Survival, quality-adjusted survival, and other clinical end points in older advanced non-small-cell lung cancer patients treated with albumin-bound paclitaxel.

BACKGROUND: This analysis compared the quality-adjusted survival and clinical outcomes of albumin-bound paclitaxel+carboplatin (nab-PC) vs solvent-based paclitaxel+carboplatin (sb-PC) as first-line therapy in advanced non-small-cell lung cancer (NSCLC) in older patients. METHODS: Using age-based subgroup data from a randomised Phase-3 clinical trial, nab-PC and sb-PC were compared with respect to overall response rate (ORR), overall survival (OS), progression-free survival (PFS), quality of life (QoL), safety/toxicity, and quality-adjusted time without symptoms or toxicity (Q-TWiST) with ages ⩾60 and ⩾70 years as cut points. RESULTS: Among patients aged ⩾60 years (N=546), nab-PC (N=265) significantly increased ORR and prolonged OS, despite a non-significant improvement in PFS, vs sb-PC (N=281). Nab-PC improved QoL and was associated with less neuropathy, arthralgia, and myalgia but resulted in more anaemia and thrombocytopenia. Nab-PC yielded significant Q-TWiST benefits (11.1 vs 9.8 months; 95% CI of gain: 0.2-2.6), with a relative Q-TWiST gain of 10.8% (ranging from 6.4% to 15.1% in threshold analysis). In the ⩾70 years age group, nab-PC showed similar, but non-significant, ORR, PFS, and Q-TWiST benefits and significantly improved OS and QoL. CONCLUSION: Nab-PC as first-line therapy in older patients with advanced NSCLC increased ORR, OS, and QoL and resulted in quality-adjusted survival gains compared with standard sb-PC.

The outcome and prognostic factors in patients with aspiration pneumonia during concurrent chemoradiotherapy for head and neck cancer.

This study aimed to investigate the outcome in patients with aspiration pneumonia during definitive concurrent chemoradiotherapy for head and neck cancer. The data of 595 patients with head and neck cancer treated by chemoradiotherapy were reviewed. Forty-one patients were identified as developing symptomatic aspiration pneumonia during treatment and were analysed for this study. The definition of symptomatic aspiration pneumonia fit three criteria: (1) at least one event of aspiration during the treatment or evidence of grade 2 or above dysphagia during treatment; (2) clinical or radiographic signs of pneumonia or pneumonitis; and (3) no evidence of grade 4 haematological toxicity before the outbreak of pneumonia. Termination of allocated radiotherapy was noted in 10 patients. A treatment break was observed in 26 patients, whereas irradiation was prolonged more than 1 week in 11 patients. Logistic regression analysis showed the dysphagia score during the treatment course and the chest roentgenography pattern following symptomatic aspiration pneumonia were found to independently influence the outcome. Aspiration pneumonia occurring during chemoradiotherapy for head and neck cancer has a detrimental effect on the treatment outcome. Intensive medical care is essential for this group of patients with a dysphagia score of 3 during treatment and an unfavourable chest film pattern.

Late toxicities in concurrent chemoradiotherapy using high-dose-rate intracavitary brachytherapy plus weekly cisplatin for locally advanced cervical cancer: a historical cohort comparison against two previous different treatment schemes.

