Gallbladder disease and pancreatic cancer risk: a multicentric case-control European study.

BACKGROUND AND AIMS: The overall evidence on the association between gallbladder conditions (GBC: gallstones and cholecystectomy) and pancreatic cancer (PC) is inconsistent. To our knowledge, no previous investigations considered the role of tumour characteristics on this association. Thus, we aimed to assess the association between self-reported GBC and PC risk, by focussing on timing to PC diagnosis and tumour features (stage, location, and resection). METHODS: Data derived from a European case-control study conducted between 2009 and 2014 including 1431 PC cases and 1090 controls. We used unconditional logistic regression models to estimate odds ratios (ORs) and corresponding 95% confidence intervals (CIs) adjusted for recognized confounders. RESULTS: Overall, 298 (20.8%) cases and 127 (11.6%) controls reported to have had GBC, corresponding to an OR of 1.70 (95% CI 1.33-2.16). The ORs were 4.84 (95% CI 2.96-7.89) for GBC diagnosed <3 years before PC and 1.06 (95% CI 0.79-1.41) for ≥3 years. The risk was slightly higher for stage I/II (OR = 1.71, 95% CI 1.15-2.55) vs. stage III/IV tumours (OR = 1.23, 95% CI 0.87-1.76); for tumours sited in the head of the pancreas (OR = 1.59, 95% CI 1.13-2.24) vs. tumours located at the body/tail (OR = 1.02, 95% CI 0.62-1.68); and for tumours surgically resected (OR = 1.69, 95% CI 1.14-2.51) vs. non-resected tumours (OR = 1.25, 95% CI 0.88-1.78). The corresponding ORs for GBC diagnosed ≥3 years prior PC were close to unity. CONCLUSION: Our study supports the association between GBC and PC. Given the time-risk pattern observed, however, this relationship may be non-causal and, partly or largely, due to diagnostic attention and/or reverse causation.

Burden of compensated and decompensated cirrhosis: real world data from an Italian population-based cohort study.

OBJECTIVE: To quantify the annual healthcare resource utilization, costs and mortality rate for a large cohort of Italian patients with compensated (CC) and decompensated cirrhosis (DC). PATIENTS AND METHODS: A population-based cohort study was conducted through the data-linkage of mortality for all-cause, hospitalizations and outpatient drugs and service databases of the Campania Region. All adults hospitalized with cirrhosis diagnosis (2007-2015) were grouped in CC and DC (prevalent patients) on January 1, 2016 and followed for 1-year. Incident patients with DC (2015) were also retrieved and followed from discharge date up to 1-year. Negative binomial regression was used to estimate Incidence Rate Ratios (IRRs) for predictors of all-cause hospitalizations. Costs were evaluated from the Italian National Health Service perspective and expressed in euro patient/year. RESULTS: A total of 21,433 prevalent cirrhotic patients (57.1% CC and 42.9% DC) and 1,371 incident patients with DC were identified. During a 1-year, 21.5% of prevalent patients with CC were admitted for acute events, 26.8% of those with DC and 55.4% of incident patients with DC. Ascites (IRR=1.71;95% CI: 1.37-2.14) and hepatic encephalopathy (IRR=1.35; 95% CI: 1.04-1.77) at index admission were strong predictors of hospitalizations in incident DC patients. The 1-year mortality rate was respectively 5.8% and 10.1% for prevalent patients with CC and DC and 35.6% for incident patients with DC. Direct costs amounted to 3,194€ patient/year for the prevalent CC group and 4,001€ patient/year for the DC group and 13,806 € patient/year for incident individuals with DC. CONCLUSIONS: The burden of cirrhosis dramatically differs between CC and DC patients, especially after the first decompensation episode. Ascites and hepatic encephalopathy at index admission were strong predictors of hospitalizations in incident DC patients.

