu. Lijecena je terapijskom izmjenom plazme (engl. therapeutic plasma exchange, TPE), hemodijalizom te kombinacijom parenteralne pulsne terapije kortikosteroidima, kasnije oralnom primjenom metilprednisolona i ciklofosfamida. Doslo je do regresije krvarenja u plucima ali se bubrezna funkcija nije oporavila, zbog cega smo nastavili s redovitim hemodijalizama. Ovaj prikaz bolesnice pokazuje kako u DPD, plucna simptomatologija moze biti vodeci simptom PRS sa urednom bubreznom funkcijom u pocetku. Rano prepoznavanja i dijagnoza su znacajni za pravovremeni pocetak lijecenja. Potrebno je naglasiti znacaj rane biopsije bubrega, ranog pocetka TPE te po potrebi i nadomjestanje bubrezne funkcije hemodijalizom. Kljucne rijeci: bolest protiv glomerularne bazalne membrane (anti-GBM), Goodpasturov sindrom, p-ANCA (anti-neutrofilna citoplazmatska protutijela), pulmo-renalni sindrom, brzoprogresivni glomerulonefritis s plucnom hemoragijom
Purpose
The aim of this prospective observational study was to evaluate the relationship between changes in pulmonary artery systolic pressure (ΔPASP) and both severity of community‐acquired ...pneumonia (CAP) and changes in peripheral blood oxygen partial pressure (PaO2).
Materials and Methods
Seventy‐five consecutive adult patients hospitalized for treatment of CAP were recruited in this single‐center cohort study. Doppler echocardiographic measurement of PASP was performed by 2 staff cardiologists. Follow‐up assessment was performed within 2 to 4 weeks of ending antibiotic treatment at radiographic resolution of CAP. Fifteen patients were excluded during follow‐up due to confirmation of chronic obstructive pulmonary disease.
Results
Pneumonia was unilateral in 40 (66.7%) and bilateral in 20 (33.3%) patients. Radiographic extent of pneumonia involved 2 pulmonary segments in 31 patients (51.7%), 3 to 5 pulmonary segments in 25 (41.7%), and 6 pulmonary segments in 4 patients (6.6%). ΔPASP between hospital admission and follow‐up correlated with the number of pulmonary segments involved (Rho = 0.953; P < .001) and PaO2 (Rho = −0.667; P < .001). The maximum PASP was greater during pneumonia than after resolution (34.82 ± 3.96 vs. 22.67 ± 4.04, P < .001).
Conclusions
Changes in PASP strongly correlated with radiological severity of CAP and PaO2. During pneumonia, PASP appeared increased without significant change in left ventricular filling pressures. This suggests that disease‐related changes in lung tissue caused by pneumonia may easily and reproducibly be assessed using conventional noninvasive bedside diagnostics such as echocardiography and arterial blood gas analysis.
Adie's syndrome (AS) and paraneoplastic sensorimotor neuropathy with cerebellar ataxia (PSN CA) are extremely rare, rapidly progressive, autoimmune diseases associated with the development of ...antibodies against neuronal-specific Hu proteins that are abnormally expressed in small-cell lung cancer (SCLC). We herein present the unique case of a 55-year-old obese woman, previous heavy smoker, who, during treatment with standard cisplatin-etoposide chemotherapy for limited-stage SCLC, developed simultaneous AS and worsening symptoms consistent with PSN CA that led to significant neurological disability and severe axonal electrophysiological pattern on nerve conduction studies. Serology confirmed the presence of low-titre type 1 antineuronal nuclear antibodies (ANNA-1), previously referred to as anti-Hu antibodies. Following plasmapheresis, immunosuppressive therapy and physical rehabilitation, the neurological symptoms progressively improved. The tumour completely regressed, with no recurrence detected on subsequent radiological examinations. The aim of this case was to highlight the importance of a multidisciplinary team approach for early recognition and rapid treatment of paraneoplastic neurological syndromes (PNS) as key to achieving significant recovery and marked improvement of the neurological deficit. This report extends the literature by confirming earlier studies showing that the presence of serum ANNA-1 in SCLC, an aggressive type of pulmonary carcinoma that is challenging to treat, may portend a more favourable prognosis and response to chemotherapy. Thus, patients with SCLC and new-onset neurological symptoms should be tested for ANNA-1. The role of a multimodality approach to treating PNS is also emphasized.
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