PURPOSE: To determine the long-term toxicity of concurrent chemoradiotherapy (CCRT), using high-dose rate intracavitary brachytherapy (HDRICB) compared to radiation (RT) alone in patients with advanced cervical cancer using a control-cohort study. METHODS: A total of 332 cases of Stage IIB-III disease were included in this comparative study. Seventy-three patients were treated with a 3-insertion schedule and labeled group A, whereas the other 146 patients with a 4-insertion schedule became group B. One hundred and thirteen patients treated by a 4-insertion protocol with concurrent weekly cisplatin were labeled group C. RESULTS: The cumulative rate of grade 2 or above rectal complication was 13.7% for group A, 9.6% for the group B and 15.9% for group C (p = 0.76), whereas the grade 3 to 4 non-rectal radiation-induced intestinal injury was 6.8% for group A, 6.2% for group B and 9.7% for group C (p = 0.20). Grade 2 to 4 late bladder toxicity was higher in group C, with the cumulative rate being 5.5% for group A, 4.8% for group B and 15.0% for group C (p = 0.004). The independent factor for a rectal complication was the occurrence of a bladder complication (p = 0.01, hazard ratio 3.06). The independent factors for bladder complications were the use of CCRT (p = 0.01, hazard ratio 2.08), and the occurrence of rectal complications (p = 0.02, hazard ratio 2.77). CONCLUSIONS: When treating advanced cervical cancer, HDRICB consisting of four 6 Gy insertions and weekly cisplatin shows a trend of increasing late bladder complications. The interval between drug administration and HDRICB should be kept long enough to avoid any synergistic effect of both regimens.

Decreased cerebral Irp-1B limits impact of social isolation in wild type and Alzheimer's disease modeled in Drosophila melanogaster.

Environmental factors, such as housing conditions and cognitively stimulating activities, have been shown to affect behavioral phenotypes and to modulate neurodegenerative conditions such as Alzheimer's disease (AD). AD is a progressive neurodegenerative disorder affecting cognitive functions. Epidemiological evidence and experimental studies using rodent models have indicated that social interaction reduces development and progression of disease. Drosophila models of Aß42-associated AD lead to AD-like phenotypes, such as long-term memory impairment, locomotor and survival deficits, while effects of environmental conditions on AD-associated phenotypes have not been assessed in the fly. Here, we show that single housing reduced survival and motor performance of Aß42 expressing and control flies. Gene expression analyses of Aß42 expressing and control flies that had been exposed to different housing conditions showed upregulation of Iron regulatory protein 1B (Irp-1B) in fly brains following single housing. Downregulating Irp-1B in neurons of single-housed Aß42 expressing and control flies rescued both survival and motor performance deficits. Thus, we provide novel evidence that increased cerebral expression of Irp-1B may underlie worsened behavioral outcome in socially deprived flies and can additionally modulate AD-like phenotypes.

Photic signaling by cryptochrome in the Drosophila circadian system.

Oscillations of the period (per) and timeless (tim) gene products are an integral part of the feedback loop that underlies circadian behavioral rhythms in Drosophila melanogaster. Resetting this loop in response to light requires the putative circadian photoreceptor cryptochrome (CRY). We dissected the early events in photic resetting by determining the mechanisms underlying the CRY response to light and by investigating the relationship between CRY and the light-induced ubiquitination of the TIM protein. In response to light, CRY is degraded by the proteasome through a mechanism that requires electron transport. Various CRY mutant proteins are not degraded, and this suggests that an intramolecular conversion is required for this light response. Light-induced TIM ubiquitination precedes CRY degradation and is increased when electron transport is blocked. Thus, inhibition of electron transport may "lock" CRY in an active state by preventing signaling required either to degrade CRY or to convert it to an inactive form. High levels of CRY block TIM ubiquitination, suggesting a mechanism by which light-driven changes in CRY could control TIM ubiquitination.

Use of a recombinant protein containing major epitopes of hnRNP G to detect anti-hnRNP G antibodies in dogs with systemic lupus erythematosus.

The objective of this study was to express major epitopes of heterogeneous nuclear ribonucleoprotein G (hnRNP G) for detecting anti-hnRNP G antibodies in dogs with systemic lupus erythematosus (SLE). HnRNP G cDNA clone was isolated from HEp-2 cells, and a DNA fragment encoding immunodominant region (residues 189-272) of hnRNP G (hnRNP Gi) was subcloned into pET32 vector to construct a prokaryotic expression plasmid named pEThnRNPGi. After induction, Escherichia coli carrying pEThnRNPGi expressed a recombinant protein of 28 kDa, comprising recombinant hnRNP Gi and fusion tag. Purified recombinant hnRNP Gi protein was further analyzed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) and its identity was confirmed. Western blot analysis showed that recombinant hnRNP Gi was specifically recognized by anti-hnRNP G positive sera of SLE dogs, and not by negative control sera. In conclusion, recombinant hnRNP Gi protein expressed in this study may serve as a useful reagent to assist in the immunological diagnosis of canine SLE.