A systems approach identifies time-dependent associations of multimorbidities with pancreatic cancer risk.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is usually diagnosed in late adulthood; therefore, many patients suffer or have suffered from other diseases. Identifying disease patterns associated with PDAC risk may enable a better characterization of high-risk patients. METHODS: Multimorbidity patterns (MPs) were assessed from 17 self-reported conditions using hierarchical clustering, principal component, and factor analyses in 1705 PDAC cases and 1084 controls from a European population. Their association with PDAC was evaluated using adjusted logistic regression models. Time since diagnosis of morbidities to PDAC diagnosis/recruitment was stratified into recent (<3 years) and long term (≥3 years). The MPs and PDAC genetic networks were explored with DisGeNET bioinformatics-tool which focuses on gene-diseases associations available in curated databases. RESULTS: Three MPs were observed: gastric (heartburn, acid regurgitation, Helicobacter pylori infection, and ulcer), metabolic syndrome (obesity, type-2 diabetes, hypercholesterolemia, and hypertension), and atopic (nasal allergies, skin allergies, and asthma). Strong associations with PDAC were observed for ≥2 recently diagnosed gastric conditions [odds ratio (OR), 6.13; 95% confidence interval CI 3.01-12.5)] and for ≥3 recently diagnosed metabolic syndrome conditions (OR, 1.61; 95% CI 1.11-2.35). Atopic conditions were negatively associated with PDAC (high adherence score OR for tertile III, 0.45; 95% CI, 0.36-0.55). Combining type-2 diabetes with gastric MP resulted in higher PDAC risk for recent (OR, 7.89; 95% CI 3.9-16.1) and long-term diagnosed conditions (OR, 1.86; 95% CI 1.29-2.67). A common genetic basis between MPs and PDAC was observed in the bioinformatics analysis. CONCLUSIONS: Specific multimorbidities aggregate and associate with PDAC in a time-dependent manner. A better characterization of a high-risk population for PDAC may help in the early diagnosis of this cancer. The common genetic basis between MP and PDAC points to a mechanistic link between these conditions.

Dietary acrylamide and the risk of pancreatic cancer in the International Pancreatic Cancer Case-Control Consortium (PanC4).

Background: Occupational exposure to acrylamide was associated with excess mortality from pancreatic cancer, though in the absence of dose-risk relationship. Few epidemiological studies have examined the association between acrylamide from diet and pancreatic cancer risk. Patients and methods: We considered this issue in a combined set of 1975 cases of pancreatic cancer and 4239 controls enrolled in six studies of the Pancreatic Cancer Case-Control Consortium (PanC4). We calculated pooled odds ratios (ORs) and their 95% confidence intervals (CI) by estimating study-specific ORs through multivariate unconditional logistic regression models and pooling the obtained estimates using random-effects models. Results: Compared with the lowest level of estimated dietary acrylamide intake, the pooled ORs were 0.97 (95% CI, 0.79-1.19) for the second, 0.91 (95% CI, 0.71-1.16) for the third, and 0.92 (95% CI, 0.66-1.28) for the fourth (highest) quartile of intake. For an increase of 10 µg/day of acrylamide intake, the pooled OR was 0.96 (95% CI, 0.87-1.06), with heterogeneity between estimates (I2 = 67%). Results were similar across various subgroups, and were confirmed when using a one-stage modelling approach. Conclusions: This PanC4 pooled-analysis found no association between dietary acrylamide and pancreatic cancer.

Pharmacotherapy of alcoholic liver disease in clinical practice.

AIMS: Alcohol is the most commonly used addictive substance and alcoholic liver disease (ALD) is a major cause of chronic liver disease worldwide, responsible for 47.9% of all liver chronic deaths. Despite ALD has a significant burden on the health, few therapeutic advances have been made in the last 40 years, particularly in the long-term management of these patients. METHODS: we searched in PubMed, Scopus, Google Scholar, and MEDLINE databases to identify relevant English language publications focused on long-term therapy of ALD. RESULTS: From the huge literature on this topic, including about 755 studies, 75 were selected as eligible including clinical trials and meta-analysis. CONCLUSIONS: Abstinence remains the cornerstone of ALD therapy but it is also the most difficult therapeutic target to achieve and the risk of recidivism is very high at any time. Several drugs (disulfiram, naltrexone, acamprosate, sodium oxybate) have proven to be effective to prevent alcohol relapse and increase the abstinence, although the psychotherapeutic support remains crucial. Baclofen seems to be effective to improve abstinence, showing an excellent safety and tolerability. ALD is often complicated by a state of malnutrition, which is related to a worst mortality. A nutritional therapy may improve survival in cirrhotic patients, reversing muscle wasting, weight loss and specific nutritional deficiencies. While in aggressive forms of alcoholic hepatitis are recommended specific drug treatments, including glucocorticoids or pentoxifylline, for the long-term treatment of ALD, specific treatments aimed at stopping the progression of fibrosis are not yet approved, but there are some future perspective in this field, including probiotics and antibiotics, caspase inhibitors, osteopontin and endocannabinoids.

Photocatalytic degradation of selected anticancer drugs and identification of their transformation products in water by liquid chromatography-high resolution mass spectrometry.

