Retrospective study of 613 canine cytologically normal bone marrows associated to altered hemograms: description, possible interpretation, and review of the principal physiological hematopoietic mechanisms.

Background: In clinical routine, it can happen that to an abnormal hemogram corresponds an unexpected cytological normal bone marrow examination that can be difficult to interpret and to manage. Aim: This cytologically retrospective study wants to evaluate a consistent number of qualitative and quantitative normal bone marrow exams according to the hematological and clinical-pathological data to judge if this normality is by itself a pathologic state. Methods: Six hundred and thirteen bone marrow samples were examined. The bone marrow cytological examinations were performed using morphological and numerical criteria together with a complete hemogram, after the identification of clinical or hematological alterations such as multiple lymph nodes enlarged, positive leishmania serological result, staging of neoplasia, cytopenia, increased number of cells, or suspicion of malignant blood disorders. Results: Of the 613 bone marrow samples evaluated, 85 (14%) were classified as normal or without cytological abnormalities; however, only 28 (33%) of those cases had a normal hemogram associated, whereas 55 (65%) had one or more cytopenia and 2 (2%) had increased blood cells count. Conclusion: From this study emerges that cytological bone marrow examinations without any morphological or numerical abnormalities are often associated with altered hematological exams and for this reason, they should not be considered normal and should lead to other deepened investigations.

A Primer for the Evaluation of Bone Marrow.

The traditional role of cytologic and histologic evaluation of bone marrow remains important in understanding diseases and conditions that affect this tissue. It is only through correlation of historical and clinical findings with hematologic, bone marrow, and other ancillary data that an accurate diagnosis can be made. Thus, the clinician is an essential link in helping establish a correct diagnosis. This article is a primer for understanding key features of bone marrow evaluation and provides practical tips for developing the best practices for optimal patient care.

Retrospective study of 152 feline cytological bone marrow examinations: preliminary classification and ranges.

OBJECTIVES: Cytological assessment of the bone marrow is an essential tool for understanding and investigating haematological abnormalities. Sometimes it represents the only way to reach a definitive diagnosis. The purpose of this study was to provide a general overview regarding the prevalence of feline bone marrow disorders encountered in a private European laboratory setting, to classify them and to assess the differential cell counts related to such disorders. METHODS: In total, 152 bone marrow samples were classified using cytological and numerical criteria. The bone marrow cytological examinations were performed after the identification of haematological alterations, such as cytopenias, increased number of cells or suspicion of malignant blood disorders. RESULTS: Of the 152 bone marrow samples evaluated, 71 (46.7%) were classified as hyperplastic, primarily granulocytic and erythroid hyperplasia (50.7% and 45.1%, respectively, of the total hyperplasia); 23 (15.1%) showed dysmyelopoiesis, mainly in the form of myelodysplastic syndrome (39.1% of the total dysmyelopoiesis); 21 (13.8%) had no cytological abnormalities; 17 (11.2%) were malignant blood disorders; 15 (9.9%) had hypoplastic conditions; and two (1.3%) were miscellaneous diseases. Metastatic disease was detected in only two cases (1.3%). Differential cell counts and myeloid-to-erythroid (M:E) ratios were reported for normal, erythroid hypoplastic, erythroid and granulocytic hyperplastic and dysplastic conditions. CONCLUSIONS AND RELEVANCE: This study provides a general overview of the prevalence and incidence of feline bone marrow disorders together with ranges for differential nucleated cell counts and M:E ratios for the various conditions reported.

Diagnostic bone marrow sampling in cats.

Practical relevance: Hematologic disorders are relatively common in cats, as inflammatory, immune-mediated and infectious diseases have the potential to impact erythroid, myeloid and thrombopoietic lines within the bone marrow. Clinical challenges: Clinicians often benefit from information obtained from bone marrow cytology and histopathology in diagnosing hematologic disorders in feline patients. However, these sampling procedures are ones that many veterinarians are intimidated by and thus not comfortably performing in clinical practice. AUDIENCE: This review, aimed at all veterinarians who treat cats, highlights the reasons a clinician may elect to sample bone marrow, and details the collection of bone marrow for both cytology and histopathology. Potential complications and limitations of each procedure are also reviewed. Evidence base: The collection of bone marrow for cytology and histopathology is not new to feline medicine and several research studies have investigated various sampling modalities in cats. This article offers a comprehensive review of the currently accepted best practices.

