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.

Assessing prospective and retrospective metacognitive accuracy following traumatic brain injury remotely across cognitive domains.

The ability to monitor one's behaviour is frequently impaired following TBI, impacting on patients' rehabilitation. Inaccuracies in judgement or self-reflection of one's performance provides a useful marker of metacognition. However, metacognition is rarely measured during routine neuropsychology assessments and how it varies across cognitive domains is unclear. A cohort of participants consisting of 111 TBI patients [mean age = 45.32(14.15), female = 29] and 84 controls [mean age = 31.51(12.27), female = 43] was studied. Participants completed cognitive assessments via a bespoke digital platform on their smartphones. Included in the assessment were a prospective evaluation of memory and attention, and retrospective confidence judgements of task performance. Metacognitive accuracy was calculated from the difference between confidence judgement of task performance and actual performance. Prospective judgment of attention and memory was correlated with task performance in these domains for controls but not patients. TBI patients had lower task performance in processing speed, executive functioning and working memory compared to controls, maintaining high confidence, resulting in overestimation of cognitive performance compared to controls. Additional judgments of task performance complement neuropsychological assessments with little additional time-cost. These results have important theoretical and practical implications for evaluation of metacognitive impairment in TBI patients and neurorehabilitation.

A multicenter phase II study of cetuximab in combination with chest radiotherapy and consolidation chemotherapy in patients with stage III non-small cell lung cancer.

BACKGROUND: Cetuximab has demonstrated improved efficacy in combination with chemotherapy and radiotherapy. We evaluated the integration of cetuximab in the combined modality treatment of stage III non-small cell lung cancer (NSCLC). METHODS: Patients with surgically unresectable stage IIIA or IIIB NSCLC were treated with chest radiotherapy, 73.5 Gy (with lung and tissue heterogeneity corrections) in 35 fractions/7 weeks, once daily (63 Gy without heterogeneity corrections). Cetuximab was given weekly during radiotherapy and continued during consolidation therapy with carboplatin and paclitaxel up to a maximum of 26 weekly doses. The primary endpoint was overall survival. Baseline tumor tissue was analyzed for EGFR by fluorescence in situ hybridization (FISH). RESULTS: Forty patients were enrolled in this phase II study. The median overall survival was 19.4 months and the median progression-free survival 9.3 months. The best overall response rate in 31 evaluable patients was 67%. No grade 3 or 4 esophagitis was observed. Three patients experienced grade 3 rash; 16 patients (69%) developed grade 3/4 neutropenia during consolidation therapy. One patient died of pneumonitis, possibly related to cetuximab. EGFR gene copy number on baseline tumor tissues, analyzed by FISH, was not predictive of efficacy outcomes. CONCLUSIONS: The addition of cetuximab to chest radiotherapy and consolidation chemotherapy was tolerated well and had modest efficacy in stage III NSCLC. Taken together with the lower incidence of esophagitis, our results support evaluation of targeted agents instead of chemotherapy with concurrent radiotherapy in this setting.

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.

Differentially expressed genes in the rat cochlear nucleus.

The cochlear nucleus is the first central pathway involved in the processing of peripheral auditory activity. The anterior ventral cochlear nucleus (AVCN), posterior ventral cochlear nucleus (PVCN) and dorsal cochlear nucleus (DCN) each contain predominant populations of neurons that have been well characterized regarding their morphological and electrophysiological properties. Little is known, however, of the underlying genetic factors that contribute to these properties and the initial steps in auditory processing. Serial analysis of gene expression (SAGE), supported by microarray experiments, was performed on each subdivision of the rat cochlear nucleus to identify genes that may sub-serve specialized roles in the central auditory system. Pair-wise comparisons between SAGE libraries from the AVCN, PVCN and DCN were correlated with microarray experiments to identify individual transcripts with significant differential expression. Twelve highly correlated genes were identified representing cytoskeletal, vesicular, metabolic and g-protein regulating proteins. Among these were Rgs4 which showed higher expression in the DCN, Sst and Cyp11b1 with very high expression in the AVCN and Calb2 with preferential expression in the PVCN. The differential expression of these genes was validated with real-time reverse transcriptase-polymerase chain reaction. These experiments provide a basis for understanding normal auditory processing on a molecular level and a template for investigating changes that may occur in the cochlear nucleus with hearing loss, the generation and percept of tinnitus, and central auditory processing disorders.