Oscillation and light induction of timeless mRNA in the mammalian circadian clock.

Circadian rhythms in Drosophila melanogaster depend on a molecular feedback loop generated by oscillating products of the period (per) and timeless (tim) genes. In mammals, three per homologs are cyclically expressed in the suprachiasmatic nucleus (SCN), site of the circadian clock, and two of these, mPer1 and mPer2, are induced in response to light. Although this light response distinguishes the mammalian clock from its Drosophila counterpart, overall regulation, including homologous transcriptional activators, appears to be similar. Thus, the basic mechanisms used to generate circadian timing have been conserved. However, contrary to expectations, the recently isolated mammalian tim homolog was reported not to cycle. In this study, we examined mRNA levels of the same tim homolog using a different probe. We observed a significant (approximately threefold) diurnal variation in mTim expression within mouse SCN using two independent methods. Peak levels were evident at the day-to-night transition in light-entrained animals, and the oscillation persisted on the second day in constant conditions. Furthermore, light pulses known to induce phase delays caused significant elevation in mTim mRNA. In contrast, phase-advancing light pulses did not affect mTim levels. The mTim expression profile and the response to nocturnal light are similar to mPer2 and are delayed compared with mPer1. We conclude that temporal ordering of mTim and mPer2 parallels that of their fly homologs. We predict that mTIM may be the preferred functional partner for mPER2 and that expression of mTim and mPer2 may, in fact, be driven by mPER1.

A multivariate analysis of prognostic factors in management of pineal tumor.

PURPOSE: A multivariate analysis of prognostic factors of treatment outcome of pineal tumor. METHODS AND MATERIALS: From February 1979 to June 1987, 25 patients with primary pineal tumors were treated in our department. Patients were treated with either AECL Co-60 unit or 10 MV linear accelerator to the primary tumor with an adequate margin or to the whole brain (median dose of 36 Gy) with or without a cone-down boost of 10 to 20 Gy. Craniospinal irradiation was performed in two patients with positive CSF cytology. Minimum follow-up was 40 months. Patients were further stratified according to tumor type. Group I consisted of seven patients with pineal germinoma. Group II included nine patients with nongerminoma, and Group III represented nine patients treated without a histological verification but clinical diagnosis. RESULTS: The relapse-free survival (RFS) of Group I patients was 100% and 86% at 2 and 5 years, respectively. Relapse-free survival was 55% and 21% at 2 and 5 years, respectively, for Group II patients. Six of 9 patients in Group II died of disease due to either local recurrence or tumor seeding. Eight of 9 patients in Group III remain no evidence of disease, and RFS was 89% at 2 and 5 years. Multivariate analysis revealed that tumor histology is the only significant prognosticator. Age, gender, type of surgical procedure, RT field, and tumor dose were not. Cox's regression model also failed to demonstrate a significant correlation of tumor seeding with the type of surgery. CONCLUSION: The type of tumors in the pineal region dictates the treatment outcome. Definitive radiation therapy is effective in controlling germinoma, whereas a more aggressive approach is needed to improve local control for nongerminoma. For a localized pineal lesion, we advocate that treatment can be tailored to the primary tumor with adequate margins. However, for locally advanced tumors whole brain or craniospinal irradiation should be considered. No definitive correlation between type of surgery and the probability of tumor seeding was identified.

Prognostic assessment of tumor regression after external irradiation for cervical cancer.

