Sarcopenia and cachexia: the adaptations of negative regulators of skeletal muscle mass

Recent advances in our understanding of the biology of muscle, and how anabolic and catabolic stimuli interact to control muscle mass and function, have led to new interest in the pharmacological treatment of muscle wasting. Loss of muscle occurs as a consequence of several chronic diseases (cachexia) as well as normal aging (sarcopenia). Although many negative regulators [Atrogin-1, muscle ring finger-1, nuclear factor-kappaB (NF-κB), myostatin, etc.] have been proposed to enhance protein degradation during both sarcopenia and cachexia, the adaptation of mediators markedly differs among these conditions. Sarcopenic and cachectic muscles have been demonstrated to be abundant in myostatin- and apoptosis-linked molecules. The ubiquitin–proteasome system (UPS) is activated during many different types of cachexia (cancer cachexia, cardiac heart failure, chronic obstructive pulmonary disease), but not many mediators of the UPS change during sarcopenia. NF-κB signaling is activated in cachectic, but not in sarcopenic, muscle. Some studies have indicated a change of autophagic signaling during both sarcopenia and cachexia, but the adaptation remains to be elucidated. This review provides an overview of the adaptive changes in negative regulators of muscle mass in both sarcopenia and cachexia

Effects of hospital facilities on patient outcomes after cancer surgery: an international, prospective, observational study

Background Early death after cancer surgery is higher in low-income and middle-income countries (LMICs) compared with in high-income countries, yet the impact of facility characteristics on early postoperative outcomes is unknown. The aim of this study was to examine the association between hospital infrastructure, resource availability, and processes on early outcomes after cancer surgery worldwide.Methods A multimethods analysis was performed as part of the GlobalSurg 3 study-a multicentre, international, prospective cohort study of patients who had surgery for breast, colorectal, or gastric cancer. The primary outcomes were 30-day mortality and 30-day major complication rates. Potentially beneficial hospital facilities were identified by variable selection to select those associated with 30-day mortality. Adjusted outcomes were determined using generalised estimating equations to account for patient characteristics and country-income group, with population stratification by hospital.Findings Between April 1, 2018, and April 23, 2019, facility-level data were collected for 9685 patients across 238 hospitals in 66 countries (91 hospitals in 20 high-income countries; 57 hospitals in 19 upper-middle-income countries; and 90 hospitals in 27 low-income to lower-middle-income countries). The availability of five hospital facilities was inversely associated with mortality: ultrasound, CT scanner, critical care unit, opioid analgesia, and oncologist. After adjustment for case-mix and country income group, hospitals with three or fewer of these facilities (62 hospitals, 1294 patients) had higher mortality compared with those with four or five (adjusted odds ratio [OR] 3.85 [95% CI 2.58-5.75]; p<0.0001), with excess mortality predominantly explained by a limited capacity to rescue following the development of major complications (63.0% vs 82.7%; OR 0.35 [0.23-0.53]; p<0.0001). Across LMICs, improvements in hospital facilities would prevent one to three deaths for every 100 patients undergoing surgery for cancer.Interpretation Hospitals with higher levels of infrastructure and resources have better outcomes after cancer surgery, independent of country income. Without urgent strengthening of hospital infrastructure and resources, the reductions in cancer-associated mortality associated with improved access will not be realised

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Enhancements in ElectroKinetic Remediation Technology: Environmental assessment in comparison with other configurations and consolidated solutions

The extraction of contaminants from an earthy matrix using the ElectroKinetic Remediation Technology (EKRT) requires suitable electric fields to be applied through the soil. In some cases, the further addition of appropriate chemicals helps the dissolution and thus the removal of the pollutants. EKRT has the potential to achieve results similar to other on-site and/or off-site interventions, but with substantially higher levels of acceptability, thus representing a very interesting approach in dealing with contamination by heavy metals. However, due to the use of consumable materials and basically high energy consumption, this technology can heavily impact on the environment, if non appropriately configured. In this study, the electrokinetic approach for the remediation of a