Elevated serum lactate dehydrogenase to albumin ratio is a useful poor prognostic predictor of nivolumab in patients with non-small cell lung cancer.

OBJECTIVE: This study aimed to evaluate the prognostic significance of the LDH-to-albumin ratio (LAR) in patients with non-small cell lung cancer (NSCLC) receiving nivolumab monotherapy. We comprehensively analyzed the associations between LAR and clinical parameters, progression-free survival (PFS), and overall survival (OS) to identify reliable biomarkers for treatment selection. PATIENTS AND METHODS: A total of 144 patients with metastatic NSCLC treated with nivolumab were included. Patient characteristics, including demographic data, smoking history, albumin, lactate dehydrogenase (LDH) levels, and LAR were recorded. Univariate and multivariate analyses were conducted to determine the associations between these factors and PFS/OS. The LAR cut-off value was determined using receiver-operating characteristics (ROC) curve analysis. RESULTS: The median overall survival was 14.2 months, and the median progression-free survival was 5.28 months. Univariate analysis showed that smoking, ECOG performance score, brain metastasis, PD-L1 level, nivolumab treatment line, albumin, hemoglobin, LDH levels, platelet count, monocyte count, lymphocyte count, and LAR were associated with PFS. In the multivariate analysis, only LAR remained significantly associated with PFS. For overall survival, smoking, ECOG performance score, albumin level, LDH level, platelet count, monocyte count, lymphocyte count, brain metastasis, LAR, nivolumab treatment line, and PD-L1 level were significant in the univariate analysis. Albumin level, ECOG performance score, and LAR were independently associated with overall survival in the multivariate analysis. CONCLUSIONS: The LAR, reflecting tumor burden, tumor hypoxia, immune response, nutritional status, and systemic inflammation, emerged as a potential prognostic biomarker in NSCLC receiving nivolumab monotherapy. This study highlights the importance of considering multiple factors in treatment decisions and supports the need for personalized approaches in NSCLC immunotherapy. Further research is needed to validate the utility of LAR as a predictive biomarker in this patient population.

High body-mass index is not associated with worse clinicopathological characteristics in predominantly obese breast cancer patients.

BACKGROUND: Breast cancer (BC) is the most common cancer among women. A high body-mass index (BMI) is related to increased incidence of BC with poorer prognosis. AIM: The aim of the study was to evaluate the association in patients with BC between BMI at the time of diagnosis and biological characteristics, according to the menopausal status. MATERIALS AND METHODS: This retrospective study comprised a total of 318 women with BC. Clinicopathological differences between normal, overweight and obese patients according to menopausal status were evaluated. RESULTS: Premenopausal women had a significantly lower BMI than postmenopausal patients (28.7 vs. 31.5, respectively; p = 0.00001). No statistically significant association was determined between BMI and clinicopathological characteristics in either the premenopausal or the postmenopausal group (all p values are > 0.05). CONCLUSIONS: There are many conflicting results in literature on this relationship. The results of this study showed that a high BMI is not associated with worse clinicopathological characteristics in a predominantly obese population. In current medical oncology practice, BC should be evaluated on an individual patient basis and the impact of obesity on BC prognosis seems to be difficult to estimate especially in an obese population.

Single dose regorafenib-induced hypertensive crisis.

Gastrointestinal stromal tumors (GISTs) are uncommon tumors of the gastrointestinal (GI) tract. Regorafenib is a new multikinase inhibitor and is approved for the treatment of GISTs in patients who develop resistance to imatinib and sunitinib. The most common drug-related adverse events with regorafenib are hypertension, hand-foot skin reactions, and diarrhea. Grade IV hypertensive side effect has never been reported after a single dose. In this report, we present a case of Grade IV hypertensive side effect (hypertensive crisis and seizure) after a single dose of regorafenib. A 54-year-old male normotensive GIST patient was admitted to the emergency department with seizure and encephalopathy after the first dosage of regorafenib. His blood pressure was 240/140 mmHg upon admission. After intensive treatment with nitrate and nitroprusside, his blood pressure returned to normal levels in five days. Regorafenib was discontinued, and he did not experience hypertension again. This paper reports the first case of Grade IV hypertension after the first dosage of regorafenib. We can suggest that hypertension is an idiosyncratic side effect unrelated to the dosage.

Assembly of Marek's disease virus (MDV) capsids using recombinant baculoviruses expressing MDV capsid proteins.

The genes UL18, UL19, UL26, UL26.5, UL35 and UL38 of Marek's disease virus 1 (MDV-1) strain RB1B, encoding the homologues of herpes simplex virus type 1 (HSV-1) capsid proteins VP23, VP5, VP21-VP24, preVP22a, VP26 and VP19C, were identified and sequenced. Recombinant baculoviruses were used to express the six capsid genes in insect cells. Coexpression of the six genes or of UL18, UL19, UL26.5 and UL38 in insect cells resulted in the formation of capsids with a large core. In addition, electron microscopy of thin sections clearly revealed the presence of large numbers of small spherical particles. Experimental coinfection demonstrated that these small particles were associated with production of the preVP22a protein.

