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Industry representatives on the ICH S1B(R1) Expert Working Group (EWG) worked closely with colleagues from the Drug Regulatory Authorities to develop an addendum to the ICH S1B guideline on carcinogenicity studies that allows for a weight-of-evidence (WoE) carcinogenicity assessment in some cases, rather than conducting a 2-year rat carcinogenicity study. A subgroup of the EWG composed of regulators have published in this issue a detailed analysis of the Prospective Evaluation Study (PES) conducted under the auspices of the ICH S1B(R1) EWG. Based on the experience gained through the Prospective Evaluation Study (PES) process, industry members of the EWG have prepared the following commentary to aid sponsors in assessing the standard WoE factors, considering how novel investigative approaches may be used to support a WoE assessment, and preparing appropriate documentation of the WoE assessment for presentation to regulatory authorities. The commentary also reviews some of the implementation challenges sponsors must consider in developing a carcinogenicity assessment strategy. Finally, case examples drawn from previously marketed products are provided as a supplement to this commentary to provide additional examples of how WoE criteria may be applied. The information and opinions expressed in this commentary are aimed at increasing the quality of WoE assessments to ensure the successful implementation of this approach.

Introduction: Anatomical resection—often by lobectomy—is the standard of care for patients with early stage NSCLC. With increased diagnosis, survival, and prevalence of persons with early stage NSCLC, the incidence of second primary NSCLC, and consequently, the need for contralateral lobectomy for a metachronous cancer, is increasing. Perioperative outcomes after contralateral lobectomy are unknown. Methods: Among patients who underwent contralateral lobectomy for second primary NSCLC during 1995 to 2020, we evaluated 90-day mortality and major morbidity (Clavien-Dindo grades 3–5) rates and their association with clinicopathologic variables, including the year of contralateral lobectomy and duration between lobectomies. Results: A total of 98 patients underwent contralateral lobectomy for second primary NSCLC; 51 during an early time period (1995–2009) and 47 from a late time period (2010–2020). There were five mortalities and 23 patients with major morbidities after contralateral lobectomy; both rates decreased in 2010 to 2020 compared with 1995 to 2009 (mortality 10%–0%, major morbidity 35%–11%). Major morbidity was associated with an interval of less than 1 year between lobectomies, a diffusing capacity of the lung for carbon monoxide

Meningitis caused by Staphylococcus aureus is an unusual illness that is often associated with bacteremia, contiguous infection and/or a post-neurosurgical state. Until recently, most cases were caused by methicillin-susceptible strains, but there are a few reports of methicillin-resistant S aureus strains causing meningitis. A new case of meningitis caused by methicillin-resistant S aureus in a neonatal intensive care nurse who did not have bacteremia or neurosurgery is reported. The patient made a full recovery after treatment with vancomycin and rifampin.

Case Presentation A 43-year-old man presented to the emergency room in September 2004 with a two-day history of increasing headache, myalgias and low-grade fever. No family members had been ill recently and he denied having nausea or diarrhea. On examination, he was nontoxic, with a temperature of 37.5¡ãC, pulse of 90 beats/min and blood pressure of 146/84 mmHg. Skin rashes were not present, and the neck was supple. The patient claimed that he seldom had headaches but that he had been hospitalized in England 15 years ago for viral meningitis. He remembered receiving antibiotics at the time despite being told it was a viral meningitis. The patient underwent a computed tomography scan of the brain, which was normal, followed by a lumbar puncture. The opening pressure was not recorded, but there were 23x106/L polymorphonuclear cells and 308x106/L lymphocytes in the cerebrospinal fluid (CSF). The CSF protein was elevated at 1.26 g/L (N¡Ü0.45), with a CSF glucose of 2.9 mmol/L compared with a serum value of 5.3 mmol/L. The peripheral white blood cell count was 10.5x109/L, with 8.0x109/L neutrophils.