Bone Marrow Aspirate Evaluation.

Important steps in bone marrow aspirate evaluation include determining if bone marrow evaluation is indicated; using appropriate aspirate collection, smear preparation, and staining techniques; and performing a systematic approach for the cytologic evaluation. The cytologic evaluation of bone marrow requires knowledge of the morphology of bone marrow cell types, the proportion of these cell types normally present, and the ability to evaluate overall cellularity of bone marrow. Accurate interpretation of bone marrow cytologic findings depends on evaluation of a current complete blood cell count. These components are the pillars of getting the most useful information in the diagnosis of hematologic disorders.

Cytological Bone Marrow Cell Differential Counts and Morphologic Findings in Healthy Cynomolgus Monkeys ( Macaca fascicularis) from Nonclinical Toxicology Studies.

Cytological bone marrow evaluation is utilized in nonclinical toxicology studies to characterize hematopoietic effects when the combined interpretation of histologic and complete blood count data does not yield sufficient information. Results from cytological bone marrow examination should be interpreted in the context of variability observed in concurrent control animals with consideration of cytologist experience and historical/published data. Cytological bone marrow differential counts and cellular morphologic findings from 130 (66 male, 64 female) healthy control cynomolgus monkeys from nonclinical toxicology studies were retrospectively analyzed. Myeloid to erythroid (M:E) ratios and the percentage of total cells for each cell type were determined from differential cell count data. M:E ratios ranged from 0.6:1 to 2.3:1. Percentages of total granulocytic cells, total erythroid cells, and lymphocytes ranged from 26.6% to 60.6%, 25.7% to 52.2%, and 5.5% to 40.4%, respectively. Monocytes, plasma cells, mast cells, and mitotic figures were typically <1% of total cells. Notable morphologic findings included occasional giant neutrophilic metamyelocytes and band neutrophils, ring-shaped band neutrophil nuclei, metarubricyte nuclear blebbing and binucleation, multiple or nonfused megakaryocyte nuclei, and emperipolesis. These results represent cytological bone marrow findings from healthy control cynomolgus monkeys utilized in nonclinical toxicology studies and provide insight into expected background variability.

Suspected myelodysplastic/myeloproliferative neoplasm in a feline leukemia virus-negative cat.

A 10-year-old castrated Domestic Short-Haired cat was presented to a primary care veterinarian for a wellness examination and laboratory examination for monitoring of diabetes mellitus. The CBC revealed marked thrombocytosis, leukopenia and macrocytic, normochromic anemia. The cat tested negative for FeLV and feline immunodeficiency virus, but was positive for Mycoplasma haemominutum by PCR. Hematologic abnormalities were not responsive to therapy, so a repeat CBC and a bone marrow aspiration for cytology were performed. Additional blood smear findings included anisocytosis with megaloblastic erythroid precursors, large platelets, eosinophilic myelocytes and metamyelocytes, and rare unidentified blasts. The bone marrow smear was highly cellular, and the cytologic pattern was consistent with myelodysplastic syndrome with an erythroid predominance. At that time, 15% blasts were present. The cat was treated with a vitamin K2 analog, doxycycline, and prednisolone, but without a clinical response. Within 3 months, euthanasia was elected due to declining quality of life, and a necropsy was performed. Postmortem bone marrow smears were highly cellular and dominated by monomorphic blasts of unknown line of origin (52%), persistent marked erythroid and megakaryocytic dysplasia, and ineffective erythropoiesis and granulopoiesis. Immunohistochemical, immunocytochemical, and cytochemical stains resulted in a diagnosis of acute myeloid leukemia of unclassified type. Additional histologic findings included mixed hepatitis with trematode infestation and lymphoplasmacytic interstitial nephritis with fibrosis. The marked thrombocytosis with myelodysplastic syndrome and the FeLV-negative status of this cat were unusual. The difficulty in classifying the myelodysplasia and subsequent leukemia highlights a need for further reporting and characterization of these types of disease.