multi-metal contaminated real site in terms of environmental assessment has been investigated by using the GaBi LCA software, to demonstrate that, in spite of expectation, a suitable system configuration can make this technology an excellent choice also in terms of environmental sustainability. The environmental assessment was conducted in terms of Global Warming Potential (GWP-100. years): the proposed technology has been compared with a different EKRT configuration taken from the literature, and the environmental impact evaluated against that of a conventional treatment, i.e. the excavation and disposal of contaminated soil in landfill. Despite the different configuration, the results show the advantages of the EKRT and in particular, how the specific improvements introduced are effective for reducing the ecological footprint. Moreover, having decreased the impacts related to the installation of the system above all, its simple coupling with alternative solutions for the production of energy could further increase the advantages of the approach, bringing the intervention to very high levels of environmental sustainability

EVOLUZIONE RECENTE, REGIME, ASSETTI, CRITICITÀ, TENDENZA DEL SISTEMA SPIAGGIA DI PORTO LISCIA

L’assetto morfosedimentario dell’areale costiero tra Porto Pozzo e Porto Puddu risulta fortemente legato all’assetto passato ed attuale del Fiume Liscia ed alle interazioni tra la posizione della foce ed il livello medio mare del Quaternario (Bua, 2008; Tocco, 2008; DeMuro e Pusceddu, 2010a; Bartole e DeMuro, 2009, 2011, 2012; DeMuro e Bartole, 2010). Il Fiume Liscia è uno dei maggiori corsi d’acqua della Sardegna settentrionale, nasce nel massiccio del Limbara (1.359m) e sfocia nell’omonima spiaggia dopo un percorso di 64Km (Fadda e Pala, 1992). Il bacino ha un’estensione di 562Kmq, si sviluppa con un prevalente orientamento S-N ed è quasi totalmente impostato su rocce granitiche, escludendo la parte centrale del bacino in cui affiorano rocce scistose appartenenti al complesso metamorfico paleozoico. Lungo il corso del Liscia, nella parte iniziale del suo percorso ed in quella finale, si possono incontrare tutta una serie di morfologie tipiche degli affioramenti granitici (serre, tor, inselberg e tafoni). Per una migliore descrizione il bacino può essere suddiviso in due porzioni: - La prima, altimetricamente più elevata, compresa tra la sua origine e la confluenza con il Riu Badu Pitrosu (Riu Platu), ha una superficie di 268,4Kmq. In quest’area il reticolo idrografico si presenta complesso e cambia configurazione da pinnato a dendritico fino a sub-dendritico. - La seconda, dal Riu Badu Pitrosu alla foce, ha una superficie di 156,8Kmq. In questa parte del bacino il corso del fiume è stato sbarrato da una diga alta 69m, che forma un invaso di 104 milioni di mc, posto a 180m sul livello del mare (località Calamaiu – Comune di Luras), impostato sugli affioramenti scistosi. L’invaso è stato realizzato tra il 1958 e il 1962 ed è stato portato a massimo regime solo nel 2005. Il fiume, a valle dello sbarramento, incontra il suo maggior affluente (il Riu Bassacutena), il corso d’acqua poi prosegue in direzione S-N fino alla foce sulla spiaggia di Porto Liscia, dove forma una vasta area umida e un delta sottomarino (DeMuro et alii, 2000a,b,c,d; Ministero dell’Ambiente e della Tutela del Territorio, 2002; Pusceddu, 2003; DeMuro et alii, 2003; DeMuro, 2004; DeMuro et alii, 2004; DeMuro et alii, 2007; Pusceddu, 2009; DeMuro et alii, 2011a,b)

2002; 09.def

© F e r r a t a S t o r t i F o u n d a t i o n Indications CML in chronic phase To date the major experience with use of imatinib has been gained in patients classified as intolerant of or refractory to interferon-α. Both in our series of 145 patients and the multinational phase II trial with 454 patients 3,5 the incidence of complete hematologic remission exceeds 95% and about 30% of these patients achieve CCR after 9-12 months of imatinib therapy but there are as yet no long-term survival data. Experience with the use of imatinib in previously untreated patients is still limited but it appears that the incidence of CCR at 6 months will be of the order of 50-60%. CML in blastic phase At present the clinical value of imatinib for patients with advanced phase disease (accelerated phase or blastic transformation) is still not clear. Many patients treated in blast crisis will achieve a short-lived hematologic remission and some cytogenetic remissions have been seen. CML in accelerated phase The responses of patients in accelerated phase to imatinib vary according to the definition of acceleration © F e r r a t a S t o r t i F o u n d a t i o n Relapse after allogeneic SCT The majority of patients in early relapse and 50% of patients in hematologic relapse after allogeneic SCT achieve a sustained molecular remission with donor