Objective: To study the relationship of echocardiographic epicardial adipose tissue (EAT) with coronary artery disease (CAD) risk factors and the extent of coronary atherosclerosis. Methods: EAT thickness was measured in 527 patients undergoing their first coronary angiography. EAT was defined as an echo-lucent area on the free wall of the right ventricle on the still image of the two-dimensional echocardiogram at end diastole in the parasternal long-axis and parasternal short-axis views. A CT scan at the umbilicus was acquired to measure abdominal visceral adipose tissue (VAT) from a random sample of 30 patients. The extent of coronary atherosclerosis was assessed using a coronary atherosclerosis score based on the quantitative coronary angiography results. Results: EAT thickness was correlated with abdominal VAT (r(s) = 0.626, p<0.001), age (r(s) = 0.480, p<0.001), waist circumference (r(s) = 0.309, p<0.001), body mass index (r(s) = 0.233, p<0.001), C reactive protein (r(s) = 0.224, p<0.001), and the homoeostasis model assessment score (r(s) = 0.249, p<0.001). EAT was thicker in subjects with CAD than in those without CAD (4.0 vs 1.5 mm, p<0.001). Patients with unstable angina had thicker EAT than those with stable angina or atypical chest pain (4.0, 3.0, and 1.5 mm, respectively, p<0.001). EAT (> or =3.0 mm) was an independent factor of CAD on multiple logistic analysis (odds ratio = 3.357; 95% CI 2.177 to 5.175, p<0.001). Conclusions: These results suggest that EAT may reflect the amount of visceral fat, which is associated with insulin resistance and inflammation. The echocardiographic measurement of EAT may provide additional information for assessing CAD risk and predicting the extent and activity of CAD. [ABSTRACT FROM AUTHOR]

Background and Objectives: Contrast-induced nephropathy (CIN) is associated with increased morbidity and mortality. This observational, non-randomized study evaluated the effect of rosuvastatin loading before percutaneous coronary intervention (PCI) on the incidence of CIN in patients with acute coronary syndrome (ACS)., Subjects and Methods: A total of 824 patients who underwent PCI for ACS were studied (408 patients in the statin group=40 mg rosuvastatin loading before PCI; 416 patients of control group=no statin pretreatment). Serum creatinine concentrations were measured before and 24 and 48 hours after PCI. The primary endpoint was development of CIN defined as an increase in serum creatinine concentration of ≥0.5 mg/dL or ≥25% above baseline within 72 hours after PCI., Results: The incidence of CIN was significantly lower in the statin group than that in the control group (18.8% vs. 13.5%, p=0.040). The maximum percent changes in serum creatinine and estimated glomerular filtration rate in the statin group within 48 hours were significantly lower than those in the control group (5.84±22.59% vs. 2.43±24.49%, p=0.038; -11.44±14.00 vs. -9.51±13.89, p=0.048, respectively). The effect of rosuvastatin on preventing CIN was greater in the subgroups of patients with diabetes, high-dose contrast medium, multivessel stents, high baseline C-reactive protein, and myocardial infarction. A multivariate analysis revealed that rosuvastatin loading was independently associated with a decreased risk for CIN (odds ratio, 0.64; 95% confidence interval, 0.43-0.95, p=0.026)., Conclusion: High-dose rosuvastatin loading before PCI was associated with a significantly lower incidence of CIN in patients with ACS.

Background and Objectives: High dose rosuvastatin loading before percutaneous coronary interventions (PCI) reduces the myocardial damage and the incidence of adverse cardiac events in patients with stable angina and acute coronary syndrome. However, no studies are present yet about rosuvastatin loading in patients with ST-segment elevation myocardial infarction (STEMI) in a primary PCI setting., Subjects and Methods: A total of 475 patients who underwent primary PCI for STEMI were studied. The study population was divided into two groups with 208 patients in the statin group=40 mg rosuvastatin loading before primary PCI and 267 patients in the control group=no statin pretreatment. At median 3 days after PCI a single-photon emission computed tomography (SPECT) was performed with technetium 99m tetrofosmin For this study were compared infarct size, corrected Thrombolysis in Myocardial Infarction (TIMI) frame count and the myocardial blush grade (MBG) between the both groups., Results: Baseline clinical and procedural characteristics were similar between the groups. Infarct size, as assessed by SPECT, was significantly smaller (19.0±15.9% vs. 22.9±16.5%, p=0.009) in the statin group than in the control group. Patients of the statin group showed a lower corrected TIMI frame count (28.2±19.3 vs. 32.6±21.4, p=0.020), and higher MBG (2.49±0.76 vs. 2.23±0.96, p=0.001) than the patients of the control group. The multivariate analysis revealed that rosuvastatin loading {odds ratio (OR) 0.61}, pain to balloon time (OR 2.05), anterior myocardial infarction (OR 3.89) and final the MBG (OR 2.93) were independent predictors of a large infarct size., Conclusion: A high dose rosuvastatin loading before the primary PCI reduced the infarct size by microvascular myocardial perfusion improvement.