Avaliação da confiabilidade entre dois observadores em exames citopatológico e imunocitoquímico de aspirado de medula óssea no diagnóstico da leishmaniose visceral canina / Reliability evaluation between two evaluators in the cytopathologic and immunocytochemical exams from bone marrow aspirate in the canine visceral leishmaniasis diagnosis

Visceral leishmaniasis is a zoonosis in which the dog appears as the main source of infection in urban areas. Its diagnosis is complex and the cytopathological exam is a fast and cheap alternative to parasite direct visualization and its sensitivity can be increased by immunocytochemistry, though with a higher cost. The accuracy of such methods is dependent on the microscopist's experience and therefore, this study evaluated the reliability of such techniques between two observers, from bone marrow aspirates of 50 dogs from an endemic area for the disease. The parasitological culture in Novy-MacNeal-Nicolle medium was used as the reference standard. Among the main findings, the sensitivities obtained by observers I and II were respectively 62.5% and 37.5%, while specificities were 81.1% and 100%. On immunocytochemistry evaluation, the sensitivity was 0% for both evaluators and the specificity 97.3% and 100%. The agreement between evaluators was weak (κ = 0.167) for the cytopathological test and it could not be evaluated for immunocytochemistry, for which there was no detection by the evaluator II. The agreements among the diagnostic methods and the standard reference for the observer I were reasonable (κ = 0.364) for cytopathological examination and bad (κ = -0.041) for immunocytochemistry. For observer II, such agreement could be assessed only for the cytopathological test, being moderate (κ = 0.497). The results point to the possible expertise difference between evaluators, with the evaluator II demonstrating greater experience when interpreting the citopathological test. Although there was the expected sensitivity increase with immunocytochemistry, the technique used in this study was not effective for the diagnosis of infection, regardless of the evaluator.(AU)

Canine bone marrow cytological examination, classification and reference values: A retrospective study of 295 cases.

Cytologic assessment of bone marrow with knowledge of the hemogram represents an effective method to investigate hemic tissue and its function. To determine the spectrum and prevalence of canine bone marrow disorders over a 2 year period in a diagnostic laboratory setting achieved through a standard approach to cytologic bone marrow assessment. A retrospective study of bone marrow fine needle aspirates sample preparations, blood smears, hemogram data and case records. Of the 295 bone marrow samples evaluated, 90 (30.5%) were nondiagnostic samples. Of the remaining samples, 25.1% were classified as hyperplasia of which most were granulocytic hyperplasia (58.1% of the total hyperplasia), 19.3% had no cytological abnormalities, 12.9% had malignant hemopathy and 7.8% had hypo-aplastic conditions. Only a small proportion of cases involved dysplasia (1.7%) and metastatic disease was detected in only one case (0.3%). Reference values of nucleated cells and the M/E ratio were calculated for normal and erythroid and granulocytic hyperplastic bone marrow. This study provides the spectrum and the prevalence of canine bone marrow disorders as well as a differential bone marrow cell counting and determination of reference intervals for diseases.

Diagnosis of secondary dysmyelopoiesis via costochondral rib aspirate in a dog.

OBJECTIVE: To describe a novel bone marrow sampling technique utilized in a dog diagnosed with secondary dysmyelopoiesis. CASE SUMMARY: A 1.5-year-old female spayed Lhasa Apso was treated for generalized seizures, aspiration pneumonia, and severe sepsis. Pertinent history included administration of phenobarbital (2.1 mg/kg PO q 12 h) for the 6 months prior to presentation for suspected idiopathic epilepsy. Initial leukopenia and thrombocytopenia was attributed to underlying sepsis and disseminated intravascular coagulation. Progressive decline in all cell lines (ie, leukopenia, thrombocytopenia, and anemia), along with history of phenobarbital administration, suggested myelodysplastic disease. Bone marrow cytology via serial costochondral rib aspirates confirmed secondary dysmyelopoiesis. Phenobarbital therapy was abruptly discontinued and replaced with alternative anticonvulsant therapy. Complete resolution of the observed leukopenia, thrombocytopenia, and anemia were observed 2 weeks after discontinuation of phenobarbital. NEW OR UNIQUE INFORMATION PROVIDED: Costochondral rib aspirate appears to be a simple, viable method for bone marrow evaluation in dogs. Dysmyelopoiesis is a rare adverse effect of phenobarbital administration that can possess fatal consequences if not quickly recognized. Prompt diagnosis and discontinuation of the inciting drug is imperative to successful case management. Prognosis for return of bone marrow function appears good following drug discontinuation.

