Treatment decisions and survival for people with small-cell lung cancer.

BACKGROUND: Chemotherapy improves survival for many patients with SCLC, and hence it is important to understand variations in practice and outcomes for this treatment strategy. METHODS: We used the National Lung Cancer Audit and Hospital Episodes Statistics to determine the proportion of patients who received chemotherapy for SCLC, and assess the effects of patient and organisational factors on the odds of receiving chemotherapy and of completing four cycles. We calculated median survival and used Cox regression to determine factors that predicted survival. RESULTS: Of 15 091 cases of SCLC, 70% received at least one cycle of chemotherapy. More deprived people were less likely to receive chemotherapy, but patients were more likely to receive chemotherapy, and to complete ≥ four cycles, if they were referred to the lung cancer team by their GP. Median survival for those treated with chemotherapy was 12.9 months for limited and 7.3 months for extensive stage disease. CONCLUSIONS: The Linked NLCA and HES data provide real-life measures of survival in people treated with chemotherapy and show how this is influenced by patient and tumour characteristics. These data show the characteristics of patients who are less likely to complete a full course of treatment, an adverse predictor of survival.

Sequential vs myeloablative vs reduced intensity conditioning for patients with myelodysplastic syndromes with an excess of blasts at time of allogeneic haematopoietic cell transplantation: a retrospective study by the chronic malignancies working party of the EBMT.

The optimal conditioning for patients with higher risk MDS receiving potentially curative allogeneic haematopoietic stem cell transplant(allo-HCT) remains to be defined. This is particularly the case for patients with excess of blasts at time of allo-HCT. Sequential (Seq) conditioning, whereby chemotherapy is followed rapidly by transplant conditioning, offers an opportunity to decrease disease burden, potentially improving outcomes allo-HCT outcomes. Herein we present the only analysis comparing Seq to myeloablative (MAC) and reduced intensity conditioning (RIC) specifically focussed on MDS patients with excess of blasts at allo-HCT. 303 patients were identified in the EBMT registry, receiving RIC (n = 158), Seq (n = 105), and MAC (n = 40). Median follow-up was 67.2 months and median age at allo-HCT was 59.5 years (IQR 53.5-65.6). For the entire cohort, 3 y overall survival (OS) was 50% (95% CI 45-56%) and relapse free survival (RFS) 45% (95% CI 40-51%). No significant differences in OS (log-rank p = 0.13) and RFS (log-rank p = 0.18) were observed between conditioning protocols. On multivariable analysis, lower performance status, worse IPSS-R cytogenetics, sibling donor (compared to 8/8 MUD) and ≥20% blasts at allo-HCT were associated with worse outcomes. In conclusion, the Seq protocol did little to influence the outcome in this high-risk group of patients, with outcomes mostly determined by baseline disease risk and patient characteristics such as performance status.

Autologous stem cell transplantation for multiple myeloma patients with chronic kidney disease: a safe and effective option.

Chronic Kidney Disease (CKD) is a frequent complication in patients with multiple myeloma (MM) and is associated with adverse outcomes. The use of autologous stem cell transplantation (ASCT) has improved disease outcomes, however, the safety and efficacy of ASCT in patients with CKD has been the subject of debate. To investigate this, we conducted a retrospective analysis of 370 MM patients who underwent their first ASCT, including those with mild, moderate and severe CKD as well as normal renal function at the time of transplant. No significant difference in ASCT-related mortality, Progression-Free or Overall Survival was noted between the different renal function groups. A decline in estimated glomerular filtration rate (eGFR) at 1-year of >8.79% was associated with poorer overall survival (p < 0.001). The results of this study show that ASCT is a safe and effective option for myeloma patients with CKD, including those on dialysis. Patients who demonstrate renal deterioration at 1-year post-transplant should be closely monitored as this is a predictor for poor survival.

Human parainfluenza virus type 3 infections in a haemato-oncology unit: social distancing measures needed in outpatient clinics.