A study on the fate of two antineoplastic drugs, methotrexate and doxorubicin, in the aquatic environment is presented. The investigation involved a study of their decomposition under dark experiments, homogeneous photolysis and heterogeneous photocatalysis using titanium dioxide, the identification of intermediate compounds, as well as the assessment of acute toxicity over time. The analysis were carried out using LC (ESI positive mode) coupled with LTQ-Orbitrap analyser; accurate mass-to-charge ratios of parent ions were reported with inaccuracy below 10mmu, which guarantee the correct assignment of their molecular formula in all cases, while their MS(2) and MS(3) spectra showed several structural-diagnostic ions that allowed to characterize the different transformation products and to discriminate the isobaric species. Fourteen and eight main species were identified subsequently to doxorubicin or methotrexate transformation. The major transformation processes for doxorubicin involved (poli)hydroxylation and/or oxidation of the molecule, or the detachment of the sugar moiety. Methotrexate transformation involved decarboxylation or the molecule cleavage. Acute toxicity measurements showed that not only the two drugs exhibit high toxicity, but also their initial transformation products are highly toxic.

Diabetes, antidiabetic medications, and pancreatic cancer risk: an analysis from the International Pancreatic Cancer Case-Control Consortium.

BACKGROUND: Type 2 diabetes mellitus has been associated with an excess risk of pancreatic cancer, but the magnitude of the risk and the time-risk relationship are unclear, and there is limited information on the role of antidiabetic medications. PATIENTS AND METHODS: We analyzed individual-level data from 15 case-control studies within the Pancreatic Cancer Case-Control Consortium, including 8305 cases and 13 987 controls. Pooled odds ratios (ORs) were estimated from multiple logistic regression models, adjusted for relevant covariates. RESULTS: Overall, 1155 (15%) cases and 1087 (8%) controls reported a diagnosis of diabetes 2 or more years before cancer diagnosis (or interview, for controls), corresponding to an OR of 1.90 (95% confidence interval, CI, 1.72-2.09). Consistent risk estimates were observed across strata of selected covariates, including body mass index and tobacco smoking. Pancreatic cancer risk decreased with duration of diabetes, but a significant excess risk was still evident 20 or more years after diabetes diagnosis (OR 1.30, 95% CI 1.03-1.63). Among diabetics, long duration of oral antidiabetic use was associated with a decreased pancreatic cancer risk (OR 0.31, 95% CI 0.14-0.69, for ≥15 years). Conversely, insulin use was associated with a pancreatic cancer risk in the short term (OR 5.60, 95% CI 3.75-8.35, for <5 years), but not for longer duration of use (OR 0.95, 95% CI 0.53-1.70, for ≥15 years). CONCLUSION: This study provides the most definitive quantification to date of an excess risk of pancreatic cancer among diabetics. It also shows that a 30% excess risk persists for more than two decades after diabetes diagnosis, thus supporting a causal role of diabetes in pancreatic cancer. Oral antidiabetics may decrease the risk of pancreatic cancer, whereas insulin showed an inconsistent duration-risk relationship.

Dietary patterns and gastric cancer risk: a systematic review and meta-analysis.

BACKGROUND: Declines in gastric cancer (GC) incidence and mortality have been related to improvements in diet. It is therefore important to consider dietary patterns. DESIGN: We conducted a systematic review and meta-analysis of the literature through Medline and Embase databases. RESULTS: We identified 16 papers, of these 9 derived dietary patterns through an a posteriori method, 5 through a priori scores, and 2 used both approaches. Eight studies that used the a posteriori approach were considered for the meta-analysis. A favorable role on GC emerged for the 'Prudent/healthy', with an odds ratio (OR) of 0.75 [95% confidence interval (CI): 0.63-0.90], for the highest versus the lowest category. Similar results emerged for separate anatomical subtypes. An unfavorable role on GC emerged for the 'Western/unhealthy' dietary pattern, with an OR of 1.51 (95% CI: 1.21-1.89). This association was weaker for the distal/NOS (not otherwise specified) category (OR = 1.36) compared with the cardia GC (OR = 2.05). Among the a priori scores, the ORs ranged from 0.2 to 0.7 for the favorable and from 1.8 to 6.9 for the unfavorable ones. CONCLUSION: There is a ~2-fold difference in GC risk between a 'Prudent/healthy' diet-rich in fruits and vegetables, and a 'Western/unhealthy' diet-rich in starchy foods, meat and fats.