From February 1980 to December 1986, 428 cases of cervical cancer in Stage I through IVA were given curative radiation therapy at Chang Gung Memorial Hospital, Taipei. All of them received external irradiation and intracavitary brachytherapy. The degree of tumor regression was assessed immediately before the first intracavitary brachytherapy treatment. Patients were classified at this time as having (a) no gross residual tumor, or (b) gross residual tumor. Factors found to be associated with tumor regression by logistic regression analysis were stage, age and hemoglobin level. Patients with advanced cancer (Stage III, IVA), young age (less than 40 years), and low hemoglobin level (less than 10 g/dl) had a low incidence of no gross residual tumor. Five-year survival rate was 77% in patients with no gross residual tumor and 31% in patients with gross residual tumor (p less than 0.001). This significant difference held true even when one compared these two groups stage for stage; the difference was 77% versus 41% (p less than 0.001) in Stage II and 72% versus 28% (p less than 0.001) in Stage III. The local relapse rate was 59% in the gross residual tumor groups, significantly greater (p less than 0.001) than the 12% found in the no gross residual tumor group. It was concluded that patients whose tumors did not regress after external pelvic irradiation tended to recur after intracavitary brachytherapy, most often locally. This would justify a more aggressive treatment to improve local tumor control in this subset of high risk patients.

The prediction of late rectal complications following the treatment of uterine cervical cancer by high-dose-rate brachytherapy.

PURPOSE: This study aimed to correlate patient, treatment, and dosimetric factors with the risk of late rectal sequelae in patients with uterine cervical cancer treated with external beam radiation therapy (EBRT) and high dose rate intracavitary brachytherapy (HDRICB). METHODS AND MATERIALS: From September 1992 to December 1995, a total of 128 patients with uterine cervical cancer, who were treated and survived more than 12 months, were evaluated. After EBRT with 40-44 Gy/20-22 Fr/4-5 weeks to the whole pelvis, the dose was boosted up to 54-58 Gy with central shielding for patients with bilateral parametria of Stage IIb or greater. HDRICB consisted of three to four insertions at doses of 5-7.2 Gy (to Point A) at intervals of 1 week. Patient and treatment factors were analyzed using logistic regression analysis and the cumulative rectal biologic equivalent dose (CRBED) was calculated. RESULTS: After 30-75 months of follow-up (median, 43 months), 38 patients (29.7%) had late rectal sequelae. Patients who had Stage IIb-IVa disease, cumulative rectal dose (external RT + total ICRU rectal dose) greeater than 65 Gy, or age greater than 70 years had a high risk of developing late rectal sequelae. When 110 Gy was used as the cut-off value, 19.6% (10 of 51) of patients whose CRBED was less than 110 Gy had rectal complications, while 36.4% (28/77) of patients whose CRBED was greater than 110 Gy developed rectal complications. CONCLUSION: Risk factors of late rectal complications were advanced stage, age greater than 70 years, and cumulative rectal dose of greater than 65 Gy.

Prognostic factors of nasopharyngeal carcinoma: a multivariate analysis.

Between 1979 and 1985, 561 patients with nasopharyngeal carcinoma were reviewed to determine prognostic factors that may influence survival. Sex (p = 0.294) and histopathology (p = 0.677) had no correlation to the actuarial survival, whereas the site of cervical metastasis (p = 0.001) and the radiation doses to the nasopharynx and regional lymph nodes (p = 0.03) were both significant when one used univariate analyses. Cox's multivariate regression model revealed that the presence rather than the site of distant metastases was the single most important independent factor influencing the treatment outcome (p less than 0.0001). The addition of chemotherapy, on the other hand, did not show a survival benefit even when one took available confounding factors into account. There are, however, survival advantages associated with: (a) young age (less than or equal to 40 years), (b) asymptomatic status, (c) Stage I or II lesions, and (d) biopsy via nasopharynx instead of neck nodes. These favorable prognostic factors may be used for therapeutic guidance and end-result reporting.

High-dose-rate afterloading technique in the radiation treatment of uterine cervical cancer: 399 cases and 9 years experience in Taiwan.

