Georgiadi EC, Sachinis N, Dimtsas G, et al.
Evaluation of apoptosis in classical Hodgkin's lymphoma comparing different methods.
J BUON. 2012 Oct-Dec; 17(4):746-52 [PubMed]

PURPOSE: Apoptosis is a type of programmed cell death (PCD) with specific morphologic changes in the dying cell. Since classical Hodgkin's lymphoma (cHL) is characterised by abnormalities in the apoptotic pathways, apoptosis may play a central role in its pathogenesis. Our purpose was to estimate the apoptotic process in cases of cHL using 3 different, widely accepted methods, comparing their results as well as with those found in the literature.
METHODS: Detection of apoptosis was performed in 76 cases of cHL, using morphological criteria, TUNEL assay (TUNEL apoptotic index; T-AI) and immunohistochemical detection of active caspase 3 (casp3-AI) on paraffin embedded sections.
RESULTS: When both apoptotic (MA) and mummified (mummi-I) cells were evaluated by morphological apoptotic index (morph-AI), the median value was 10.3%, while for MA and mummi-I the results were 3.4% and 6%, respectively. T-AI and casp3-AI values were 10.9% and 1.9%, respectively. Morph-AI was significantly higher in the mixed cellularity (MC) subtype (p7equals;0.047rpar;, while MA was significantly higher in the male subgroup (p7equals;0.03). MA was strongly correlated with casp37horbar;AI (p=0.01).
CONCLUSION: Detection of apoptosis has become an important parameter in understanding tumor pathology and in designing antitumor treatment. A combination of methods is proposed in order to estimate accurately this form of cell death.

Venkataraman G, Song JY, Tzankov A, et al.
Aberrant T-cell antigen expression in classical Hodgkin lymphoma is associated with decreased event-free survival and overall survival.
Blood. 2013; 121(10):1795-804 [PubMed] Article available free on PMC after 07/03/2014

Hodgkin/Reed-Sternberg (HRS) cells of classical Hodgkin lymphoma (cHL) rarely express T-cell-associated antigens (TCA), but the clinical significance of this finding is uncertain. Fifty cHLs expressing any TCA on the HRS cells (TCA-cHL) were identified in two cohorts (National Cancer Institute, n = 38; Basel, n = 12). Diagnostic pathology data were examined in all cases with additional T-cell receptor γ rearrangements (TRG@) polymerase chain reaction (PCR) in a subset of cases. The outcome data were compared with a cohort of cHLs negative for TCA (n = 272). Primary end points examined were event-free survival (EFS) and overall survival (OS). The median age in the TCA-cHL group was 40 years (range, 10-85 years). Seventy percent presented in low stage (stage I/II) at presentation with nodular sclerosis (NS) histology predominating in 80% of cases. Among the TCA, CD4 and CD2 were most commonly expressed, seen in 80.4% and 77.4% of cases, respectively. TRG@ PCR was negative for clonal rearrangements in 29 of 31 cases. During a median follow up of 113 months, TCA expression predicted shorter OS (adjusted hazard ratio [HRadj] = 3.32 [95% confidence interval (CI): 1.61, 6.84]; P = .001) and EFS (HRadj = 2.55 [95% CI: 1.45, 4.49]; P = .001). TCA-cHL often display NS histology, lack T-cell genotype, and are independently associated with significantly shorter OS and EFS compared with TCA-negative cHLs.

Maraldo MV, Aznar MC, Vogelius IR, et al.
Involved node radiation therapy: an effective alternative in early-stage hodgkin lymphoma.
Int J Radiat Oncol Biol Phys. 2013; 85(4):1057-65 [PubMed]

PURPOSE: The involved node radiation therapy (INRT) strategy was introduced for patients with Hodgkin lymphoma (HL) to reduce the risk of late effects. With INRT, only the originally involved lymph nodes are irradiated. We present treatment outcome in a retrospective analysis using this strategy in a cohort of 97 clinical stage I-II HL patients.
METHODS AND MATERIALS: Patients were staged with positron emission tomography/computed tomography scans, treated with adriamycin, bleomycin, vinblastine, and dacarbazine chemotherapy, and given INRT (prechemotherapy involved nodes to 30 Gy, residual masses to 36 Gy). Patients attended regular follow-up visits until 5 years after therapy.
RESULTS: The 4-year freedom from disease progression was 96.4% (95% confidence interval: 92.4%-100.4%), median follow-up of 50 months (range: 4-71 months). Three relapses occurred: 2 within the previous radiation field, and 1 in a previously uninvolved region. The 4-year overall survival was 94% (95% confidence interval: 88.8%-99.1%), median follow-up of 58 months (range: 4-91 months). Early radiation therapy toxicity was limited to grade 1 (23.4%) and grade 2 (13.8%). During follow-up, 8 patients died, none from HL, 7 malignancies were diagnosed, and 5 patients developed heart disease.
CONCLUSIONS: INRT offers excellent tumor control and represents an effective alternative to more extended radiation therapy in the combined modality treatment for early-stage HL.