Aspirin and cancer risk: a quantitative review to 2011.

BACKGROUND: Aspirin has been associated to a reduced risk of colorectal and possibly of a few other common cancers. METHODS: To provide an up-to-date quantification of this association, we conducted a meta-analysis of all observational studies on aspirin and 12 selected cancer sites published up to September 2011. RESULTS: Regular aspirin is associated with a statistically significant reduced risk of colorectal cancer [summary relative risk (RR) from random effects models = 0.73, 95% confidence interval (CI) 0.67-0.79], and of other digestive tract cancers (RR = 0.61, 95% CI = 0.50-0.76, for squamous cell esophageal cancer; RR = 0.64, 95% CI = 0.52-0.78, for esophageal and gastric cardia adenocarcinoma; and RR = 0.67, 95% CI = 0.54-0.83, for gastric cancer), with somewhat stronger reductions in risk in case-control than in cohort studies. Modest inverse associations were also observed for breast (RR = 0.90, 95% CI = 0.85-0.95) and prostate cancer (RR = 0.90, 95% CI = 0.85-0.96), while lung cancer was significantly reduced in case-control studies (0.73, 95% CI = 0.55-0.98) but not in cohort ones (RR = 0.98, 95% CI = 0.92-1.05). No meaningful overall associations were observed for cancers of the pancreas, endometrium, ovary, bladder, and kidney. CONCLUSIONS: Observational studies indicate a beneficial role of aspirin on colorectal and other digestive tract cancers; modest risk reductions were also observed for breast and prostate cancer. Results are, however, heterogeneous across studies and dose-risk and duration-risk relationships are still unclear.

History of cholelithiasis and cancer risk in a network of case-control studies.

BACKGROUND: We analyzed the relationship between cholelithiasis and cancer risk in a network of case-control studies conducted in Italy and Switzerland in 1982-2009. METHODS: The analyses included 1997 oropharyngeal, 917 esophageal, 999 gastric, 23 small intestinal, 3726 colorectal, 684 liver, 688 pancreatic, 1240 laryngeal, 6447 breast, 1458 endometrial, 2002 ovarian, 1582 prostate, 1125 renal cell, 741 bladder cancers, and 21 284 controls. The odds ratios (ORs) were estimated by multiple logistic regression models. RESULTS: The ORs for subjects with history of cholelithiasis compared with those without were significantly elevated for small intestinal (OR=3.96), prostate (OR=1.36), and kidney cancers (OR=1.57). These positive associations were observed ≥10 years after diagnosis of cholelithiasis and were consistent across strata of age, sex, and body mass index. No relation was found with the other selected cancers. A meta-analysis including this and three other studies on the relation of cholelithiasis with small intestinal cancer gave a pooled relative risk of 2.35 [95% confidence interval (CI) 1.82-3.03]. CONCLUSION: In subjects with cholelithiasis, we showed an appreciably increased risk of small intestinal cancer and suggested a moderate increased risk of prostate and kidney cancers. We found no material association with the other cancers considered.

Metabolic syndrome and the risk of breast cancer in postmenopausal women.

BACKGROUND: Only a few small studies investigated the association between postmenopausal breast cancer and metabolic syndrome (MetS) as a single entity. MATERIALS AND METHODS: We analyzed the data of two Italian and Swiss case-control studies conducted between 1983 and 2007, including 3869 postmenopausal women with incident breast cancer and 4082 postmenopausal controls admitted to the same hospitals as cases for acute conditions. MetS was defined as the presence of at least three components among diabetes, drug-treated hypertension, drug-treated hyperlipidemia, and obesity. RESULTS: The odds ratios (ORs) of postmenopausal breast cancer were 1.33 [95% confidence interval (CI) 1.09-1.62] for diabetes, 1.19 (95% CI 1.07-1.33) for hypertension, 1.08 (95% CI 0.95-1.22) for hyperlipidemia, 1.26 (95% CI 1.11-1.44) for body mass index ≥30 kg/m(2), and 1.22 (95% CI 1.09-1.36) for waist circumference ≥88 cm. The risk of postmenopausal breast cancer was significantly increased for women with MetS (OR = 1.75, 95% CI 1.37-2.22, for three or more MetS components, P for trend for increasing number of components < 0.0001) and the risk was higher at older age (OR = 3.04, 95% CI 1.75-5.29, at age ≥70 years for three or more MetS components). CONCLUSIONS: This study supports a direct association between MetS and postmenopausal breast cancer risk.

Metabolic syndrome and endometrial cancer risk.