Acute undifferentiated leukaemia in a dog.

BACKGROUND: Acute undifferentiated leukaemia (AUL) is considered a separate entity in the context of acute leukaemias. AUL is extremely rare in both humans and dogs, has a rapid clinical course and does not respond to treatment. It is characterised by the presence of blast cells within the bone marrow and/or peripheral blood at levels ≥ 20% and even up to 100% of all nucleated cells. Blast cells are unable to be differentiated on morphological, cytochemical and phenotypic criteria into myeloid or lymphoid lineages because of their immaturity and/or atypia. CASE REPORT: An 8-year-old German Shepherd dog was referred for depression, asthenia, mild anaemia, thrombocytopenia and marked leucocytosis. Abdominal ultrasound showed hepatomegaly, splenomegaly, bilateral nephromegaly and enlargement of mesenteric lymph nodes. Echocardiography revealed biventricular hypertrophy with abnormal tissue density of the myocardium. Blood and bone marrow smears were composed of 95% unclassifiable and/or atypical blast cells and signs of dysplasia of the erythroid and thrombocytic/megakaryocytic lineages were present. Blast cells were negative for all cytochemical stains used and flow cytometry of peripheral blood revealed 85% of total leucocytes consisting of small-to-medium-sized cells, negative for all lymphoid and myeloid markers except CD45 and CD34. After necropsy, cytology and histology revealed that blast cells had diffusely infiltrated all tissues examined. Both erythroid and megakaryocytic extramedullary haemopoiesis was also detected in the spleen, lymph nodes and liver. All immunohistochemical stains used were negative. CONCLUSION: On the basis of all the results, a diagnosis of acute leukaemia involving a very primitive haematopoietic precursor was made.

Automated hematologic analysis of bone marrow aspirate samples from healthy Beagle dogs.

BACKGROUND: Interpretation of bone marrow (BM) smears typically is comprised of qualitative assessment and differential counting of cells. Analysis of BM fluid with automated hematology analyzers may provide rapid characterization of cells to supplement microscopic interpretation. OBJECTIVES: The purpose of the study was to examine the practicality and utility of analyzing BM samples in the Advia 2120 hematology analyzer; to determine if results correlate with smear assessment; and to establish descriptive statistics from hematologically normal and clinically healthy Beagle dogs. METHODS: Anticoagulated BM aspirates from 3 different sites of 26 adult Beagle dogs were collected. BM samples were analyzed in the Advia 2120, and numerical results were correlated with microscopic assessment of corresponding BM smears. Results from automated analyses and manual 500-cell differential counts were statistically analyzed. RESULTS: Forty-six samples were suitable for complete analysis. Results were available in approximately 2 (Advia) and 30 (stained and cover-slipped smear) minutes. Advia nucleated cell concentration was significantly correlated with microscopic assessment of smear particle number and smear cellularity. Significant correlations were also identified for Advia percent neutrophils with segmented, band and metamylocyte neutrophils, Advia percent lymphocytes with rubricytes, and Advia percent large unstained cells (LUC) with myeloblasts and promyelocytes. CONCLUSIONS: Automated analysis of BM aspirates was practicable, although techniques to obtain cellular samples and avoid clot formation could be improved. Automated analysis may provide rapid and useful preliminary information regarding sample cellularity, and granulocytic and erythrocytic components. Automated analysis should not supplant microscopic assessment, but may be a useful adjunct.

Citoinclusão de capa leucocitária e medula óssea de cães: padronização da técnica / Cell block of canine buffy coat and bone marrow in paraffin blocks: technique standardization