A mutant of eukaryotic protein synthesis initiation factor eIF4E(K119A) has an increased binding affinity for both m7G cap analogues and eIF4G peptides.

The eukaryotic multisubunit initiation factor eIF4F is an essential component of the translational machinery. Recognition of the cap structure of mRNA, m(7)GpppN, where N is any nucleotide, by eIF4E is required for initiation of translation. Here we compare the equilibrium and thermodynamic binding characteristics of wild-type eIF4E and a high-affinity mutant, eIF4E(K119A), with those of cap analogues and eIF4G peptides. The temperature-dependent K(d) values for cap analogues were markedly lower, indicating tighter binding, with the eIF4E(K119A) mutant compared with wild-type eIF4E. Although interactions with cap analogues were found to be enthalpically driven, entropic contributions were also significant. Moreover, the binding affinities of eIF4G peptides were 2-4-fold tighter for eIF4E(K119A) than for eIF4E(wt). These results demonstrate that the binding affinity for both the mRNA cap and eIF4G peptides can be simultaneously altered by point mutations distant from either binding site. Entropic contributions to binding suggesting hydrophobic interactions are larger in the mutant protein and are most likely due to a conformational change.

Bacterial colonization of endotracheal tubes in intubated neonates.

OBJECTIVE: To obtain in vivo bacterial colonization profiles on endotracheal tubes at different sites in the neonatal airway in an attempt to better characterize one potential element of chondritis. DESIGN: A case series in which cultures were obtained from calculated segments of 33 endotracheal tubes immediately following extubation. This allowed for sampling at specific levels of the airway corresponding to the trachea, the subglottis, and the oropharynx. Data collected included gender, race, duration of intubation, use of antibiotic therapy, comorbidities, gestational age at birth and extubation, crown-rump length, weight, radiographic distance from tube tip to carina, and culture results. SETTING: Newborn intensive care unit at a tertiary care medical center. PATIENTS: Twenty-nine neonates intubated for longer than 24 hours (range, 24 hours to 15 days). MAIN OUTCOME MEASURES: Bacterial and fungal cultures obtained from 3 endotracheal tube segments for each extubation. RESULTS: A statistically significant difference (P < .05) was found in colonization rates between patients intubated for less than 4 days and those intubated for longer periods. No significant difference was noted in bacterial profile between the 3 sites. CONCLUSIONS: Data demonstrate that bacterial colonization of an indwelling object in the neonatal airway increases with the duration of intubation. Furthermore, 4 days seems to represent a critical period in the formation of such colonization (possibly in the form of a biofilm). These bacteria may contribute to the chondritis known to precede the development of subglottic stenosis. Further studies are indicated to suggest ways to interrupt this process and reduce the incidence of airway injury.

Verbal fluency in elderly bilingual speakers: normative data and preliminary application to Alzheimer's disease.

This study investigated verbal fluency abilities in 30 healthy elderly English-Afrikaans bilingual speakers, and 6 bilingual subjects with Alzheimer's disease. Three 1-min semantic verbal fluency tasks (animals) were obtained in the bilingual mode, Afrikaans and English. Results were analysed in terms of total correct, and semantic clusters. There was no significant difference between monolingual and bilingual performance. Some healthy bilingual subjects used code switching as a strategy but with no direct increase in the number of exemplars generated, and there was no relationship between age of acquisition, pattern of use and verbal fluency scores. In comparison, subjects with Alzheimer's disease did not make use of code switching strategies, and there was some relationship between age of acquisition, pattern of use and verbal fluency scores.

Preliminary report on reduction of esophagitis by amifostine in patients with non-small-cell lung cancer treated with chemoradiotherapy.