Carcinoma of the uterine cervix has been the leading malignant neoplasm treated in our department. A comparative study was carried out using conventional low dose rate (LDR) with 137Cs sources (less than or equal to 100 cGy/hr) versus high dose rate (HDR) with 60Co sources (greater than 100 cGy/min) in the intracavitary (IC) application following external pelvic irradiation. A total of 399 patients were treated with external RT plus HDR radiation treatment alone from February 1980 through December 1985. Stage IIb and IIIb comprised 79.4% of cases (317 cases). The rate of initial complete response of the tumor, local control, and survival rate seemingly were better in the HDR group, but there was no significant difference statistically. The actuarial survival rates in all cases/definitive RT cases are 85%/85% for Stage 0-IIa, 53%/70% for IIb, 43%/49% for IIIa, 43%/53% for IIIb, 42%/47% for IVa, respectively. Complications were similar and the rectal complications were slightly higher in HDR group. The combination of pelvic irradiation with HDR intracavitary irradiation was more convenient for patients and also for personnel. The HDR technique may be a good substitution for IC treatment.

Thymic carcinomas: histopathological varieties and immunohistochemical study.

Thirteen cases of primary thymic carcinomas are described. The patients' ages ranged from 19 to 64 years, with a median of 40 years. Nine of them were male. Chest pain with or without cough was the main presenting symptom. No patient had myasthenia gravis. Five histological types were identified; two were undifferentiated (lymphoepithelioma-like) carcinoma, one was a clear-cell carcinoma, two were mixed squamous and small-cell carcinoma, and six were squamous cell carcinoma. All the tumors were variably positive for anti-keratin antibody AE1 and AE3, but negative for AE2. Anti-neuron specific enolase antibody was useful in identifying and confirming the small-cell carcinoma component of the mixed carcinomas. Anti-epithelial membrane antigen antibody aided in revealing the glandular structures in mixed adenosquamous and small-cell carcinomas. Thymic carcinomas were histopathologically differentiated from thymomas by their malignant cytological appearance, increased mitotic activity, and central tumor necrosis. All six patients with pure squamous-cell carcinoma were still alive, with a median survival time of 27 months. All but one of the other patients of different histological types died, the exception being a recent case of mixed adenosquamous and small-cell carcinoma; their median survival was 19.5 months, or 18 months when the latter surviving case is included. The prognosis of patients with pure squamous-cell carcinoma was better.

Effects of cadmium on trophoblast calcium transport.

Maternal exposure to cadmium (Cd) during pregnancy has been linked to low fetal birthweight, which may be attributed to placental damage and/or dysfunction in nutrient transport. Previous studies have suggested that Cd is accumulated in the placenta, and that placental transport of calcium (Ca) and zinc (Zn) is perturbed by Cd. To investigate the mechanism of Cd perturbation of Ca transport, we used JEG-3, a human choriocarcinoma cell line which exhibits trophoblastic properties, to analyse Cd effects in vitro. Treatment with Cd at low, physiologically relevant concentrations (e.g. 0.04 microM) did not result in obvious changes in cell morphology or integrity, whereas higher concentrations (> or = 0.16 microM) affected cell integrity. With lower concentrations of Cd treatment for 24 h, activities of cellular Ca uptake and transport, and Ca2+ binding were decreased, and intracellular [Ca2+] ([Ca2+]i) profile was also altered; however, membrane-associated Ca(2+)-activated ATPase activity remained relatively unchanged. Interestingly, cellular Ca uptake activity was unaffected by short-term (30 min) Cd pretreatment. The 24-h Cd treatment also resulted in elevated expression of the metal-binding protein, metallothionein, whereas the expression of a trophoblast-specific cytosolic Ca(2+)-binding protein (HCaBP) was drastically reduced. These results strongly suggest that Cd exposure significantly compromises the Ca handling ability of trophoblastic cells; this effect is probably not due to perturbations in Ca channel or membrane Ca pump activities, but rather a consequence of alterations in subcellular, cytosolic Ca2+ binding activities.