Gordon LI, Hong F, Fisher RI, et al.
Randomized phase III trial of ABVD versus Stanford V with or without radiation therapy in locally extensive and advanced-stage Hodgkin lymphoma: an intergroup study coordinated by the Eastern Cooperative Oncology Group (E2496).
J Clin Oncol. 2013; 31(6):684-91 [PubMed] Article available free on PMC after 20/02/2014

PURPOSE: Although ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) has been established as the standard of care in patients with advanced Hodgkin lymphoma, newer regimens have been investigated, which have appeared superior in early phase II studies. Our aim was to determine if failure-free survival was superior in patients treated with the Stanford V regimen compared with ABVD.
PATIENTS AND METHODS: The Eastern Cooperative Oncology Group, along with the Cancer and Leukemia Group B, the Southwest Oncology Group, and the Canadian NCIC Clinical Trials Group, conducted this randomized phase III trial in patients with advanced Hodgkin lymphoma. Stratification factors included extent of disease (localized v extensive) and International Prognostic Factors Project Score (0 to 2 v 3 to 7). The primary end point was failure-free survival (FFS), defined as the time from random assignment to progression, relapse, or death, whichever occurred first. Overall survival, a secondary end point, was measured from random assignment to death as a result of any cause. This design provided 87% power to detect a 33% reduction in FFS hazard rate, or a difference in 5-year FFS of 64% versus 74% at two-sided .05 significance level.
RESULTS: There was no significant difference in the overall response rate between the two arms, with complete remission and clinical complete remission rates of 73% for ABVD and 69% for Stanford V. At a median follow-up of 6.4 years, there was no difference in FFS: 74% for ABVD and 71% for Stanford V at 5 years (P = .32).
CONCLUSION: ABVD remains the standard of care for patients with advanced Hodgkin lymphoma.

Scott DW, Chan FC, Hong F, et al.
Gene expression-based model using formalin-fixed paraffin-embedded biopsies predicts overall survival in advanced-stage classical Hodgkin lymphoma.
J Clin Oncol. 2013; 31(6):692-700 [PubMed] Article available free on PMC after 20/02/2014

PURPOSE: Our aim was to reliably identify patients with advanced-stage classical Hodgkin lymphoma (cHL) at increased risk of death by developing a robust predictor of overall survival (OS) using gene expression measured in routinely available formalin-fixed paraffin-embedded tissue (FFPET).
METHODS: Expression levels of 259 genes, including those previously reported to be associated with outcome in cHL, were determined by digital expression profiling of pretreatment FFPET biopsies from 290 patients enrolled onto the E2496 Intergroup trial comparing doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) and Stanford V regimens in locally extensive and advanced-stage cHL. A model for OS separating patients into low- and high-risk groups was produced using penalized Cox regression. The model was tested in an independent cohort of 78 patients enriched for treatment failure but otherwise similar to patients in a population-based registry of patients treated with ABVD. Weighted analysis methods generated unbiased estimates of predictor performance in the population-based registry.
RESULTS: A 23-gene outcome predictor was generated. The model identified a population at increased risk of death in the validation cohort. There was a 29% absolute difference in 5-year OS between the high- and low-risk groups (63% v 92%, respectively; log-rank P < .001; hazard ratio, 6.7; 95% CI, 2.6 to 17.4). The predictor was superior to the International Prognostic Score and CD68 immunohistochemistry in multivariate analyses.
CONCLUSION: A gene expression-based predictor, developed in and applicable to routinely available FFPET biopsies, identifies patients with advanced-stage cHL at increased risk of death when treated with standard-intensity up-front regimens.

Crump C, Sundquist K, Sieh W, et al.
Perinatal and family risk factors for Hodgkin lymphoma in childhood through young adulthood.
Am J Epidemiol. 2012; 176(12):1147-58 [PubMed] Article available free on PMC after 15/12/2013

The incidence of Hodgkin lymphoma has increased among adolescents and young adults in recent decades, but the relevant risk factors in early life are still unknown. A national cohort study was conducted of 3,571,574 individuals born in Sweden in 1973-2008 and followed up for Hodgkin lymphoma incidence through 2009, to examine perinatal and family risk factors for Hodgkin lymphoma in childhood through young adulthood (ages 0-37 years). There were 943 Hodgkin lymphoma cases identified in 66.3 million person-years of follow-up. High fetal growth was associated with an increased risk of Hodgkin lymphoma after adjustment for gestational age at birth and other potential confounders (P(trend) = 0.005). Family history of Hodgkin lymphoma in a sibling or parent also was strongly associated with an increased risk, with adjusted hazard ratios = 8.83 (95% confidence interval: 3.67, 21.30) and 7.19 (95% confidence interval: 3.58, 14.44), respectively. No association was found between gestational age at birth, birth order, twinning, parental age, or parental education and Hodgkin lymphoma. These findings did not vary by age at Hodgkin lymphoma diagnosis. Similar associations were found for nodular sclerosis and mixed cellularity subtypes. These findings suggest that perinatal factors including possible growth factor pathways may contribute to the risk of Hodgkin lymphoma in childhood through young adulthood.