A técnica de citoinclusão é amplamente utilizada e reconhecida por profissionais da área da saúde, em particular médicos patologistas, porém as informações sobre a aplicação desse método em medicina veterinária ainda são raras. Análises citológicas de medula óssea e da capa leucocitária (porção do sangue formada por concentrados de leucócitos) são amplamente utilizadas no diagnóstico de patologias de origem neoplásica e não neoplásica e de agentes infecciosos. Embora a importância do uso da técnica seja amplamente reconhecida, não há registro da utilização de amostras citológicas de medula óssea e capa leucocitária na confecção de citoinclusões em blocos de parafina, como meio de diagnóstico no segmento médico veterinário. Assim, este trabalho tem como objetivo elaborar um protocolo de citoinclusão em parafina para amostras citológicas de medula óssea e capa leucocitária de cães. Foram submetidas à técnica de citoinclusão 110 amostras de capa leucocitária e 44 de medula óssea de cães portadores ou não de enfermidade sistêmica, sendo que em 68% destas, tanto para a capa leucocitária quanto para a medula óssea, as amostras se mostraram viáveis. A utilização do álcool 95% como fixador e de etapas no processamento histológico de 20 minutos (álcool absoluto, xilol e parafina, três banhos cada) foi crucial para a qualidade dos cortes histológicos e para a análise microscópica dos espécimes corados pela hematoxilina-eosina. A separação mecânica da capa leucocitária e a centrifugação do aspirado de medula óssea foram eficientes e de baixo custo no preparo das citoinclusões. Ressalta-se a importância na padronização da técnica de citoinclusão, em particular para amostras de capa leucocitária e medula óssea, visando à obtenção de espécimes de qualidade independentemente das limitações de equipamentos...

The cell block technique is widely used and recognized by health professionals, but lacks in information regarding the specific contribution of this method to veterinary medicine. The cytology of bone marrow and buffy coat (cellular portion of the hole blood) are widely used in the diagnosis of neoplastic and non-neoplastic diseases, and also for the detection of infectious agents. Although the importance of these samples is widely recognized, there is no information about the use of buffy coat and bone marrow samples in the cell block procedure among the research material used for this paper. This work aims for the cell block standardization for canine buffy coat and bone marrow samples. We collected 110 buffy coat samples and 44 bone marrow samples for the cell block preparation, and 68.2% of buffy coat and bone marrow proved to be viable at the end of the procedure. The 95% ethanol fixatives along with the 20 minute processing steps (absolute ethanol, xilol and paraffin, 3 of each) were crucial for the quality of the material both in microtomy and optical microscopy. Mechanical separation of the buffy coat proved to be easy and cheap and was used to compose the cell block technique. In this research we emphasized the importance of cell block standardization in order to develop and easy, inexpensive and reproducible method, regardless of any of the professionals' limitations...

Validation of Sysmex XT-2000iV generated quantitative bone marrow differential counts in untreated Wistar rats.

BACKGROUND: Preclinical drug trials frequently require assessment of bone marrow toxicity in animals to evaluate hematopoietic safety. Since the gold standard, cytologic evaluation, is time consuming and requires highly trained individuals, automated methods remain intriguing. OBJECTIVE: The Sysmex XT-2000iV hematology analyzer allows user-developed customizable gating. This study was conducted to validate the gating of bone marrow cell populations in Sysmex cytograms from untreated rats. METHODS: B- and T-lymphocytes and myeloid cells were experimentally depleted from Charles River Wistar Han IGS (CRL: WI [Han]) rat whole bone marrow suspension using a magnetic cell sorting (MACS) method. The positively and negatively selected populations were used to verify select gates within the Sysmex cytogram. Intra- and inter-animal precision, comparability between right and left femur, as well as agreement with microscopic myelograms based on 500 counted cells, were determined. RESULTS: Intra-sample precision and right-to-left femur comparability confirmed that gating was reproducible and stable. In 50 tested rats, myeloid to erythroid ratios (M:E) were 1.32 ± 0.33 in males and 1.38 ± 0.29 in females by Sysmex compared to 1.36 ± 0.32 in males and 1.42 ± 0.32 in females by microscopic evaluations. Bland-Altman differences between methods was ≤ ± 0.35 units for M:E, ≤ 5.4% for maturing myeloid cells, ≤ 3.4% for proliferating myeloid cells, ≤ 6.0% for maturing myeloid cells, ≤ 3.4% for proliferating myeloid cells, and ≤ 4.1% for lymphocytes. CONCLUSIONS: In untreated control Charles River Wistar Han IGS (CRL: WI [Han]) rats, the Sysmex XT-2000iV produced an automated M:E and 5-part differential count equivalent to microscopic differential counts.

Comparison of sternal, iliac, and humeral bone marrow aspiration in Beagle dogs.

