A single-arm, multicenter, phase II trial of osimertinib in patients with epidermal growth factor receptor exon 18 G719X, exon 20 S768I, or exon 21 L861Q mutations.

BACKGROUND: For patients with stage IV non-small-cell lung cancer with epidermal growth factor receptor (EGFR) exon 19 deletions and exon 21 L858R mutations, osimertinib is the standard of care. Investigating the activity and safety of osimertinib in patients with EGFR exon 18 G719X, exon 20 S768I, or exon 21 L861Q mutations is of clinical interest. PATIENTS AND METHODS: Patients with stage IV non-small-cell lung cancer with confirmed EGFR exon 18 G719X, exon 20 S768I, or exon 21 L861Q mutations were eligible. Patients were required to have measurable disease, an Eastern Cooperative Oncology Group performance status of 0 or 1, and adequate organ function. Patients were required to be EGFR tyrosine kinase inhibitor-naive. The primary objective was objective response rate, and secondary objectives were progression-free survival, safety, and overall survival. The study used a two-stage design with a plan to enroll 17 patients in the first stage, and the study was terminated after the first stage due to slow accrual. RESULTS: Between May 2018 and March 2020, 17 patients were enrolled and received study therapy. The median age of patients was 70 years (interquartile range 62-76), the majority were female (n = 11), had a performance status of 1 (n = 10), and five patients had brain metastases at baseline. The objective response rate was 47% [95% confidence interval (CI) 23% to 72%], and the radiographic responses observed were partial response (n = 8), stable disease (n = 8), and progressive disease (n = 1). The median progression-free survival was 10.5 months (95% CI 5.0-15.2 months), and the median OS was 13.8 months (95% CI 7.3-29.2 months). The median duration on treatment was 6.1 months (range 3.6-11.9 months), and the most common adverse events (regardless of attribution) were diarrhea, fatigue, anorexia, weight loss, and dyspnea. CONCLUSIONS: This trial suggests osimertinib has activity in patients with these uncommon EGFR mutations.

Pharmacokinetic study of pegylated liposomal CKD-602 (S-CKD602) in patients with advanced malignancies.

S-CKD602 is a pegylated liposomal formulation of CKD-602. This study is the first to evaluate the factors affecting the high interpatient variability in the pharmacokinetic disposition of S-CKD602. S-CKD602 was administered intravenously (i.v.) every 3 weeks as part of a phase I study. Pharmacokinetics studies of the liposomal encapsulated and released CKD-602 in plasma were performed. The pharmacokinetic variability of S-CKD602 is associated with both linear and nonlinear clearances. Patients > or =60 years of age have a 2.7-fold higher exposure of S-CKD602 as compared with patients <60 years of age (P = 0.02). Patients with a lean body composition have a higher plasma exposure of S-CKD602 (P = 0.02). Patients who have received prior therapy with pegylated liposomal doxorubicin (PLD) have a 2.2-fold higher exposure of S-CKD602 as compared with patients who have not received PLD (P = 0.045). Prolonged exposure of the encapsulated drug in plasma over 1-2 weeks provides significant pharmacologic advantages. The high interpatient variability in the pharmacokinetic disposition of S-CKD602 was associated with age, body composition, saturable clearance, and prior PLD therapy.

The role of oral etoposide in non-small cell lung cancer.

Oral etoposide has been tested alone and in combination in a number of tumour types since the late 1980s because of its mild toxicity, high response rates, ease of administration, and comparatively low cost. Encouraging early results with protracted oral etoposide therapy in small cell lung cancer have not been borne out in non-small cell lung cancer (NSCLC), particularly in the advanced-disease setting. However, in stage IV NSCLC, oral etoposide does appear to be as compatible with most of the newer agents as it has been with platinum compounds; these combinations continue to be explored, although they have not penetrated into standard usage. In stage III NSCLC, large combined-modality studies are ongoing. Other investigations examining protracted administration in combination with radiation 'sensitisers' are planned. It is possible that by exploiting the 'radiosensitising effect' of prolonged low dose oral etoposide, combined with that of other proven radiosensitisers such as paclitaxel, gemcitabine, and topotecan, we may identify a niche for oral etoposide in the future.

Molecular alterations to human chromosome 3p loci in neuroendocrine lung tumors.

BACKGROUND: The origins of and interrelations between low grade and high grade neuroendocrine lung tumors, typical and atypical carcinoids, and small cell lung carcinoma (SCLC) have not been elucidated. Karyotypic and molecular genetic studies have demonstrated deletions in 3p in 100% of SCLCs and the candidate lung tumor suppressor gene, FHIT, at 3p14.2 is not expressed in the majority of SCLCs. Similar studies of typical and atypical carcinoids could clarify the interrelations among these tumors. METHODS: For molecular genetic analyses, archival carcinoids and paired normal cells were microdissected from paraffin sections, deparaffinized, and DNA prepared. Oligonucleotide primer pairs for 12 microsatellite markers mapping between 3p14.2 and 3p21.3 were used to amplify allelic DNA fragments from 13 typical and 6 atypical carcinoids. In addition, an independent series of archival sections of carcinoids and SCLCs was tested by immunohistochemistry for expression of Fhit protein. RESULTS: Of the six atypical carcinoids examined, three had lost an allele at all informative markers, whereas one had lost alleles in two distinct regions and two showed allele loss in a subregion of the chromosome region tested. Of the 13 typical carcinoids, 3 showed allele loss at only 1 or 2 loci each. Typical carcinoids, similar to normal lung epithelia, were strongly positive for the cytoplasmic Fhit protein, SCLCs were uniformly negative, and atypical carcinoids appeared to express an intermediate level of Fhit protein. CONCLUSIONS: Loss of heterozygosity at 3p14.2-p21.3 is significantly more extensive in all atypical carcinoids. Atypical carcinoids, which exhibit clinicopathologic features intermediate between typical carcinoids and small cell carcinomas and have been considered well differentiated neuroendocrine carcinomas, also are intermediate between typical carcinoids and SCLC on the basis of extent of loss of 3p alleles and reduced expression of Fhit protein.