Corazzelli G, Angrilli F, D'Arco A, et al.
Efficacy and safety of bendamustine for the treatment of patients with recurring Hodgkin lymphoma.
Br J Haematol. 2013; 160(2):207-15 [PubMed]

The management of patients with Hodgkin lymphoma (HL) recurring after stem cell transplantation (SCT) and multiply relapsed disease remains challenging. We report on 41 such patients who received bendamustine hydrochloride, a bifunctional mechlorethamine derivative mechanistically unrelated to traditional alkylators, after a median of four prior chemotherapy lines, including SCT in 85% of cases. Bendamustine was given at doses of 90-120 mg/m(2) every 21 or 28 d. At first assessment (2-4 cycles), the overall response rate (ORR) was 78% with 12 (29%) complete (CR) and 20 (49%) partial responses (PR). Upon treatment prolongation to 6-8 courses, 40% of PRs progressed, yielding a final ORR of 58% with 31% of CRs. Eight patients (two CRs, six PRs) were subsequently allotransplanted. Median progression-free and overall survival exceeded 11 and 21 months respectively; complete responders displayed a median disease-free survival above 9 months with a relapse rate of only 30%. Outcomes were independent of disease chemosensitivity, previous transplant and bendamustine dose-intensity. No life-threatening or unexpected adverse events occurred. Within the limits of a retrospective analysis and schedule heterogeneity, these results appear very encouraging and prompt prospective trials to confirm bendamustine as a valuable option in the palliative setting and in cytoreductive strategies before allotransplantation.

Koh YW, Kang HJ, Park C, et al.
Prognostic significance of the ratio of absolute neutrophil count to absolute lymphocyte count in classic Hodgkin lymphoma.
Am J Clin Pathol. 2012; 138(6):846-54 [PubMed]

The aim of this study was to determine the prognostic effect of the absolute neutrophil count/absolute lymphocyte count ratio (ANC/ALC ratio) in patients with classic Hodgkin lymphoma (cHL). We performed a retrospective analysis of 312 patients with cHL. Univariate analysis revealed that a high ANC/ALC ratio (≥4.3) correlated with poor overall survival (OS) (P < .001). Subgroup analysis of advanced-stage disease showed that the ANC/ALC ratio was significant for OS (P = .032). Multivariate analysis revealed the ANC/ALC ratio to be an independent prognostic factor for OS (P = .048). The ANC/ALC ratio allowed further risk stratification in patients who were considered to be at low risk on the basis of an International Prognostic Score less than 4 (P = .002). The ANC/ALC ratio is a simple, inexpensive, and independent prognostic factor for OS that may improve the ability to identify high-risk patients with cHL.

El-Galaly TC, d'Amore F, Mylam KJ, et al.
Routine bone marrow biopsy has little or no therapeutic consequence for positron emission tomography/computed tomography-staged treatment-naive patients with Hodgkin lymphoma.
J Clin Oncol. 2012; 30(36):4508-14 [PubMed]

PURPOSE: To investigate whether bone marrow biopsy (BMB) adds useful information to [(18)F]fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) staging in patients with Hodgkin lymphoma (HL).
PATIENTS AND METHODS: Newly diagnosed patients with HL undergoing a pretherapeutic staging that encompasses both PET/CT and BMB were included in this retrospective study. The pattern of skeletal FDG uptake was categorized as uni-, bi-, or multifocal (≥ three lesions). Clinical stage, risk assessment, and treatment plan were determined with and without the contribution of BMB results according to the Ann Arbor classification and the guidelines from the German Hodgkin Study Group.
RESULTS: A total of 454 patients with HL were included of whom 82 (18%) had focal skeletal PET/CT lesions and 27 (6%) had positive BMB. No patients with positive BMB were assessed as having stage I to II disease by PET/CT staging. BMB upstaged five patients, assessed as being stage III before BMB; none of the 454 patients would have been allocated to another treatment on the basis of BMB results. Focal skeletal PET/CT lesions identified positive and negative BMBs with a sensitivity and specificity of 85% and 86%, respectively. The positive and negative predictive values of focal skeletal PET/CT lesions for BMB results were 28% and 99%, respectively.
CONCLUSION: A consistent finding of this study was the absence of positive BMBs in PET/CT-assessed stage I to II disease. The omission of staging BMB would not have changed the risk assessment or treatment strategy in this cohort of 454 newly diagnosed patients with HL.

Hartridge-Lambert SK, Schöder H, Lim RC, et al.
ABVD alone and a PET scan complete remission negates the need for radiologic surveillance in early-stage, nonbulky Hodgkin lymphoma.
Cancer. 2013; 119(6):1203-9 [PubMed]

BACKGROUND: Patients with early-stage, nonbulky classic Hodgkin lymphoma (cHL) undergo intensive posttreatment radiologic surveillance despite having a low risk of disease recurrence. The current study attempted to evaluate the risk of disease recurrence and the value of radiologic surveillance in patients treated with the combination of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) alone who achieved a complete remission (CR) as noted on posttreatment positron emission tomography (PET).
METHODS: Forty-seven patients who underwent therapy with interim and/or posttreatment PET scans were evaluated for disease recurrence during ≥ 24 months of follow-up. Their presenting characteristics and imaging results were assessed and interpreted in relation to clinical outcome.
RESULTS: All 47 patients were eligible for analysis. The majority of patients were female (35 patients) with a median age of 28 years (range, 17 years-65 years.). The nodular sclerosing subtype was the predominant histology (41 patients). A total of 34 patients were staged with IIA disease, 6 with IA disease, 6 with IIB disease, and 1 with IIEA disease (lung) (according to Cotswolds modification of the Ann Arbor staging system). All patients completed 6 cycles of planned ABVD therapy and achieved a CR. Two had a positive PET scan (1 interim scan and 1 posttreatment scan); both were biopsy-proven sarcoidosis. Two patients developed disease recurrence at 7 months and 24 months, respectively, after negative interim and posttreatment imaging. One case of recurrence was identified through surveillance imaging and the other was identified simultaneously by the patient and surveillance scan. A total of 45 patients experienced a durable CR; 21 had additional unscheduled imaging/workup during surveillance to investigate symptoms or imaging signs of concern.
CONCLUSIONS: Because of a low risk of disease recurrence, posttreatment radiologic surveillance appears to be unnecessary in patients with early-stage, nonbulky (CD20 negative) cHL who achieve a PET-detected CR with the ABVD combination alone. This will reduce cumulative radiation exposure and health care costs in a predominantly young patient population.