BACKGROUND: Sternal bone marrow aspiration in dogs is not commonly performed as it is considered technically challenging in smaller dogs. However, the sternum is readily accessible and associated with less pain from aspiration compared with other sites. OBJECTIVES: The aim of the study was to investigate feasibility, ease, number of attempts, safety, and sample quality of sternal bone marrow aspirates in small dogs. METHODS: Bone marrow aspirates were obtained in a randomized order from 3 sites in 26 clinically healthy Beagles under general anesthesia. Samples were obtained from the sternum using one-inch 20- or 22-gauge hypodermic needles, from the right greater tubercle of the humerus, and the right iliac crest using 18-gauge Illinois needles. The difficulty of each procedure was scored. Two types of bone marrow smears were prepared and reviewed by a pathologist unaware of site of aspiration or dog. The number of particles per slide and overall slide quality were scored. The site of aspiration and the cranial thoracic wall were evaluated at autopsy for evidence of trauma or pneumothorax. RESULTS: The number of attempts and time for bone marrow aspiration were greater for ilium than for sternum or humerus, but the sternum was the easiest to aspirate. Smear quality and particle number were similar for all sites. Neither trauma at the site of aspiration nor pneumothorax were identified. CONCLUSIONS: Aspiration of sternal bone marrow with hypodermic needles is feasible and safe in Beagle dogs. Samples equivalent in quality to those from the humerus or ilium can be obtained from clinically normal dogs.

Chronic anemia and effects of iron supplementation in a research colony of adult Rhesus macaques (Macaca mulatta).

A cohort of rhesus macaques used in neuroscience research was found at routine examinations to have chronic anemia (spun Hct less than 30%). Four anemic (Hct, 24.8% ± 3.4%) and 10 control (39.6% ± 2.9%) macaques were assessed to characterize the anemia and determine probable cause(s); some animals in both groups had cephalic implants. Diagnostic tests included CBC, bone marrow evaluations, iron panels, and serum erythropoietin and hepcidin concentrations. Serum iron and ferritin were 15.8 ± 11.1 µg/dL and 103.8 ± 53.1 ng/mL, respectively, for the anemic group compared with 109.8 ± 23.8 µL/dL and 88.5 ± 41.9 ng/mL, respectively, for the control group. Erythropoietin levels were 16.2 to over 100 mU/mL for the anemic macaques compared with 0 to 1.3 mU/mL for the control group. Hepcidin results were similar in both groups. Because the findings of low iron, high erythropoietin, and normal hepcidin in the anemic macaques supported iron-deficiency anemia or anemia of chronic disease combined with iron-deficiency anemia, a regimen of 4 doses of iron dextran was provided. In treated macaques, Hct rose to 36.3% ± 6.8%, serum iron levels increased to 94.0 ± 41.9 µg/dL, and erythropoietin levels fell to 0.15 to 0.55 mU/mL. Maintenance of normal Hct was variable between macaques and reflected individual ongoing clinical events.

Hemophagocytic syndrome in dogs: 24 cases (1996-2005).

OBJECTIVE: To determine the frequency, potential causes, and clinical and clinicopathologic features of hemophagocytic syndrome in dogs. DESIGN: Retrospective study. ANIMALS: 24 client-owned dogs. PROCEDURES: Records for dogs in which diagnostic bone marrow specimens (including an aspiration smear and core biopsy material) were obtained from 1996 to 2005 were reviewed. Inclusion criteria were presence of bicytopenia or pancytopenia in the blood and > 2% hemophagocytic macrophages in the bone marrow aspirate. RESULTS: Of 617 bone marrow specimens evaluated, evidence of hemophagocytic syndrome was detected in 24 (3.9%). The Tibetan Terrier breed was overrepresented among dogs with hemophagocytic syndrome. Clinical signs associated with hemophagocytic syndrome included fever, icterus, splenomegaly, hepatomegaly, and diarrhea. Hemophagocytic syndrome was associated with immune-mediated, infectious, and neoplastic-myelodysplastic conditions and also occurred as an idiopathic condition. Overall, dogs with infection-associated hemophagocytic syndrome had better 1-month survival rates than dogs with immune-associated and idiopathic hemophagocytic syndrome. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that hemophagocytic syndrome may occur more frequently in dogs than has previously been suspected on the basis of the paucity of reported cases. Although most dogs had definable underlying disease conditions, idiopathic hemophagocytic syndrome was also identified. Hemophagocytic syndrome of any cause is potentially life-threatening; however, the prognosis should be adjusted on the basis of the associated disease process and potential for successful treatment.