BACKGROUND: Various studies reported direct associations between endometrial cancer risk and individual components of the metabolic syndrome (MetS), i.e. obesity, diabetes, hypertension, and dyslipidemia, but only a few epidemiological studies considered the association with MetS overall. METHODS: We analyzed data from a case-control study including 454 women with incident endometrial cancer and 798 controls admitted to the same hospitals as cases for acute conditions. Different definitions of MetS were considered, including a combination of self-reported history of diabetes, drug-treated hypertension, drug-treated hyperlipidemia, and various measures of (central) obesity. Odds ratios (ORs) were computed from unconditional logistic regression models, adjusted for major confounding factors. RESULTS: The multivariate ORs of endometrial cancer were 2.18 for type 2 diabetes, 1.77 for hypertension, 1.20 for hyperlipidemia, between 1.62 and 2.23 for various definitions of central obesity, and 3.83 for women with a body mass index (BMI) >30 kg/m(2). The risk of endometrial cancer was significantly increased for subjects with MetS, the ORs ranging between 1.67 and 2.77 when waist circumference was included in MetS definition, and 8.40 when BMI was considered instead. CONCLUSIONS: This study indicates a direct association between various MetS components, besides overweight, with the risk of endometrial cancer.

Understanding structural/functional properties of immunoconjugates for cancer therapy by computational approaches.

Monoclonal antibodies coupled to highly toxic molecules (immunoconjugates) are currently being developed for cancer therapy. We have used an in silico procedure for evaluating some physicochemical properties of two tumor-targeting anti-HER2 immunoconjugates: (a) the single-chain antibody scFv(FRP5) linked to a bacterial toxin, that has been recently progressed to phase I clinical trial in human cancer; (b) the putative molecule formed by the intrinsically stable scFv(800E6), which has been proposed as toxin carrier to cancer cells in human therapy, joined to the same toxin of (a). Structural models of the immunoconjugates have been built by homology modeling and assessed by molecular dynamics simulations. The trajectories have been analyzed to extract some biochemical properties and to assess the potential effects of the toxin on the structure and dynamics of the anti-HER2 antibodies. The results of the computational approach indicate that the antibodies maintain their correct folding even in presence of the toxin, whereas a certain stiffness in correspondence of some structural regions is observed. Furthermore, the toxin does not seem to affect the antibody solubility, whereas it enhances the structural stability. The proposed computational approach represent a promising tool for analyzing some physicochemical properties of immunoconjugates and for predicting the effects of the linked toxin on structure, dynamics, and functionality of the antibodies.

IMAGE: a new tool for the prediction of transcription factor binding sites.

IMAGE is an application tool, based on the vector quantization method, aiding the discovery of nucleotidic sequences corresponding to Transcription Factor binding sites. Starting from the knowledge of regulation regions of a number of co-expressed genes, the software is able to predict the occurrence of specific motifs of different lengths (starting from 6 base pairs) with a defined number of punctual mutations.

A fine functional homology between chitinases from host and parasite is relevant for malaria transmissibility.

High levels of plasma chitotriosidase are a marker of macrophage activation in several pathologies and, in particular, in human malaria. Plasmodium falciparum, during its maturative cycle in the midgut of the Anopheles mosquito, secretes a chitinase to disrupt the peritrophic membrane, a necessary step in the migration of the parasite from the midgut to the salivary glands of malaria's vector. The cooperation between human chitotriosidase (Chit) and the chitinase from P. falciparum in attacking the peritrophic membranes in the Anopheles midgut has been recently demonstrated by in vivo experiments. The present study confirms, by computational methods, this functional homology. A simple sequence analysis method, potentially useful to assess fine textual closeness in families of homologous proteins, is reported here and applied to a set of chitinases from mammals and plasmodia. This analysis confirms the clustering and the phylogenetic relationships obtained with well-known alignment methods, but also shows that the sequences of chitinases from malaria hosts and malaria parasites are correlated. This correlation, a sign of functional homology, is discussed as a condition for the spreading of different forms of malaria. From this perspective, one can get insight into the origins of malaria and its genetic or pharmacological control.

[Laparoscopic surgery: from clinic to legal medicine]. / Chirurgia Laparoscopica: dalla clinica alla medicina legale.