Chen J, Yang ZG, Shao H, et al.
Differentiation of tuberculosis from lymphomas in neck lymph nodes with multidetector-row computed tomography.
Int J Tuberc Lung Dis. 2012; 16(12):1686-91 [PubMed]

BACKGROUND: Tuberculosis (TB) of the cervical lymph nodes may mimic lymphoma.
OBJECTIVE: To evaluate multidetector-row computed tomographic (MDCT) imaging criteria for differentiating between the two diseases.
MATERIALS AND METHODS: We retrospectively reviewed the anatomical distribution and CT enhancement patterns of the nodes in 81 patients, 27 (33%) with untreated TB and 54 (67%) with untreated lymphomas involving cervical lymph nodes. Of the patients with lymphomas, 19 (35%) had Hodgkin's disease and 35 (65%) had non-Hodgkin's lymphoma.
RESULTS: TB predominantly involved the upper cervical nodes. The supraclavicula fossa nodes on MDCT were involved more often in Hodgkin's disease (n = 15, 79%) and non-Hodgkin's lymphoma (n = 25, 71%) than in TB (n = 3, 11%). Tuberculous lymphadenopathy commonly showed peripheral enhancement, frequently with a multilocular appearance. Peripheral enhancement was significantly more frequent in TB (n = 19, 70%) than in Hodgkin's disease (n = 1, 5%) and non-Hodgkin's lymphoma (n = 1, 3%), but homogeneous enhancement was less common in the TB group.
CONCLUSION: Our findings indicate that a specific enhancement pattern of lymphadenopathy seen on MDCT was useful in differentiating between untreated TB and lymphomas of the cervical lymph nodes.

Büyükkapu-Bay S, Corapcioğlu F, Gürkan B, et al.
Mediastinal Hodgkin lymphoma arising from cystic lymphangioma: case report in a child.
Turk J Pediatr. 2012 May-Jun; 54(3):298-300 [PubMed]

Mediastinal disease is a frequent clinical presentation in children with Hodgkin lymphoma. It is usually due to mediastinal lymphadenopathy or involvement of the thymus gland. Cystic lymphangiomas are benign tumors of the lymphatic system, and less than 1% present as a solitary mediastinal mass. To our knowledge, there has been no report in the literature describing Hodgkin lymphoma arising from cystic lymphangioma. In this report, we describe a patient with mediastinal cystic lymphangioma, from which Hodgkin lymphoma was determined to have arisen.

Trehan A, Singla S, Marwaha RK, et al.
Hodgkin lymphoma in children: experience in a tertiary care centre in India.
J Pediatr Hematol Oncol. 2013; 35(3):174-9 [PubMed]

BACKGROUND: In developing countries Hodgkin lymphoma (HL) has been seen to have a high male to female ratio, younger age at presentation, a high proportion of patients in advanced stage of disease, constitutional symptoms, and predominance of mixed cellularity histologic type. The results of treatment appear to be comparable to the results attained in developed nations.
METHODS: Children with HL who were diagnosed and treated at our center between 1990 and 2006 were retrospectively analyzed.
RESULTS: A total of 206 children with a mean age of 7.9±2.6 (range, 3 to 16) years were treated for HL. Among them, 52% presented with advanced-stage (stages III and IV) disease, 54% had B symptoms, and 69.6% had mixed cellularity type of HL. Multiagent chemotherapy was the mainstay of treatment. The 5-year overall survival and event-free survival rates were 92.7% and 77.75%, respectively. Children with early-stage disease and absence of B symptoms had a better overall survival of 97.7% each, as compared with 87.2% and 88.2% in those with late-stage disease and B symptoms, respectively.
CONCLUSIONS: Even though developing countries have a different epidemiological profile, the outcome is good. Chemotherapy alone has shown excellent results in children with HL.

Lütgendorf-Caucig C, Fotina I, Gallop-Evans E, et al.
Multicenter evaluation of different target volume delineation concepts in pediatric Hodgkin's lymphoma. A case study.
Strahlenther Onkol. 2012; 188(11):1025-30 [PubMed]