Small-cell lung cancer: a perspective on the past and a preview of the future.

Despite advances in the treatment of small-cell lung cancer during the 1970s, with the use of combination chemotherapy, and in the 1980s, with the combination of etoposide and cisplatin plus concurrent radiation therapy, treatment success seems to have reached a plateau in the current decade. Research should now be directed into three areas: (1) strategies to prevent the development of second cancers, one of the major causes of death in people "cured" of their first primary cancer; (2) introduction of new agents such as paclitaxel (Taxol) and other newer chemotherapeutic drugs into clinical trials, particularly in conjunction with radiation therapy in limited disease; and (3) development of new therapeutic approaches, such as the modulation of drug resistance, molecular biology interventions, and monoclonal antibody therapy, strategies that are based on increased understanding of small-cell lung cancer biology. Although it is doubtful that any single strategy will be curative, selective approaches that exploit new research findings in conjunction with moderately effective, more conventional treatments might allow us to raise remission and survival rates significantly.

Recurrent methicillin-resistant Staphylococcus aureus osteomyelitis: combination antibiotic therapy with evaluation by serum bactericidal titers.

OBJECTIVE: To report on a patient with recurrent methicillin-resistant Staphylococcus aureus (MRSA) osteomyelitis and bacteremia successfully treated with combination antibiotic therapy. CASE SUMMARY: Two sets of blood cultures from a 55-year-old man with fever, malaise, and low back pain grew MRSA. Radiologic studies of the spine showed bony changes consistent with osteomyelitis. Soon after completing 6 weeks of vancomycin, the patient experienced a recurrence of back pain. Laboratory values included an increase in the sedimentation rate to 53 mm/h and positive blood cultures for MRSA. Vancomycin, gentamicin, and rifampin were administered for 8 weeks. Serum inhibitory and bactericidal titers were more than 1:1024 for both the peak and trough concentrations. Radiologic studies of the spine showed healing osteomyelitis. Two years after completion of antibiotic therapy, the infection has not recurred. DISCUSSION: Antibiotic therapy alone was attempted because the patient was considered a risky surgical candidate. Serum inhibitory and bactericidal titers documented the high in vivo activity of the vancomycin, gentamicin, and rifampin combination. Initiation of vancomycin, gentamicin, and rifampin combination. Initiation of vancomycin therapy led to disappearance of the fever and back pain. Cure was documented by sustained normalization of the erythrocyte sedimentation rate and radiologic evidence of healing. CONCLUSIONS: Combination antibiotic therapy with vancomycin, rifampin, and low-dose gentamicin (1 mg/kg q12h) may be useful for deep-seated tissue infection caused by MRSA.

New chemotherapy agents in the treatment of advanced non-small cell lung cancer: an update including data from the Seventh World Conference on Lung Cancer.

Over the past two decades, modest gains have been made in chemotherapy for non-small cell lung cancer with the addition of cisplatin-based regimens to the therapeutic armamentarium. Over the last decade, several new agents with significant activity have reached the level of Phase II and III testing. This list of new drugs includes: navelbine, the taxanes--taxol and taxotere, gemcitabine, edatrexate and the camptothecins--irinotecan and topotecan. During this period, oral etoposide and epirubicin were re-investigated and biological agents such as the retinoids, interferons and interleukins were also explored as alternatives to traditional chemotherapy. As these new drug investigations proceeded, basic scientists made important discoveries which are now beginning to be applied to therapy. The future promises to combine these active new drugs with therapies directed against targets unique to non-small cell lung cancer cells.

Properties of chicken erythrocyte delta-aminolevulinate synthase.

A procedure is described for preparing a fraction highly enriched for chicken blood delta-aminolevulinate synthase (ALA-S) using animals recovering from acetylphenylhydrazine-induced anemia. 1. Blood cells collected from chickens recovering from anemia were disrupted by nitrogen cavitation, and the mitochondrial fraction was prepared from the cell homogenates. ALA-S was released then from mitochondria by sonication and isolated by a procedure involving gel filtration chromatography on Sephadex G-150, fractionation with ammonium sulfate, ion exchange chromatography on DEAE-Sephacel, and preparative isoelectric focusing. 2. Electrophoretic analyses under denaturing conditions indicated that the final ALA-S preparation was particularly enriched from a 62,200 Da polypeptide. The enzyme eluted from Sephadex G-200 with an equivalent molecular weight of 115,000; this suggested that active ALA-S was a dimer. 3. ALA-S was most active in the pH range of 7.0-8.0, with an apparent KM of 13 microM for succinyl-CoA and of 4.0 mM for glycine. The activity was inhibited 50% by 30 microM hemin.

Biogenesis of liver delta-aminolevulinate synthase. The role of cAMP in the induction.

In primary cultures of chick embryo hepatocytes pulse labeled with [35S]methionine, immunochemical analyses indicated that adenosine 3':5'-cyclic monophosphate (cAMP) did not affect either the rate of production or the maturation of delta-aminolevulinate synthase (ALA synthase). In addition, allylisopropylacetamide caused a slight drop in intracellular cAMP while testosterone caused the levels of cAMP to rise to 260% of the basal levels measured in hepatocytes in culture. Thus the results of this study did not indicate a direct short-term role for cAMP in the regulation of production of ALA synthase.