Esophagitis is a major toxicity of chemoradiotherapy for lung cancer. Twenty-four patients with non-small-cell lung cancer received induction chemotherapy (paclitaxel/carboplatin) followed by concurrent thoracic irradiation (RT) and weekly paclitaxel. Acute esophagitis was scored weekly. Since a high rate of grade 3 esophagitis was noted in the initial group of 12 patients, amifostine (AMI) 500 mg intravenously twice weekly was added to the regimen in the subsequent 12 patients. Esophagitis Index (EI) was calculated as an area under the curve reflecting esophagitis grade over time. Median number of AMI doses was 12 per patient. AMI was well tolerated. Two patients were not evaluable for esophagitis. The incidence of grade 3 esophagitis was 18% in the initial 11 patients versus 9% in the AMI-treated patients (P = not significant). Mean EI was numerically lower in the AMI-treated patients than in the initial group (5.1 vs. 11.6, P = 0.14). The product of RT dose and length of esophagus in the RT field was larger in the AMI group (934 vs. 761, P = 0.035). Median survival time for all patients was 12.4 months. Esophagitis Index, a novel measure of the severity and duration of acute esophagitis, may be reduced in lung cancer patients receiving twice-weekly AMI with thoracic RT and paclitaxel. Twice weekly AMI did not eliminate grade 3 esophagitis; therefore, dose escalation of AMI is planned. The effect of AMI was not due to the shorter irradiated esophageal length. A phase III randomized trial is now open to assess AMI's effect on esophagitis.

Lymphatic malformation: predictive factors for recurrence.

OBJECTIVE: Although lymphatic malformations are often found to be well circumscribed when surgery is undertaken in early childhood, complete surgical excision can be difficult when the lesion is infiltrative. This study retrospectively evaluates these patients in an attempt to identify prognostic factors that may predict recurrence. STUDY DESIGN AND SETTING: A retrospective chart review was conducted covering the years 1991 to 1998. Seventeen patients were identified having undergone 32 surgical resections of tumors described as lymphatic malformations. Data abstracted from the charts included the site of the lesion, surgical and histologic assessment of encapsulation, and status at follow-up examination. RESULTS: Six of 17 patients developed a recurrence after surgery. Correlation between recurrence and histologic or operative impressions of encapsulation was significant by chi(2) analysis (P<0.01). CONCLUSION: On the basis of the findings of this case series, lymphatic malformations that are found to be nonencapsulated and infiltrative by intraoperative or histologic assessment are more likely to recur.

Rapid resolution of fetal goiter associated with maternal Grave's disease: a case report.

The incidence of abnormal fetal thyroid function with maternal Grave's disease is about 2-12%. The development of larger fetal goiters can complicate labor and precipitate life-threatening airway obstruction at delivery. A case is presented of a large stable goiter confirmed by sonography, which unexpectedly resolved by the time of parturition. A 3 x 6 cm fetal goiter was detected at 34 weeks gestation in a mother treated with propylthiouracil for Grave's disease. A repeat sonogram at 36 weeks showed no change in goiter size. Umbilical blood sampling showed the fetus to be markedly hyperthyroid. Planned Cesarean section took place 11 days after the final sonogram. A multi-disciplinary operative team was present including the Otolaryngology service with equipment for emergency intubation, bronchoscopy and tracheotomy. Upon delivery, the infant had no evidence of goiter and no airway compromise. Fetal goiter is a rare entity, and recent advances in the field of maternal-fetal medicine have enabled intra-uterine diagnosis and treatment of such conditions. A review of published case reports demonstrates two trends in treated fetuses: preterm progressive resolution of the goiter, or delivery with gross evidence of goiter. This reported case is unique, as a persistent goiter resolved completely in less than 2 weeks. Otolaryngologic response to and management of potential congenital airway compromise is discussed.

Cochlear implantation for auditory rehabilitation in Camurati-Engelmann disease.