BACKGROUND AND PURPOSE: In pediatric Hodgkin's lymphoma (PHL) improvements in imaging and multiagent chemotherapy have allowed for a reduction in target volume. The involved-node (IN) concept is being tested in several treatment regimens for adult Hodgkin's lymphoma. So far there is no consensus on the definition of the IN. To improve the reproducibility of the IN, we tested a new involved-node-level (INL) concept, using defined anatomical boundaries as basis for target delineation. The aim was to evaluate the feasibility of IN and INL concepts for PHL in terms of interobserver variability.
PATIENTS AND METHODS: The INL concept was defined for the neck and mediastinum by the PHL Radiotherapy Group based on accepted concepts for solid tumors. Seven radiation oncologists from six European centers contoured neck and mediastinal clinical target volumes (CTVs) of 2 patients according to the IN and the new INL concepts. The median CTVs, coefficient of variation (COV), and general conformity index (CI) were assessed. The intraclass correlation coefficient (ICC) for reliability of delineations was calculated.
RESULTS: All observers agreed that INL is a feasible and practicable delineation concept resulting in stronger interobserver concordance than the IN (mediastinum CI(INL) = 0.39 vs. CI(IN) = 0.28, neck left CI(INL) = 0.33; CI(IN) = 0.18; neck right CI(INL) = 0.24, CI(IN) = 0.14). The COV showed less dispersion and the ICC indicated higher reliability of contouring for INL (ICC(INL) = 0.62, p < 0.05) as for IN (ICC(IN) = 0.40, p < 0.05).
CONCLUSION: INL is a practical and feasible alternative to IN resulting in more homogeneous target delineation, and it should be therefore considered as a future target volume concept in PHL.

Kriz J, Mueller RP, Mueller H, et al.
Large mediastinal tumor mass as a prognostic factor in Hodgkin's lymphoma. Is the definition on the basis of a chest radiograph in the era of CT obsolete?
Strahlenther Onkol. 2012; 188(11):1020-4 [PubMed]

PURPOSE: The risk factor "large mediastinal tumor mass" is an internationally accepted unfavorable prognostic factor in the staging of Hodgkin's lymphoma (HL). The definition of this risk factor varies considerably between large cooperative study groups. The purpose of the present analysis was to determine to which degree data obtained from chest radiograph (CRX) give the same results as those from CT scans (CT).
METHODS: A total of 145 de novo HL patients in early unfavorable and advanced stages were included in this study. A total of 94 patients had a large mediastinal tumor mass according to the guidelines of the German Hodgkin Study Group (GHSG), while 51 had mediastinal lymph node involvement only. The size of mediastinal involvement and the thoracic diameter were measured on CRX and CT. Agreement between CRX and CT was determined by sensitivity and specificity analysis as well as descriptive statistics and correlations.
RESULTS: The correlation of the diameters on CRX with those of CT was 0.95 for the tumor size and 0.77 for the thoracic diameter. The diagnostic decision-large mediastinal mass or not-correlated with 0.81 between CRX and CT and was identical in 90.3% of cases. The sensitivity was 0.87 and the specificity 0.96 for CRX, which is considered the current standard.
CONCLUSION: The results show that there is a high agreement between the measurements of CRX and CT. Diagnosis of a large mediastinal mass disagreed in 10% of patients. Since the correct diagnosis of this risk factor is decisive for the adequate multimodal treatment choice, CRX should not be omitted.

Haase R, Vilser C, Mauz-Körholz C, et al.
Evaluation of the prognostic meaning of C-reactive protein (CRP) in children and adolescents with classical Hodgkin's lymphoma (HL).
Klin Padiatr. 2012; 224(6):377-81 [PubMed]

BACKGROUND: In adult cancer patients the negative predictive value of elevated CRP levels has been described for several malignancies. Only few studies have analyzed the prognostic role of CRP in children and adolescents with classical HL. In these studies elevated CRP levels correlate with the presence of classical risk factors and adverse outcome.
PATIENTS AND METHODS: The prognostic role of CRP for patients with classical HL admitted to the GPOH-HD-2002 study was analyzed retrospectively.
RESULTS: CRP levels were documented for 369 of 573 patients. Significant (p<0.05) increased median CRP levels were found in the presence of B-Symptoms (25.7 vs. 5.1 mg/l), extranodal involvement (21.5 vs. 7.5 mg/l), elevated erythrocyte sedimentation rate (ESR, 13.0 vs. 1.0 mg/l) and stage III/IV disease (15.5 vs. 5.3 mg/l). 83.9% of patients with elevated and 45.8% of patients with normal CRP had an ESR >30 mm/h.
CONCLUSION: Elevated CRP levels were associated with classical risk factors of HL. CRP and ESR may reflect different biological processes. CRP was prognostic within early stage TG-1 patients treated with reduced treatment, but not within advanced stage TG-2+3.

Hentrich M, Berger M, Wyen C, et al.
Stage-adapted treatment of HIV-associated Hodgkin lymphoma: results of a prospective multicenter study.
J Clin Oncol. 2012; 30(33):4117-23 [PubMed]

PURPOSE: Although the outcome of patients with HIV-related Hodgkin lymphoma (HIV-HL) has markedly improved since the introduction of combined antiretroviral therapy, standard therapy is still poorly defined. This prospective study investigates a stage- and risk-adapted treatment strategy in patients with HIV-HL.
PATIENTS AND METHODS: Patients with early favorable HIV-HL received two to four cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) followed by 30 Gy of involved-field (IF) radiation. In patients with early unfavorable HIV-HL, four cycles of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP baseline) or four cycles of ABVD + 30 Gy of IF radiation were administered. Six to eight cycles of BEACOPP baseline were given in patients with advanced-stage HIV-HL. In patients with advanced HIV infection, BEACOPP was replaced with ABVD.
RESULTS: Of 108 patients (including eight female patients) included in the study, 23 (21%) had early favorable HL, 14 (13%) had early unfavorable HL, and 71 (66%) had advanced-stage HL. The median CD4 count at HL diagnosis was 240/μL. The complete remission rates for patients with early favorable, early unfavorable, and advanced-stage HL were 96%, 100%, and 86%, respectively. The 2-year progression-free survival of the entire study population was 91.7%. Eleven patients (11%) have died, and treatment-related mortality was 5.6%. The 2-year overall survival rate was 90.7% with no significant difference between early favorable (95.7%), early unfavorable (100%), and advanced-stage HL (86.8%).
CONCLUSION: In patients with HIV-HL, stage- and risk-adapted treatment is feasible and effective. The prognosis for patients with HIV-HL may approach that of HIV-negative patients with HL.