lymphocyte infusions (DLI). A number of groups have now used imatinib in the management of patients relapsing after allogeneic SCT. Kantarjian criteria (Kantarjian et al.) • Blasts plus promyelocytes in peripheral blood or bone marrow <30% • Basophils in peripheral blood or bone marrow <20% • Platelet count >100 × 10 9 /L Accelerated phase (one of the following) • 15-29% blasts in peripheral blood or bone marrow • >30% blasts plus promyelocytes in peripheral blood or bone marrow • >20% basophils in peripheral blood or bone marrow • Platelets < 100 × 10 9 /L unrelated to therapy Blastic phase (one of the following) • Blasts in peripheral blood or bone marrow ≥30% • Presence of extramedullary blastic disease 2. WHO criteria (Jaffe et al.) © F e r r a t a S t o r t i F o u n d a t i o n Some of these patients received imatinib relatively soon after DLI and responses could have been the result of the DLI. In our standard practice, imatinib is used as a second-line therapy for relapse. Pharmacokinetics and drug interactions Imatinib has very good oral absorption -its oral bioavailability is close to 100% and absorption is not impaired by food. Major inhibitors include erythromycin and ketoconazole. Grapefruit juice is also an inhibitor and excessive intake should be avoided. Patients on warfarin have demonstrated both increases and decreases in INR, so it is advisable to use low molecular weight heparin in place of warfarin for patients requiring anticoagulation. Switching a patient from hydroxyurea or interferon α to imatinib Patients whose counts were well controlled on interferon α do not normally experience problems when the interferon is discontinued abruptly in order to start treatment with imatinib. For patients receiving hydroxyurea it was at one time our practice to stop the drug abruptly when starting imatinib, but on occasion this resulted in dramatic increases in leukocyte and/or platelet counts. Thus we now routinely taper the dosage of hydroxyurea over a few weeks after starting imatinib if the patient's hydroxyurea dosage was 1.5 g per day or more or if the leukocyte count was not well controlled; for patients on lower doses of hydroxyurea, abrupt discontinuation may be reasonable. Imatinib may take 6 weeks or longer to control the platelet count. If, at the time of starting treatment with imatinib, the platelet count is raised, the count may rise very rapidly if hydroxyurea is withdrawn abruptly; in such cases gradual withdrawal of hydroxyurea or short-term use of anagrelide may be advisable. One possible schedule is to combine imatinib 400 mg daily with anagrelide 2 mg daily and to reduce the anagrelide by 0.5 mg decrements every one or two weeks. If the patient was previously receiving a combination of two drugs (e.g. hydroxyurea and anagrelide or hydroxyurea and interferon-α) we usually replace one drug and then taper the other according to blood counts. For example, if the combination was hydroxyurea and anagrelide it may be preferable to substitute imatinib for hydroxyurea while temporarily continuing the anagrelide at full dosage. We usually administer allopurinol until the white cell count is consistently in the normal range. Although only rare cases of tumor lysis syndrome have been reported thus far in advanced phase patients, 4 patients should ideally be monitored closely for this complication and advised to increase their fluid intake when treatment is started. We currently perform a full blood cell count and tests of renal and liver chemistry weekly for the first 4 weeks, then every 2-3 weeks for the next 3 months and every 4-8 weeks thereafter. Some 10-20% of patients will experience temporary cytopenias within the first few weeks of treatment with imatinib. This is probably more common in patients who have been treated previously with interferon-α but has also been observed in newly diagnosed patients. The dose of imatinib can be adjusted as described below and the majority of these patients will stabilize within 12 weeks of starting treatment. The remaining patients will tolerate imatinib without hematologic problems. Most patients are actually very stable on imatinib; once a patient is stable on a given dose, he/she seldom needs any dose adjustment. Thus, a change in blood counts may indicate disease progression or a new pharmacological interaction. Imatinib dosage Imatinib is used at standard doses of 400 mg/day for patients in chronic phase and 600 mg/day for patients in accelerated phase and blastic transformation. There is no relationship between the body mass and response rates or the incidence of side effects Dose adjustment is often necessary due to sideeffects (see below). When serious non-hematologic adverse events develop, it is usually necessary to stop imatinib until the toxicity resolves and if more than 2 weeks have elapsed, re-start at