The laparoscopic technique introduced a new way of operating but inevitably causing new problems for the surgeon. After a comprehensive review of the history and the evolution of laparoscopic surgery from its beginning, the technical aspects of minimally invasive surgery and its fields of application are described. The close dependence on instruments and technology is emphasized. A detailed analysis of the advantages and limitations of laparoscopy is made with emphasis on the importance of a risk-benefit evaluation by the health care provider. Of key importance is to obtain a detailed and clear informed consent. The medico legal aspects of intraoperative complications and the liability of the surgical team in case of patients' injury or death are examined. However, it is always necessary to consider if the potential complications are predictable and/or preventable in accordance to the parameters of negligence, imprudence and lack of knowledge. The same criteria have to be applied to assure compliance with the preventive sanitary rules and that the conversion to laparotomy has been promptly carried out.

Evaluation of communicative and functional abilities in Wolf-Hirshhorn syndrome.

BACKGROUND: Wolf-Hirschhorn syndrome (WHS) is a genetic condition characterized by many clinical disorders, learning difficulties, dysphagia, neuromotor deficits and communicative deficits. Up until now, no studies in the literature have described the development of communicative and functional abilities in subjects with WHS. METHOD: In the present study of 11 patients with WHS, a descriptive analysis was made of several abilities and three groups of patients were identified on the basis of the severity of their functional deficit. RESULTS: A non-homogeneous picture of impairment emerged in various areas of development. Overall, the neuromotor abilities of these patients were more adequate than their abilities related to autonomy in personal life, alimentary function, and cognitive and communicative-linguistic aspects. CONCLUSION: Based on the identification of specific patterns of communicative and functional impairment in subjects with WHS, rehabilitative intervention strategies can be planned to increase their communicative opportunities, and possibilities for active and autonomous participation in various life contexts (e.g. home, school and the social environment).

Expression of growth factor receptors in unilineage differentiation culture of purified hematopoietic progenitors.

We have evaluated the expression of growth factor receptors (GFRs) on early hematopoietic progenitor cells (HPCs) purified from human adult peripheral blood and induced in liquid suspension culture to unilineage differentiation/maturation through the erythroid (E), granulocytic (G), megakaryocytic (Mk), or monocytic (Mo) lineage. The receptors for basic fibroblast GF (bFGF), erythropoietin (Epo), thrombopoietin (Tpo), and macrophage colony-stimulating factor (MCSF) have been only assayed at mRNA level; the majority of GFRs have been evaluated by both mRNA and protein analyses: the expression patterns were consistent at both levels. In quiescent HPCs the receptors for early-acting [flt3 ligand (FL), c-kit ligand (KL), bFGF, interleukin-6 (IL-6)] and multilineage [IL-3, granulocyte-macrophage CSF (GM-CSF)] HGFs are expressed at significant levels but with different patterns, eg, kit and flt3 are detected on a majority and minority of HPCs, respectively, whereas IL-3Rs and GM-CSFRs are present on almost all HPCs. In the four differentiation pathways, expression of early-acting receptors shows a progressive decrease, more rapidly for bFGFR-1 and flt3 than for c-kit; furthermore, c-kit is more slowly downmodulated in the E and Mk than the G and Mo lineages. As a partial exception, IL-6Rs are still detected through the early or late stages of maturation in the Mk and Mo lineages, respectively. IL-3R expression is progressively and rapidly downmodulated in both E and Mk pathways, whereas it moderately decreases in the Mo lineage and is sustained in the G series. The expression of GM-CSFR is gradually downmodulated in all differentiation pathways, ie, the receptor density markedly decreases but late erythroblasts are still partially GM-CSFR+ and terminal G, Mk and Mo cells are essentially GM-CSFR+. Expression of receptors for late-acting cytokines is lineage-specific. Thus, EpoR, G-CSFR, TpoR, and M-CSFR exhibit a gradual induction followed by a sustained expression in the E, G, MK, and Mo lineages, respectively. In the other differentiation pathways the expression of these receptors is either absent or initially low and there-after suppressed. These observations are compatible with the following multi-step model. (1) The early-acting GFRs are expressed on quiescent HPCs with different patterns, whereas the multilineage GFRs are present on > or = 90% to 95% HPCs. (2) Multilineage GFs, potentiated by early-acting HGFs, trigger HPCs into cycling. HPC proliferation/differentiation is followed by declining expression of the early-acting GFRs and in part of multilineage GFRs (see above). (3) Multilineage GFs trigger the expression of the unilineage GFRs (see Testa U, et al: Blood 81:1442, 1993). Interaction of each unilineage GF with its receptor leads to sustained expression of the receptor (possibly via transcription factors activating the receptor promoter) and thus mediates differentiation/maturation through the pertinent lineage.