Camurati-Engelmann disease (progressive hereditary diaphyseal dysplasia) is a rare sclerotic bone disease involving the diaphyses of the long bones, skull base, and clavicles. Progressive sclerosis of cranial nerve foramina has been implicated in cranial nerve deficits. including facial nerve palsy, vestibular disturbances, and hearing loss. Two patients with Camurati-Engelmann disease and concomitant sensorineural hearing loss are presented. Both patients were evaluated for cochlear implantation. One patient was successfully implanted after preoperative imaging revealed no involvement of the internal auditory canals. The porous nature of the affected bone, however. necessitated the inactivation of 1 electrode to prevent facial nerve stimulation. A second patient was rejected as a potential implant recipient due, in part, to narrow internal auditory canals and rapidly progressive disease. The otologic manifestations of Camurati-Engelmann disease are reviewed, and issues related to cochlear implantation in this rare disease are discussed.

A phase II trial of docetaxel (Taxotere) in hormone-refractory prostate cancer: correlation of antitumor effect to phosphorylation of Bcl-2.

Twenty-one patients with hormone refractory prostate cancer were enrolled to receive single-agent docetaxel (Taxotere; Rhône-Poulenc Rorer, Collegeville, PA) 75 mg/m2 intravenously every 21 days. Six patients consented to biopsies of the prostate tumor before and following the first cycle of chemotherapy and 11 patients underwent periodic blood collection for isolation of the mononuclear cell fraction. The toxicities of treatment were moderate but included eight episodes of grade III and two episodes of grade IV nonhematologic toxicity as well as seven episodes of grade III and 11 episodes of grade IV hematologic toxicity (primarily neutropenia, including four episodes of febrile neutropenia). An objective response of more than 50% reduction in prostate-specific antigen was observed in seven patients (38%) and more than half of the patients with symptomatic disease at the initiation of therapy had improvements on treatment. Radiographic or scintigraphic evidence of tumor regression was observed in six patients. Nine patients experienced a prolonged period of stable disease on treatment (median, six cycles). Tumor specimens are currently being analyzed for bcl-2 expression and phosphorylation. The current series confirms the substantial single-agent activity of docetaxel in hormone refractory prostate cancer and may help to further elucidate its mechanism of action at the molecular level.

Phase I clinical/pharmacokinetic and pharmacodynamic trial of the c-raf-1 antisense oligonucleotide ISIS 5132 (CGP 69846A).

PURPOSE: Raf-1 is a protein kinase that plays a broad role in oncogenic signaling and acts as a downstream effector of Ras in the mitogen-activated protein kinase pathway. The present study was designed to determine the maximum-tolerated dose (MTD), toxicity profile, pharmacokinetics, and antitumor activity of the c-raf-1 antisense oligodeoxynucleotide ISIS 5132 (CGP 69846A; ISIS Pharmaceuticals Inc, Carlsbad, CA). The effect of ISIS 5132 on c-raf-1 gene expression in peripheral-blood mononuclear cells (PBMCs) of treated patients was studied using a reverse transcriptase polymerase chain reaction assay. PATIENTS AND METHODS: Patients with refractory malignancies received ISIS 5132 as a 2-hour intravenous infusion three times weekly for 3 consecutive weeks. Pharmacokinetic sampling was performed during the first cycle in all patients; PBMCs for c-raf-1 mRNA analysis were collected at baseline and on days 3, 5, 8, and 15 of cycle 1 and on day 1 of each cycle thereafter. RESULTS: Thirty-one patients received ISIS 5132 at one of nine dose levels ranging from 0.5 mg/kg to 6.0 mg/kg. Clinical toxicities included fever and fatigue, but these were not dose limiting. A clinically defined MTD was not reached. The harmonic mean half-life of ISIS 5132 was 59.8 minutes (range, 35.5 to 107.3 minutes). The area under the concentration-time curve increased linearly with dose, and mean plasma clearance was 1.86 mL/kg/min (range, 1.21 to 2.41 mL/kg/min). Two patients experienced prolonged stable disease lasting more than 7 months, which was associated with persistent reduction in c-raf-1 expression in PBMCs. Significant decreases in c-raf-1 expression were identified at time points after the baseline value (P <.05) at doses >/= 2.5 mg/kg. CONCLUSION: ISIS 5132 is well tolerated at doses up to 6.0 mg/kg when administered as a thrice weekly 2-hour infusion for 3 consecutive weeks. The pharmacokinetic behavior of the drug is reproducible, and suppression of target gene expression is observed in circulating PBMCs.