Folding of the rabbit hemorrhagic disease virus capsid protein and delineation of N-terminal domains dispensable for assembly.

Rabbit hemorrhagic disease virus (RHDV) and European brown hare syndrome virus (EBHSV) are caliciviruses that produce severe symptoms and are lethal to rabbits and hares. The folding of the capsid protein was studied by determination of the antigenic pattern of chimeric capsid proteins, composed of regions from RHDV and EBHSV capsid proteins. The anti-RHDV monoclonal antibody (MAb) E3, which is known to bind an external conformational epitope, recognized the RHDV C-terminal region. The anti-RHDV MAb A47, which binds a buried epitope, recognized the RHDV N-terminal region. Using a pGEX expression library, we more precisely mapped the MAb A47 epitope on a 31 residues length peptide, between residue 129 and 160 of the VP60, confirming its location in the N-terminal part of the protein. These results demonstrate that the C-terminal part of the protein is accessible to the exterior whereas the N-terminal domain of the protein constitutes the internal shell domain of the particle. With the aim of using virus-like particles (VLPs) of RHDV as epitope carriers or DNA transfer vectors, we produced in the baculovirus system three proteins, DeltaN1, DeltaN2 and DeltaN3, truncated at the N terminus. The DeltaN1 protein assembled into VLPs, demonstrating that the first 42 amino acid residues are not essential for capsid assembly. In contrast, DeltaN2, from which the first 75 residues were missing, was unable to form VLPs. The small particles obtained with the DeltaN3 protein lacking residues 31 to 93, located in the immunodominant region of the RHDV capsid protein, indicate that up to 62 amino acid residues can be eliminated without preventing assembly.

Interspecies aminopeptidase-N chimeras reveal species-specific receptor recognition by canine coronavirus, feline infectious peritonitis virus, and transmissible gastroenteritis virus.

We report that cells refractory to canine coronavirus (CCV) and feline infectious peritonitis virus (FIPV) became susceptible when transfected with a chimeric aminopeptidase-N (APN) cDNA containing a canine domain between residues 643 and 841. This finding shows that APN recognition by these viruses is species related and associated with this C-terminal domain. The human/canine APN chimera was also able to confer susceptibility to the porcine transmissible gastroenteritis virus (TGEV), whereas its human/porcine homolog failed to confer susceptibility to CCV and FIPV. A good correlation was observed between the capacity of CCV, FIPV, and TGEV to recognize the different interspecies APN chimeras and their ability to infect cells derived from the relevant species. As an exception, TGEV was found to use a human/bovine APN chimera as a receptor although itself unable to replicate in bovine cells.

Overexpression of TGEV cell receptor impairs the production of virus particles.

The porcine aminopeptidase-N (pAPN) is the cellular receptor for the transmissible gastroenteritis virus (TGEV) due to the specific binding of the spike protein S to APN. In the present study, we performed both biological and biochemical experiments to analyze how the level of expression of a virus receptor can influence the viral protein biosynthesis and the virus production. We generated two swine testis cell clones overexpressing pAPN (ST-APN clones). These clones produced 10(4) less infectious virus than control ST cells. Plaque assays revealed a four-fold reduction of the diameter of the plaques in ST-APN cells compared to ST cells. Pulse-chase experiments revealed that S transport from the endoplasmic reticulum to the Golgi apparatus was not affected in ST-APN cells. Additionally, an anti-APN antibody was able to increase the virus released in the supernatant of ST-APN cells. Likewise, BHK clones expressing variable amounts of pAPN were shown to acquire TGEV susceptibility and to produce infectious particles as an inverse function of their level of pAPN expression. In contrast, MDCK clones expressing low or large amounts of pAPN failed to produce infectious particles. Taken together, these studies strongly suggest that overexpression of receptor, but also other(s) undetermined factor(s), can impair the production of viral particles.

Determinants essential for the transmissible gastroenteritis virus-receptor interaction reside within a domain of aminopeptidase-N that is distinct from the enzymatic site.

The swine-specific coronavirus transmissible gastroenteritis virus (TGEV) uses pig aminopeptidase-N (pAPN) as a cellular receptor. We showed that the human aminopeptidase-N (hAPN) cannot substitute for pAPN in this respect, although the two enzymes have 80% amino acid sequence identity. In order to map the TGEV binding site on pAPN, we constructed a series of APN cDNA chimeras between pAPN and hAPN and analyzed them for their capacity to confer infectivity. The region between residues 717 and 813 was found to be essential for infectivity. This region also contains the epitopes for three TGEV-blocking monoclonal antibodies directed against pAPN. These data support the view that the catalytic site and the TGEV receptor site are located in different domains. Moreover, APN inhibitors and mutations in the catalytic site had no obvious effect on permissiveness for virus, thus providing evidence that the APN enzymatic activity is not involved in the process of infection.