BACKGROUND: Human parainfluenza virus type 3 (HPIV3) infections are associated with high mortality in immunocompromised settings, especially in bone marrow transplant recipients. Asymptomatic infection and lack of effective antiviral treatment makes HPIV3 prevention and treatment a real challenge. AIM: To retrospectively investigate the epidemiological characteristics, clinical characteristics and outcomes of 51 haematology patients with confirmed HPIV3 infections, detected between February and May 2019 in the haematology unit at King's College Hospital, London. METHODS: Between February and May 2019, HPIV3 RNA was detected in combined nose and throat swab samples collected from 51 symptomatic haematology patients, 41 of whom attended the haematology outpatient unit. Clinical data were reviewed retrospectively and a timeline of patients' appointments drawn up to investigate transmission. Sequencing analysis was performed on 14 stored samples. FINDINGS: Fifty-one patients were identified with HPIV3 infection. Mean age was 54 years (SD: 12; range: 19-72) and 60% (31/51) were male. There were 41 (80%) bone marrow transplant recipients, 24 had an allograft, and 17 an autograft. Thirty-day and 3-month mortality post HPIV3 was 6% and 14%, respectively. Lower respiratory tract infection and inpatient acquisition were associated with higher mortality (6/7 vs 1/7, P = 0.010; and 5/7 vs 2/7, P = 0.031). Onset of HPIV3 infection in patients within 6 days of attending the clinic was associated with the clusters identified in phylogenetic analysis (64% (9/14) vs 21% (8/37); odds ratio: 6.5 (confidence interval: 95% 1.7-25); P = 0.006). CONCLUSION: Timelines suggested community transmission, but also possible transmission patterns within the outpatients and subsequent nosocomial transmission within the same ward. Early recognition of HPIV3 infection and the use of polymerase chain reaction and sequence analysis is fundamental in identifying respiratory virus outbreaks and person-to-person transmission. Careful planning of outpatient clinic attendance is required to minimize contact and prevent respiratory virus transmission in immunosuppressed patients.

DNA synthesis and interaction between controlled feeding schedules and partial hepatectomy in rats.

The rate of DNA synthesis has been measured during liver regeneration in rats adapted to a controlled feeding schedule. The results show two different phenomena in the regulation of DNA synthesis. The first is the appearance of a peak of DNA synthesis following the operation itself and independent of the time of the day; the second one is the presence of constant diurnal variations in the rate of DNA synthesis in response to the partial hepatectomy and following the stimulus or stimuli of the controlled feeding schedule.

Chronotypic action of theophylline and of pentobarbital as circadian zeitgebers in the rat.

In the rat the deep body temperature rhythm, monitored by telemetry, can be reset in a predictable direction by a stimulant (theopylline) and by a depressant (pentobarbital). When the drugs are applied immediately before or during the early active phases of the circadian cycle, the rhythm is set back (phase delay). When applied later, past the thermal peak, theophylline, but not pentobarbital, shifts the rhythm ahead (phase advance). Theophylline and pentobarbital in addition to having a number of already established pharmacological properties are now further identified as chronobiotics: they are drugs that may be used to alter the biological time structure by rephasing a circadian rhythm.

Amino acid transport in hepatoma cell cultures during tyrosine aminotransferase induction.

Alpha-aminoisobutyric acid transport in hepatoma cells in culture was increased by insulin but not by hydrocortisone. Both of these agents induce tyrosine aminotransferase activity in this system. The apparent increase in alpha-aminoisobutyric acid transport and tyrosine aminotransferase activity produced by glucagon is probably caused by insulin contamination. Insulin did not increase transport in this system until after tyrosine aminotransferase activity had reached maximum levels. The mechanisms underlying increased alpha-aminoisobutyric acid transport appear to differ from those for tyrosine aminotransferase induction with hydrocortisone despite their close association in previous whole animal experiments.

Raised serum urea predicts for early death in small cell lung cancer.