Montoto S, Shaw K, Okosun J, et al.
HIV status does not influence outcome in patients with classical Hodgkin lymphoma treated with chemotherapy using doxorubicin, bleomycin, vinblastine, and dacarbazine in the highly active antiretroviral therapy era.
J Clin Oncol. 2012; 30(33):4111-6 [PubMed]

PURPOSE: The prognosis of HIV-infected patients with non-Hodgkin lymphoma in the highly active antiretroviral therapy (HAART) era approaches that of the general population when they are treated with the same protocols. We analyzed the outcome of patients with Hodgkin lymphoma (HL) treated with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) in the HAART era according to HIV serostatus to establish whether this also holds true for HL.
PATIENTS AND METHODS: From 1997 to 2010, 224 patients newly diagnosed with HL, of whom 93 were HIV positive, were consecutively treated with ABVD chemotherapy. HIV-positive patients had more high-risk disease according to the International Prognostic Score (IPS) than HIV-negative patients (IPS≥3: 68% v 26%, respectively; P<.001). Forty-seven HIV-positive patients had a CD4 count less than 200/μL, and 92 patients received HAART during chemotherapy.
RESULTS: The complete response rate was 74% for HIV-positive patients and 79% for HIV-negative patients (P=not significant). After a median follow-up of 60 months (range, 8 to 174 months), 23 patients (16 HIV-negative and seven HIV-positive patients) have experienced relapse at a median time of 6 months (range, 1 to 106 months). Five-year event-free survival (EFS) was 59% (95% CI, 47% to 70%) for HIV-positive patients and 66% (95% CI, 57% to 74%) for HIV-negative patients (P=not significant). Five-year overall survival (OS) was 81% (95% CI, 69% to 89%) and 88% (95% CI, 80% to 93%) for HIV-positive and HIV-negative patients, respectively (P=not significant). HIV status did not predict OS or EFS on multivariate analysis including IPS and HIV status.
CONCLUSION: This mature study demonstrates that HIV-positive patients with HL have more extensive disease with more adverse prognostic factors than HIV-negative patients, but when treated with ABVD, HIV infection does not adversely affect OS or EFS.

van der Kaaij MA, Heutte N, Meijnders P, et al.
Parenthood in survivors of Hodgkin lymphoma: an EORTC-GELA general population case-control study.
J Clin Oncol. 2012; 30(31):3854-63 [PubMed]

PURPOSE: We investigated the impact of Hodgkin lymphoma (HL) on parenthood, including factors influencing parenthood probability, by comparing long-term HL survivors with matched general population controls.
PATIENTS AND METHODS: A Life Situation Questionnaire was sent to 3,604 survivors treated from 1964 to 2004 in successive clinical trials. Responders were matched with controls (1:3 or 4) for sex, country, education, and year of birth (10-year groups). Controls were given an artificial date of start of treatment equal to that of their matched case. The main end point was presence of biologic children after treatment, which was evaluated by using conditional logistic regression analysis. Logistic regression analysis was used to analyze factors influencing spontaneous post-treatment parenthood.
RESULTS: In all, 1,654 French and Dutch survivors were matched with 6,414 controls. Median follow-up was 14 years (range, 5 to 44 years). After treatment, the odds ratio (OR) for having children was 0.77 (95% CI, 0.68 to 0.87; P < .001) for survivors compared with controls. Of 898 survivors who were childless before treatment, 46.7% achieved post-treatment parenthood compared with 49.3% of 3,196 childless controls (OR, 0.87; P = .08). Among 756 survivors with children before treatment, 12.4% became parents after HL treatment compared with 22.2% of 3,218 controls with children before treatment (OR, 0.49; P < .001). Treatment with alkylating agents, second-line therapy, and age older than 35 years at treatment appeared to reduce the chances of spontaneous post-treatment parenthood.
CONCLUSION: Survivors of HL had slightly but significantly fewer children after treatment than matched general population controls. The difference concerned only survivors who had children before treatment and appears to have more personal than biologic reasons. The chance of successful post-treatment parenthood was 76%.

Shankar A, Daw S
Nodular lymphocyte predominant Hodgkin lymphoma in children and adolescents--a comprehensive review of biology, clinical course and treatment options.
Br J Haematol. 2012; 159(3):288-98 [PubMed]

Nodular lymphocyte predominant Hodgkin lymphoma (nLPHL) is a unique variant of Hodgkin lymphoma with an overall good prognosis. It is conspicuously different from classical Hodgkin lymphoma (cHL) and is now recognized as distinctive form of B cell lymphoma. Although it has an indolent clinical course, it has a propensity for multiple and often late relapses. Although the majority of children present with early stage disease and without B symptoms, treatment strategy has, until recently, been identical to that used for cHL. This approach is excessively toxic as it predisposes these children and adolescents to serious late effects including end organ damage to heart, gonads, lungs, thyroid and second malignant neoplasms. The aim of this article is to review the published literature on the treatment outcomes of nLPHL in affected children and adolescents, and discuss the options for treatment including surgery, chemotherapy, radiotherapy and targeted anti-CD 20 antibody therapy.