a lower dose. Corticosteroid cover (0.5 to 1.0 mg/kg/day) may be useful to prevent recurrence of allergic reactions or to treat recurrent hepatotoxicity. Hematologic and cytogenetic responses have been observed in patients taking 200 or 300 mg/day but are less frequent at the 300 mg dosage and rare at 200 mg daily Monitoring the response to therapy with imatinib For patients in chronic phase, cytogenetic responses can occur within 3 months of starting therapy. We recommend bone marrow assessment with metaphase cytogenetics (± fluorescence in situ hybridization) every 3 months for the first year and six-monthly thereafter. Patients in major cytogenetic remission should be monitored by real-time reverse transcriptase polymerase chain reaction (RT-PCR) for the presence of BCR-ABL transcripts. Ideally blood samples should be tested by PCR at -3 monthly intervals. It is important to continue to perform conventional cytogenetics at regular intervals since this is the only method able to detect additional chromosomal abnormalities. These can occur in both Ph-positive and Ph-negative cells. 28 STI571 in CML: practical considerations © F e r r a t a S t o r t i F o u n d a t i o n For patients in advanced phase we assess the morphology of the bone marrow after treatment for 4-6 weeks and 3 monthly thereafter. In most cases cytogenetic responses are infrequent or transient. Hematologic remissions in blastic transformation are short-lived (median duration 8-12 weeks), so alternative strategies should be provided. Side effects -Myelosuppression Grade III-IV neutropenia (neutrophils < 1 Anemia Our policy for managing anemia (hemoglobin < 10.0 g/dL) is not to adjust the dose of imatinib but rather to transfuse the patient when required. This approach is in part inherited from the design of the phase II trials. It is not based on solid clinical data but rather on the analogous considerations that apply to the management of neutropenia and thrombocytopenia. We have not explored the possibility of treating anemia with erythropoietin. Neutropenia and thrombocytopenia There are some general points that may apply to the neutropenia and thrombocytopenia that occur during treatment with imatinib. Myelosuppression may be an indicator of therapeutic benefit. This is true particularly in advanced phase patients with little or no residual normal hematopoiesis. In this case therapy with imatinib should not be interrupted. Our data suggest that patients who receive imatinib as treatment for chronic phase disease on account of intolerance of or refractoriness to interferon-α and who then experience significant degrees of neutropenia or thrombocytopenia may obtain less benefit from the drug than those whose blood counts are maintained during therapy. Moreover, in our series, 29,30 patients in chronic phase in whom imatinib has been interrupted or reduced on account of myelosuppression are significantly less likely to achieve cytogenetic responses and have a higher risk of progression to advanced phase than those whose treatment has not had to be interrupted The management of the myelosuppression is difficult and must be tailored to the individual circumstances of each patient. General principles are suggested below. Chronic phase patients. Our current policy is to interrupt imatinib at the first episode of grade III-IV neutropenia and/or thrombocytopenia. Treatment can be resumed once the absolute neutrophil count (ANC) has risen above 1×10 9 /L and/or the platelet count has risen above 100×10 9 /L. If the blood count fails to recover within two weeks, we reintroduce imatinib at the lower dosage of 300 mg daily and attempt to increase the dose thereafter if the blood count permits. With this approach in a considerable proportion of patients the neutropenia or thrombocytopenia does not recur. If, however, the neutropenia does recur we add granulocyte colony-stimulating factor (G-CSF) (e.g. 5 mg/kg 2 to 5 times per week) adjusting the G-CSF dosage to keep the ANC above 1×10 9 /L. In the majority of patients in whom we have used this approach it has been possible to reduce the frequency of G-CSF or discontinue it after a few months of therapy. Some of these patients have then achieved cytogenetic remissions. Accelerated phase. For patients in accelerated phase it is more difficult to give general advice. Cytopenic episodes may be handled depending on the estimated risk of disease progression. Patients thought to have a high risk of progression should be managed as blastic phase patients. However, for patients in less aggressive accelerated phase, a more conservative approach akin to that used in chronic phase may be appropriate. These considerations may need to be revised after 3-4 months of imatinib therapy since, in our hands, patients who continue to have more than 5% blasts in the bone marrow are at high