AIMS: Previous studies have defined prognostic factors predicting a favourable response to treatment and long-term survival in small cell lung cancer (SCLC) patients. Here we sought specific pre-treatment features predicting early death in SCLC. MATERIALS AND METHODS: An exploratory cohort of 62 patients with poor prognosis SCLC and a separate confirmatory independent cohort of 152 unselected SCLC patients were identified to determine risk factors for early death, defined as within 8 weeks of diagnosis. RESULTS: In an exploratory cohort of patients with poor prognosis SCLC, 46 received chemotherapy and 16 patients received no chemotherapy. Multivariate analysis of chemotherapy patients showed a raised serum urea to be predictive of early death - increasing the risk by 13-fold (odds ratio 13.3, 95% confidence interval=2.8-64). In a separate cohort of 152 unselected SCLC patients, 123 received chemotherapy and 29 did not. Logistic regression analysis of treated patients showed that performance status >2 (P=0.009), urea>upper limit of normal (P=0.01), neutrophil count >10 (P=0.024) and weight loss >10% (P=0.03) significantly contributed to the risk of early death. Of note, raised serum urea increased the risk of early death by 12-fold (odds ratio 11.8, 95% confidence interval=1.8-76.9). CONCLUSION: We have shown that pre-treatment raised serum urea is a significant predictor of early death. This readily available information will be useful for assessing SCLC patients at the bedside and discussing the risks of chemotherapy with them.

Effects of a maternal high-fat diet on offspring behavioral and metabolic parameters in a rodent model.

Maternal diet-induced obesity can cause detrimental developmental origins of health and disease in offspring. Perinatal exposure to a high-fat diet (HFD) can lead to later behavioral and metabolic disturbances, but it is not clear which behaviors and metabolic parameters are most vulnerable. To address this critical gap, biparental and monogamous oldfield mice (Peromyscus polionotus), which may better replicate most human societies, were used in the current study. About 2 weeks before breeding, adult females were placed on a control or HFD and maintained on the diets throughout gestation and lactation. F1 offspring were placed at weaning (30 days of age) on the control diet and spatial learning and memory, anxiety, exploratory, voluntary physical activity, and metabolic parameters were tested when they reached adulthood (90 days of age). Surprisingly, maternal HFD caused decreased latency in initial and reverse Barnes maze trials in male, but not female, offspring. Both male and female HFD-fed offspring showed increased anxiogenic behaviors, but decreased exploratory and voluntary physical activity. Moreover, HFD offspring demonstrated lower resting energy expenditure (EE) compared with controls. Accordingly, HFD offspring weighed more at adulthood than those from control fed dams, likely the result of reduced physical activity and EE. Current findings indicate a maternal HFD may increase obesity susceptibility in offspring due to prenatal programming resulting in reduced physical activity and EE later in life. Further work is needed to determine the underpinning neural and metabolic mechanisms by which a maternal HFD adversely affects neurobehavioral and metabolic pathways in offspring.

A comparison of the effects of 3'-methyl-4-dimethylaminoazobenzene, 2-methyl-4-dimethylaminoazobenzene, and 2-acetylaminofluorene on rat liver DNA stability and new synthesis.

The objective of the present study was to define early biochemical changes occuring in livers of rats that were fed various chemical carcinogens. Rats were subjected to partial hepatectomy and subsequently given multiple injections of radioactive thymidine to prelabel DNA in their liver. Following a 4-week recovery period the rats were placed on either basal diets or diets containing either 0.05% 3'-methyl-4-dimethylaminoazobenzene (3'-MeDAB), 0.028% 2-acetylaminofluorene, or 0.05% 2-methyl-4-dimethylaminoazobenzene for various periods. After 5 weeks 3'-MeDAB had caused a dose-dependent loss of prelabeled DNA demonstrating the cytotoxicity of this carcinogen. The comparatively noncarcinogenic 2-methyl-4-dimethylaminoazobenzene caused only a small loss of prelabeled DNA. In contrast, the hepatocarcinogen 2-acetylaminofluorene did not cause a loss of prelabeled DNA, demonstrating its low cytotoxicity. Autoradiography and histology revealed that the loss of prelabeled DNA in livers of rats fed 3'-MeDAB was largely due to parenchymal cell death. Experiments designed to separate liver regenerative hyperplasia from neoplastic hyperplasia revealed the presence of both an early and a delayed elevation of thymidine incorporation into liver DNA in rats fed 0.05% 3'-MeDAB. An "early" elevation of incorporation occurred during and shortly after 3'-MeDAB feeding, and a "delayed" elevation of incorporation occurred some weeks after the dye was discontinued. Autoradiography revealed that parenchymal cells were largely responsible for the increased incorporation. Feeding of 2-methyl-4-dimethylaminoazobenzene depressed thymidine incorproation. A direct comparison of the effects of isomolar levels of 3'-MeDAB and 2-acetylaminogluorene on hepatic hyperplasia indicated that both carcinogens caused comparable increases in thymidine incorporation, which returned to control levels upon feeding of carcinogen-free diet. The differences and similarities between the responses to the three compounds are discussed and considered with regard to initiation and promotion of hepatoma formation.

gamma-Glutamyl transpeptidase and alpha-fetoprotein expression during alpha-naphthylisothiocyanate-induced hepatotoxicity in rats.