Elli M, Dagdemir A, Bozkurt C, et al.
Serum osteopontin and CD44 levels in lymphoreticular malignancies in children.
Bratisl Lek Listy. 2012; 113(9):534-8 [PubMed]

OBJECTIVE: Osteopontin (OPN) is an adhesive glycoprotein that interacts with a variety of cell surface receptors, including several integrins and CD44. OPN is expressed and secreted by numerous human malignancies. CD44 play an important role in tumor growth and metastasis. We aimed to evaluate serum levels of osteopontin and CD44 in patients with lymphorethicular malignancies in childhood.
METHODS: We studied serum levels of CD44 and OPN levels of 54 patients (26, 18 and 10 patients with non-Hodgkin's lymphoma (NHL), Hodgkin's lymphoma (HL) and acute lymphoblastic leukemia (ALL), respectively) at the diagnosis.
RESULTS: The mean levels of OPN were significantly higher in patients (5.42±8.24 ng/ml) than in controls (3.89 ±1.96 ng/ml). The mean levels of CD44 levels were also significantly higher in patients (3.82±2.31 ng/ml) than in controls (1.96±0.62 ng/ml), and significantly higher in the advanced stages than in early stages. The mean levels of the CD44 in NHL, HL and ALL were 3.49±2.00, 3.56±1.74, and 5.15±3.50 respectively. OPN and CD44 levels were found to be increased in parallel (p=0.003). A more advanced disease and/or poor prognostic factors were seen in 9 patients who had both serum CD44 and OPN levels higher than 2SD of the control.
CONCLUSION: Elevated levels of both CD44 and OPN at the diagnosis may predict an unfavorable outcome in childhood leukemias and lymphomas (Tab. 2, Fig. 3, Ref. 44).

Levin LI, Chang ET, Ambinder RF, et al.
Atypical prediagnosis Epstein-Barr virus serology restricted to EBV-positive Hodgkin lymphoma.
Blood. 2012; 120(18):3750-5 [PubMed] Article available free on PMC after 01/11/2013

An altered anti-Epstein-Barr virus (EBV) serologic profile preceding diagnosis is associated with an increased risk of Hodgkin lymphoma. It is unknown whether this atypical pattern predicts Hodgkin lymphoma risk further subdivided by determination of EBV in tumor cells. A nested case-control study of 128 incident Hodgkin lymphoma cases and 368 matched controls from active-duty military personnel with archived serum in the US Department of Defense Serum Repository was conducted to determine whether a panel of anti-EBV antibody titers differed in EBV(+) and EBV(-) Hodgkin lymphoma. Among 40 EBV(+) Hodgkin lymphoma cases and matched controls, statistically significant increased risks were associated with elevated anti-EBV VCA IgG antibody titers (relative risk = 3.1; 95% confidence interval [CI], 1.1-8.7), and an anti-EBNA-1/anti-EBNA-2 antibody ratio ≤ 1.0 versus > 1.0 (relative risk = 4.7; 95% CI, 1.6-13.8). In contrast, no significant associations were found among 88 EBV(-) Hodgkin lymphoma cases relative to their matched controls. In case-case analysis, EBV(+) disease was significantly associated with a low anti-EBNA-1/anti-EBNA-2 antibody ratio. This distinctive serologic response to EBV latent antigens, indicative of immune dysfunction in other clinical settings, is associated with an increased risk of developing EBV(+) but not EBV(-) Hodgkin lymphoma.

Minn AY, Riedel E, Halpern J, et al.
Long-term outcomes after high dose therapy and autologous haematopoietic cell rescue for refractory/relapsed Hodgkin lymphoma.
Br J Haematol. 2012; 159(3):329-39 [PubMed]

The standard treatment for patients with refractory or relapsed Hodgkin lymphoma (HL) is high-dose chemotherapy and/or radiation with autologous haematopoietic cell rescue (AHCR). In this study, we assessed quality of life and evaluated the risk of late morbidity and mortality for HL patients who underwent AHCR. One hundred and fifty-four patients who underwent AHCR at Stanford University from 1988 to 2002 and survived ≥2 years were evaluated. Median follow-up was 10·2 years. There were 54 deaths, 34 from HL, 20 from other causes. The 10-year cumulative incidence of death from HL or other causes was 21·7% and 12·7%, respectively. Thirteen deaths were from second malignancies. The risk ratio of second malignancies was 8·0 [95% confidence interval (CI), 4·7-12·6] compared with the general population, and 3·0 (95% CI, 1·8-4·8) compared with HL patients not undergoing AHCR. The risk ratio of second malignancies was 1·5 (95% CI, 0·9-2·4) compared with HL patients receiving non-AHCR therapy. Overall quality of life did not differ from the general population, but AHCR survivors did note reduced functioning and some worse symptoms. AHCR survivors may be at increased risk of death from HL and other causes compared with the general population, but not compared with the HL population as a whole.