risk for progression to blastic transformation. Blastic phase patients. When treating these patients with imatinib we recommend support with red cell and platelet transfusions and G-CSF. Imatinib should continue at a minimum dose of 600 mg/day for 4-6 weeks in order to assess the response. Hematologic remissions usually occur without peripheral blood recovery. Once an optimal response has been obtained, we try to introduce conventional combination chemotherapy or SCT since we know that the benefit of imatinib will not usually be maintained. Side effects other than myelosuppression Nausea Nausea due to the local irritant properties of imatinib occurs in about 70% of patients and is the single commonest side effect. It is usually mild and self-limited and can be prevented in many cases by taking imatinib with food. The pharmacokinetics do not differ whether imatinib is taken with food or when fasting. Edema and fluid retention Peripheral edema occurs in about 60% of patients. It is clearly dose-related but often limited to facial and periorbital regions. Most patients will have significant weight gain. Only 1% of the patients may have more generalized fluid retention including pulmonary edema, pleural or pericardial effusions, ascites or anasarca. Generally the fluid retention does not necessitate cessation of therapy and the addition of a mild diuretic is enough to control it. Muscle cramps Muscle cramps are also common. We try to maintain a good fluid intake. Oral administration of calcium and/or magnesium supplements (magnesium glycerophosphate 4 to 8 mM tds and calcium carbonate 500 mg tds) can sometimes relieve these cramps even when the patient's Ca 2+ and Mg 2+ serum levels are normal. This scheme is completely empirical and other schemes may be equally valid. Treatment with quinine sulphate may be useful in some cases. The cause of this problem is unknown and the response to the treatment mentioned above is very variable. Bone pain and arthralgias Bone pain and/or arthralgias may occur in up to 30% of patients and are more common in patients with a previous history of arthritis. Normally the patients respond well to non-steroidal anti-inflammatory drugs such as ibuprofen or diclofenac, but some cases require the addition of morphine or tramadol. In some cases the pain due to imatinib may be mistaken for pain due to progression of leukemia. The intensity of the pain declines with time and with discontinuation of imatinib. Skin rashes Allergic type skin rashes occur in about 30% of patients and usually appear soon after commencing imatinib therapy, but may develop many months later. The typical rash is maculopapular and pruritic and is distributed most prominently over the forearms, trunk, legs and face. It is rarely responsive to antihistamines. Mild cases will need no action but in severe cases our policy is to discontinue the drug, wait until the rash has resolved and then restart imatinib at 50-100 mg/day. Most of these patients will need the addition of prednisolone 0.5-1 mg/kg/day for several weeks and we usually start corticosteroids a few days before reintroducing the imatinib. Once the full dose of imatinib has been achieved, the steroid may be tapered. Hepatotoxicity Grade II-IV liver toxicity has been reported in 2% of the patients. It typically presents as mild hepatitis, but a cholestatic pattern can also be seen. Imatinib should be discontinued until the liver toxicity has resolved and then reintroduced at lower doses with the addition of prednisolone 0.5-1 mg/kg. A full dose of 600 mg/day may be difficult to achieve. Initial reports suggested an increase in hepatotoxicity of imatinib in combination with paracetamol. There is no evidence to support this at present. Although we do not avoid the use of paracetamol, some caution may be needed with prolonged and high doses. Other less frequent side effects Other non-hematologic side-effects reported in patients receiving imatinib include fatigue, weakness, dizziness, insomnia, dyspepsia, pyrexia, abdominal pain, cough, anorexia, constipation, diarrhea, nasopharyngitis, night sweats and hypokaliemia. Definitions of response and subsequent management Although about 30% of patients in chronic phase who were resistant to or intolerant of interferon α and 60% of the newly diagnosed patients have achieved a CCR, 10% of these patients who achieved CCR in chronic phase may have lost their response in 3-6 months. © F e r r a t a S t o r t i F o u n d a t i o n at other institutions, we have rarely observed CCR in patients in advanced phase. Despite the lack of long-term survival data, we currently recommend that patients in complete cytogenetic remission continue on the same dose of imatinib indefinitely. These patients should be monitored using quantitative RT-PCR. For patients who have not achieved CCR at 3 to 6 months after