Continuous feeding of alpha-naphthylisothiocyanate to young male Sprague-Dawley rats was shown to produce a concentration-dependent increase in the number of hepatic ductular cells and a concentration- and time-dependent elevation of serum and liver gamma-glutamyl transpeptidase and alpha-fetoprotein. In liver, the increased gamma-glutamyltranspeptidase and alpha-fetoprotein were predominantly confined to the proliferative ductular cell population. It is concluded that early stages of intoxication by the noncarcinogen alpha-naphthylisothiocyanate resemble early stages in induction of liver neoplasia by carcinogens that evoke ductular proliferation. Elevation of gamma-glutamyltranspeptidase and alpha-fetoprotein expression by an expanding ductular cell population characterizes both processes. However, the increase is rapidly reversed after alpha-naphthylisothiocyanate is discontinued, in contrast to the persistence that has been reported when acetylaminofluorene was administered.

Phenotypic diversity of gamma-glutamyltranspeptidase activity and protein secretion in hepatoma cell lines.

Characteristic and patterns of gamma-glutamyltranspeptidase (GGT) expression were studied in four rat and three human hepatoma cell lines. Phenotypic diversity of GGT expression was demonstrated by the following findings. (a) GGT specific activity increased rapidly in three of four rat lines during the first 72 hr after subculture. (b) GGT activity was detected in the fourth rat cell line only from 96 to 120 hr after subculture. (c) In late log or stationary cultures, each of the four rat lines assumed a unique and characteristic level of GGT specific activity. (d) The intracellular GGT distribution pattern was markedly varied in rat and human cell lines. (e) GGT activity was confined to isolated cell clusters in one human line in vitro and one rat line both in vivo and in vitro. And (f) there was poor correlation between GGT specific activity and several liver-associated and hepatoma-associated properties. In contrast to evidence of diversity in GGT expression, GGT was shown to be a nonsecreted protein in all four rat cell lines. The constitutive or autogenous nature of the GGT phenotype in rat hepatoma cells was demonstrated by the retention of the GGT-positive and GGT-negative phenotypes of two strains grown in mixed culture; the lack of change in GGT activity when cells were cultured on different substrata, in different media, or in media containing hormones (insulin, dexamethasone, triiodothyronine, or glucagon); and the assumption of nearly constant levels of GGT specific activity in late log or stationary cultures. The results suggest that GGT activity is expressed in hepatomas as a result of disturbed differentiation and that this expression is not necessarily linked to cell proliferation.

Application of quantitative stereology to the evaluation of enzyme-altered foci in rat liver.

The mathematical science of quantitative stereology has established relationships for the quantitation of elements in three-dimensional space from observations on two-dimensional planes. This report describes the utilization and importance of such mathematical relationships for the quantitative analysis of focal hepatic lesions in terms relative to the volume of the liver. Three examples are utilized to demonstrate the utility of such calculations in the three-dimensional quantitation of hepatic focal lesions. The first is that of a computer-simulated experiment based on defined hypothetical situations. The simulations demonstrate the applicability of the computations described in this report to the evaluation of two-dimensional data from typical animal experiments. The other two examples are taken from actual experiments and involve the transplantation of hepatic cell populations into the liver suitably prepared hosts and the quantitation of altered foci produced by initiation with diethylnitrosamine-partial hepatectomy followed by promotion with phenobarbital. The quantitation of altered foci by means of a two-dimensional analysis (simple enumeration of focal intersections/area of tissue section) is proportional to the quantitation of foci per volume of liver provided that the mean diameter of the foci for each treatment is sufficiently uniform, as exemplified in the text by the transplantation experiment. When such mean diameters are unequal as in the diethylnitrosamine-phenobarbital experiment described herein, quantitation from three-dimensional analysis gives significantly different results as compared with enumeration of focal intersections on two-dimensional areas. These studies clearly demonstrate that the frequency and size of foci intersections viewed on two-dimensional tissue sections do not necessarily reflect the number of size of foci in the three-dimensional tissue. Only by quantitating the number and size of the foci in relation to the three-dimensional volume of the tissue can one determine the validity of the proportionality of data from two-dimensional measurements to the total number of foci per volume of tissue. Such a conclusion has important implications for quantitative studies on hepatocarcinogenesis as well as for the enumeration of premalignant lesions which occur during the natural history of carcinogenesis in any solid tissue.