Objectives: We aimed to compare long-term clinical outcomes between modified mini-crush (modi-MC) technique with classic crush (crush) technique for treatment of bifurcation lesions., Background: The modi-MC technique showed excellent procedural success and favorable 9-month clinical outcomes., Methods: From January 2005 to November 2009, we enrolled patients with de novo bifurcation lesions treated with modi-MC (n = 112 lesions in 111 patients) and crush technique (n = 69 lesions in 67 patients). Primary endpoint was rate of major adverse cardiac events (MACE), a composite of all-cause death, myocardial infarction (MI), and target lesion revascularization (TLR) at 3 years., Results: There was no significant difference in baseline characteristics. The modi-MC technique showed a significantly higher success rate of final kissing balloon inflation (84.1 vs. 98.2%, P = 0.001). After 3 years, MACE rate was significantly lower in the modi-MC group (25.4 vs. 12.6%, P = 0.030). The incidence of all-cause death was 7.5 vs. 2.7% (P = 0.087), MI was 4.5 vs. 1.8% (P = 0.290), TLR was 17.4 vs. 8.9% (P = 0.093) and stent thrombosis was 3.0 vs. 1.8% (P = 0.632) in the crush and modi-MC groups, respectively., Conclusions: The modified mini-crush technique showed more favorable 3-year clinical outcomes compared to the classic crush technique., (Copyright © 2012 Wiley Periodicals, Inc.)

Systemic lupus erythematosus (SLE) is a typical autoimmune disease that's characterized by various autoantibodies to nuclear and cytoplasmic antigens. The presence of antinuclear antibodies (ANA) in serum is generally considered a decisive diagnostic sign of SLE. However, a small subset of SLE patients who had the typical clinical features of SLE was reported to show persistently negative ANA tests. Our report describes a 16-yr-old female who presented with the clinical manifestations of SLE such as malar rash, photosensitivity, arthritis, lymphopenia, pericarditis and proteinuria. The serum autoantibodies were all negative and renal biopsy showed that the histopathological changes of immune complex mediated the focal segmental necrotizing glomerulonephritis with crescent formation. She was treated with monthly pulse cyclophosphamide along with corticosteroids. During the 2-yr follow-up period, the proteinuria was markedly decreased and all of the ANA and anti-double stranded DNA antibody tests were negative. This case suggests that ANA may not be required in the pathogenesis of lupus nephritis.

Clinically important myocarditis is an unusual feature in systemic lupus erythematosus (SLE). We describe the clinical characteristics, management and outcomes of five SLE patients who developed severe left ventricular dysfunction. Four patients were female with mean age of 36.4 years. Three patients had both lupus myocarditis and lupus nephritis. Four patients had raised anti-dsDNA antibody titer and low complement level and two patients had positive IgG anticardiolipin antibody. Three patients were treated by high-dose corticosteroids, one patient by intravenous pulse methylprednisolone, and one patient by intravenous immunoglobulin and pulse cyclophosphamide with high dose corticosteroids. Left ventricular function improved markedly in four patients and all of them had no recurrence of lupus myocarditis up to follow-up of 33 months. However, one patient, who showed no improvement of left ventricular function, was expired due to sudden cardiac arrest. Lupus myocarditis should be treated by immunosuppressive therapy with high-dose corticosteroids and mostly the prognosis might be good with early treatment.