starting treatment with imatinib, we usually increase the dose to 600 mg daily if there is no obvious contraindication. Peripheral blood stem cell collection In patients who might be candidates for autografting, we collect peripheral blood stem cells (PBSC) as early as possible after they achieve CCR. Our current mobilization regimen consists of G-CSF 10 mg/kg for six consecutive days. We collect PBSC from day 5 onwards. The target is to collect 2×10 6 CD34 + cells/kg. Imatinib is not discontinued or reduced throughout the procedure. With this strategy we have managed to harvest enough cells from as many as 50% of these patients. Definitions of non-response and subsequent management Definition of non-response All chronic phase patients should have normal or low counts with no left shift within 12 weeks of starting treatment. Normally this is achieved in 6 weeks. The bone marrow examination performed at 3 months should show a normo-or hypocellular marrow with less than 5% blasts and no left shift. In many cases there is hyperplasia and dysplasia of the erythroid and megakaryocytic series. The reticulin fibrosis may need more time to normalize. Escalating the dose of imatinib There are no good data to support the value of increasing the dose of imatinib if a patient does not respond properly to standard doses. In our hands, increasing the dose of imatinib doers not usually improve the response and in many cases only adds toxicity. There are exceptions to this rule. In some cases in which a patient has achieved good hematologic control but has failed to achieve or has lost a cytogenetic response, dose escalation may on Patients who achieved at least minor cytogenetic response at 3 months and did not have neutropenia (<1×10 9 /L) between days 45 and 90 (n=38). B. Patients who did not achieve minor cytogenetic response at 3 months but did not suffer neutropenia, or patients who achieved minor cytogenetic response but had neutropenia (n=53). C. Patients who suffered neutropenia and did not achieve minor cytogenetic response at 3 months or patients who still were in chronic phase, but without hematologic control (ie WBC >13×10 9 /L) (n=33). occasion increase the degree of Ph-negativity. The maximal recommended dose is 800 mg/day which should be taken as 400 mg bd. We do not believe that increasing the dose of imatinib is appropriate in cases of disease progression. © F e r r a t a S t o r t i F o u n d a t i o n Therapeutic options It is not yet clear how to manage patients who are imatinib failures. In many circumstances the failure to respond to imatinib implies disease progression and this is true particularly when a patient fails to achieve or loses a hematologic response. In some cases an apparent failure of response may be reversed by use of hematologic growth factors (see above). We are currently exploring the capacity of autologous stem cell transplantation in combination with imatinib as a method of reversing the lack of response. 33 This has been shown for interferon resistance. Final considerations Clinical trials with imatinib have shown remarkable, although preliminary results. Despite almost 4 years' experience with imatinib there is still much to be learned regarding the best way to use this promising new agent. The story bears a striking resemblance to that of the introduction of all trans retinoic acid (ATRA) used for treating acute promyelocytic leukemia (APL). It has not been until very recently, several years after the original clinical trials, that a rational approach to using ATRA in combination with chemotherapy (mainly anthracyclines) has been established. However, the extraordinary improvement in the outcome of APL induced by ATRA should serve as an incentive for clinicians involved in the management of CML. This paper attempts to summarize the current experience with the use of imatinib but will doubtless need to be revised when we and others become more familiar with the drug's use. The ultimate objective must be to prolong the patient's survival and to this end the goal of imatinib therapy (in combination with other agents) must be the achievement of sustained RT-PCR negativity. Perhaps the combination of several therapeutic strategies (protein inhibition with imatinib, immunomodulation with interferon α and chemo-reduction with autologous SCT) either concomitantly or sequentially, will lead to a higher proportion of patients surviving long-term. Contributions and Acknowledgments We PEER REVIEW OUTCOMES Manuscript processing This manuscript was peer-reviewed by two inhouse referees and by Professor Mario Cazzola, Editor-in-Chief. The final decision to accept this paper for publication was taken by Professor Mario Cazzola. Manuscript received July 10, 2002; accepted August 8, 2002. Mario Cazzola, Editor-in-Chief © F e r r a t a S t o r t i F o u n d a t i o