Feasibility of home delivery of pemetrexed in patients with advanced non-squamous non-small cell lung cancer.

OBJECTIVES: To evaluate the feasibility and adherence to home delivery (HD) of pemetrexed maintenance treatment in patients with advanced non-squamous non-small cell lung cancer (nsqNSCLC). MATERIALS AND METHODS: Exploratory, prospective, single-arm, Phase II study in advanced nsqNSCLC patients, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0/1 that did not progress after 4 first-line induction cycles of a platinum doublet. The first cycle of pemetrexed (500mg/m(2)) was hospital administered, further cycles were HD until progressive disease or discontinuation. Feasibility was assessed by the adherence rate to HD (probability of reversion to hospital administration or treatment discontinuation due to HD) as primary endpoint, and by health-related quality-of-life (HRQoL: EQ-5D, lung cancer symptom scale [LCSS]), satisfaction with HD, overall survival (OS), and safety. RESULTS: 52 patients (UK & Sweden) received a median of 4 (range 1-19) pemetrexed maintenance cycles. Adherence rate up to Cycle 6 was 98.0% (95% confidence interval [CI]: 86.4%, 99.7%). All but 2 patients remained on HD. 1 patient discontinued after Cycle 1 (patient decision), and 1 after Cycle 6 (non-compliance with oral dexamethasone). 87% (33/38) of the patients preferred home to hospital treatment and in 90% (28/31) of cases, physicians were satisfied with distant management of patients. During HD Cycles 2-4 mean change from baseline ranged from 3.0 to 7.7 for EQ-5D visual analog scale. The 6-month OS rate was 73% (95% CI: 58%, 83%). 1 patient had an HD-related adverse event (device-related infection, Grade 2) and 1 patient died after Cycle 1, before HD, due to a possibly drug-related atypical pneumonia. CONCLUSION: HD of pemetrexed maintenance treatment in patients with advanced nsqNSCLC was feasible, safe, and preferred by patients, while maintaining HRQoL. Physicians were satisfied with distant patient management.

Determinant capture by MHC class II DR3 during processing of mycobacteria leprae 65kD heat shock protein by human B cells.

Using T cell immunoblotting we have characterised the immunogenic fragments derived from the Mycobacteria Leprae 65kD heat shock protein that become associated with MHC class II DR3 during processing by a human B cell line. After 5 h incubation with antigen, a peptide of approximately 12kD (approximately 110 amino acids) was the only major fragment found associated with the class II MHC. The association of this oligopeptide was abolished if an excess of a synthetic peptide representing the minimal epitope was included in the culture or when cells were incubated at 4 degrees C. This suggests that the generation of this moiety is dependent on cell metabolism and that its binding to MHC is specific. This large fragment may represent an intermediate in the processing pathway, directly demonstrating the role of MHC in determinant capture during antigen degradation.

Alternative hypotheses for the role of promotion in chemical carcinogenesis.

A new protocol for carcinogenesis in rat liver is described in order that confirmatory experiments might be undertaken concurrently. The basic protocol, designated IPI (initiator + promoter + initiator), is presented in several alternative forms, including the possible use of X-irradiation as the initiator. The rationale is discussed in terms of the two-hit somatic mutation theory of Armitage and Doll, with an initial hit produced by the first dose of initiator and expansion of single cells to sizable clones by promotion thereby increasing the probability of a second hit by the second dose of initiator. The question of relevant mutations was taken up and it was proposed that genes for chalones (C) and for chalone receptors (R) are logical targets for consideration in a two-mutation sequence. Alternative hypotheses pertaining to promoter action were described in terms of possible mechanisms by which nonelectrophilic promoters might simulate a second mutation by increasing or decreasing the levels of a nonchromosomal replicating particle in target cells.