A deficiency in prothoracicotropic hormone transduction pathway during the early last larval instar of Bombyx mori.

The prothoracicotropic hormone (PTTH) is an insect cerebral peptide that stimulates the prothoracic glands to produce ecdysteroids that initiate moulting and metamorphosis. During the last larval instar of holometabolous insects, a reduction in the hemolymph juvenile hormone (JH) levels is a necessary step in initiating larval-pupal transformation. Recently we have demonstrated that very low ecdysteroid levels in the early last larval instar of Bombyx mori initiate the complete inactivation of corpora allata (CA). Results presented here further indicate that PTTH signal transduction pathways undergo specific developmental changes, with a deficiency in transduction in prothoracic gland cells occurring during the early last instar. Glands from the early last instar showed no increase in either cAMP levels or steroidogenesis to the stimulation of PTTH, indicating the absence of the PTTH receptors in gland cells. We propose that this absence of PTTH receptors plays a critical role in directing larval-pupal transformation.

Comparing whole body (18)F-2-deoxyglucose positron emission tomography and technetium-99m methylene diphosphonate bone scan to detect bone metastases in patients with breast cancer.

PURPOSE: At present, bone metastases are usually assessed using conventional technetium-99m methylene diphosphonate whole-body bone scan, which has a high sensitivity but a poor specificity. However, positron emission tomography with (18)F-2-deoxyglucose (FDG-PET) can offer superior spatial resolution and improved specificity. We attempted to evaluate the usefulness of FDG-PET for detecting bone metastases in breast cancer and to compare FDG-PET results with bone scan findings. PATIENTS: The study group comprised 48 patients with biopsy-proven breast cancer and suspected of having bone metastases who underwent bone scan and FDG-PET to detect the bone metastases. The final diagnosis of bone metastases was established by operative, histopathological findings or during a clinical follow-up longer than 1 year by additional radiographs or following FDG-PET/bone scan findings showing progressive widespread bone lesions. RESULTS: A total of 127 bone lesions including 105 metastatic and 22 benign bone lesions found by either FDG-PET or bone scan were evaluated. Using FDG-PET, 100 metastatic and 20 benign bone lesions were accurately diagnosed, and using bone scan 98 metastatic and 2 benign bone lesions were accurately diagnosed. The diagnostic sensitivity and accuracy of FDG-PET were 95.2% and 94.5%, and of bone scan were 93.3% and 78.7%, respectively. CONCLUSIONS: Our findings suggest that FDG-PET shows a similar sensitivity and a better accuracy than bone scan for detecting bone metastases in patients with breast cancer.

Differentiating benign and malignant pulmonary lesions with FDG-PET.

The purpose of this retrospective study was to evaluate the efficacy of positron emission tomography (PET) with 18F-fluoro-2-deoxyglucose (FDG) to differentiate benign from malignant pulmonary lesions. Fifty-five patients, suspected of having primary pulmonary neoplasm based on chest radiographic findings, underwent FDG-PET scanning. Pathological diagnoses were obtained in 41 patients with a total of 43 pulmonary lesions. The other 14 patients (14 lesions) were followed-up clinically for at least four months. The standard uptake value (SUV) was determined in each patient. The SUV of the 15 benign and 40 malignant pulmonary lesions were 1.60+/-0.42 and 6.14+/-2.67, respectively. If SUV was > 2.50, the pulmonary lesion was considered as a malignant pulmonary lesion. FDG-PET could correctly detect 34 true-positive and 15 true-negative pulmonary lesions. However, 6 false-positive and one-false negative pulmonary lesions were misdiagnosed by FDG-PET. The sensitivity, specificity and accuracy of FDG-PET to differentiate between benign and malignant pulmonary lesions were 94%, 71% and 86%, respectively. FDG-PET can accurately detect malignant pulmonary lesions with a high sensitivity. However, false-positive FDG-PET findings caused by some inflammatory processes may decrease its specificity.