A critical appraisal of spontaneous perilymphatic fistulas of the inner ear.

OBJECTIVE: This article provides an overview of relevant data supporting and refuting the existence of spontaneous perilymph fistula, as well as critically reviewing the literature pertaining to their evaluation and management. DATA SOURCES: Sources used were relevant English language clinical and basic science publications. STUDY SELECTION: A Medline search dating back to 1966 for articles concerning perilymphatic fistula, including both human and animal data, was performed. Articles were included if they contained relevant data or were significant reviews of the subject. A traditional bibliography search was then completed to acquire articles missed by the computerized search, including works published before 1966. DATA EXTRACTION: The data from each publication were critically reviewed. Emphasis on understanding the clinical features of surgically created perilymph fistulas was used to more objectively assess the data regarding spontaneous perilymph fistulas. DATA SYNTHESIS: The data were not amenable to formal meta-analysis or valid data summarization; however, when possible trends and contrasting data were emphasized. CONCLUSIONS: Spontaneous perilymph fistulas are very rare occurrences and the majority are likely incited by a pressure-altering event. Current methodologies do not provide sufficient specificity and sensitivity to accurately diagnose perilymph fistulas. The results of endoscopic studies of the middle ear in the evaluation of perilymphatic fistula suggest a low incidence compared with the large number of fistulas reported in the literature. A high index of suspicion must be maintained, and appropriate preoperative counseling should reflect the current controversies. Questions must continue to be asked and further research pursued to help distinguish reality from myth.

Evaluation of surgical approaches to endoscopic auditory brainstem implantation.

OBJECTIVES: This study investigates the use of endoscopy for the placement of an auditory brainstem implant by translabyrinthine, retrosigmoid (suboccipital), and middle cranial fossa approaches. STUDY DESIGN: Cadaver dissection and endoscope-assisted placement of the auditory brainstem implant. METHODS: Translabyrinthine, retrosigmoid, and middle cranial fossa dissections were performed bilaterally in five cadaveric heads. An auditory brainstem implant was placed within the lateral recess of the fourth ventricle under endoscopic visualization. The implantation was performed with all approaches and documented by digital image capture followed by production of dye-sublimation photographic prints. RESULTS: The lateral recess was visualized with the endoscope in all three approaches to the brainstem. The 30 degrees endoscope provided the best visualization by translabyrinthine and retrosigmoid dissection and was essential for the middle cranial fossa approach. Refinement of implant position was readily achieved, as even the deepest portion of the recess could be seen with all three approaches. CONCLUSIONS: This study finds that endoscopy provides superior visualization of the lateral recess of the fourth ventricle than the operating microscope with all approaches. The retrosigmoid approach is recommended, as it provides the best view of the implantation site and the easiest angle for placement of the prosthesis. The use of the endoscope may allow for a smaller craniotomy than with conventional microscopic techniques, depending on tumor size. The translabyrinthine approach provides a good view of the lateral recess but had no advantage over other approaches. The middle cranial fossa approach is only possible with angled endoscopes; however, it is technically the most difficult and places the facial nerve at greatest risk.

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.

The influence of education and personality on risk propensity in nurse managers.

The current healthcare environment is demanding innovation. Nurse managers are positioned strategically to creatively change and innovate the patient care delivery process, if they are willing to take risks. The authors discuss a study that tests whether a nurse manager's education, years of experience, and personality are related to their propensity to take risks in administrative decision making. Results of the study indicate that nurse managers who achieved at least a bachelors degree, had higher autonomy orientations, and had lower control orientations were more likely to choose higher risk options in nursing administrative decisions. The authors found that self-esteem and years of experience were not related to nurse manager risk propensity.

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.