Krull KR, Sabin ND, Reddick WE, et al.
Neurocognitive function and CNS integrity in adult survivors of childhood hodgkin lymphoma.
J Clin Oncol. 2012; 30(29):3618-24 [PubMed] Article available free on PMC after 10/10/2013

PURPOSE: Long-term survivors of childhood Hodgkin lymphoma (HL) are at risk for cardiopulmonary complications and CNS stroke, although neurocognitive function has not been previously examined. The aim of this study was to examine neurocognitive and brain imaging outcomes in adult survivors of childhood HL.
PATIENTS AND METHODS: In all, 62 adult survivors (mean age, 42.2 years; standard deviation [SD], 4.77; mean age at diagnosis, 15.1 years; SD, 3.30) were identified by stratified random selection from a large cohort treated with either high-dose (≥ 30 Gy) thoracic radiation (n = 38) or lower-dose (< 30 Gy) thoracic radiation combined with anthracycline (n = 24). Patients underwent neurocognitive evaluations, brain magnetic resonance imaging (MRI), echocardiograms, pulmonary function tests, and physical examinations.
RESULTS: Compared with national age-adjusted norms, HL survivors demonstrated lower performance on sustained attention (P = .004), short-term memory (P = .001), long-term memory (P = .006), working memory (P < .001), naming speed (P < .001), and cognitive fluency (P = .007). MRI revealed leukoencephalopathy in 53% of survivors, and 37% had evidence of cerebrovascular injury. Higher thoracic radiation dose was associated with impaired cardiac diastolic function (E/E'; ratio of peak mitral flow velocity of early rapid filling [E] to early diastolic velocity of the mitral annulus [E']; P = .003), impaired pulmonary function (diffusing capacity of lungs for carbon monoxide [DL(co)(corr); P = .04), and leukoencephalopathy (P = .02). Survivors with leukoencephalopathy demonstrated reduced cognitive fluency (P = .001). Working memory impairment was associated with E/E', although impaired sustained attention and naming speed were associated with DL(co)(corr). Neurocognitive performance was associated with academic and vocational functioning.
CONCLUSION: These results suggest that adult long-term survivors of childhood HL are at risk for neurocognitive impairment, which is associated with radiologic indices suggestive of reduced brain integrity and which occurs in the presence of symptoms of cardiopulmonary dysfunction.

Tebbi CK, Mendenhall NP, London WB, et al.
Response-dependent and reduced treatment in lower risk Hodgkin lymphoma in children and adolescents, results of P9426: a report from the Children's Oncology Group.
Pediatr Blood Cancer. 2012; 59(7):1259-65 [PubMed] Article available free on PMC after 15/12/2013

BACKGROUND: Hodgkin lymphoma is highly curable but associated with significant late effects. Reduction of total treatment would be anticipated to reduce late effects. This aim of this study was to demonstrate that a reduction in treatment was possible without compromising survival outcomes.
METHODS: Protocol P9426, a response-dependent and reduced treatment for low risk Hodgkin lymphoma (stages I, IIA, and IIIA(1) ) was designed in 1994 based on a previous pilot project. Patients were enrolled from October 15, 1996 to September 19, 2000. Patients were randomized to receive or not receive dexrazoxane and received two cycles of chemotherapy consisting of doxorubicin, bleomycin, vincristine, and etoposide. After two cycles, patients were evaluated for response. Those in complete response (CR) received 2,550 cGy of involved field radiation therapy (IFRT). Patient with partial response or stable disease, received two more cycles of chemotherapy and IFRT at 2,550 cGy.
RESULTS: There were 294 patients enrolled, with 255 eligible for analysis. The 8-year event free survival (EFS) between the dexrazoxane randomized groups did not differ (EFS 86.8 ± 3.1% with DRZ, and 85.7 ± 3.3% without DRZ (P = 0.70). Forty-five percent of patients demonstrated CR after two cycles of chemotherapy. There was no difference in EFS by histology, rapidity of response, or number of cycles of chemotherapy. Six of the eight secondary malignancies in this study have been previously reported.
CONCLUSIONS: Despite reduced therapy and exclusion of most patients with lymphocyte predominant histology, EFS and overall survival are similar to other reported studies. The protocol documents that it is safe and effective to reduce therapy in low-risk Hodgkin lymphoma based on early response to chemotherapy with rapid responding patients having the same outcome as slower-responding patients when given 50% of the chemotherapy.

Greaves W, Xiao L, Sanchez-Espiridion B, et al.
Detection of ABCC1 expression in classical Hodgkin lymphoma is associated with increased risk of treatment failure using standard chemotherapy protocols.
J Hematol Oncol. 2012; 5:47 [PubMed] Article available free on PMC after 15/12/2013

BACKGROUND: The mechanisms responsible for chemoresistance in patients with refractory classical Hodgkin lymphoma (CHL) are unknown. ATP-binding cassette (ABC) transporters confer multidrug resistance in various cancers and ABCC1 overexpression has been shown to contribute to drug resistance in the CHL cell line, KMH2.
FINDINGS: We analyzed for expression of five ABC transporters ABCB1, ABCC1, ABCC2, ABCC3 and ABCG2 using immunohistochemistry in 103 pre-treatment tumor specimens obtained from patients with CHL. All patients received first-line standard chemotherapy with doxorubicin (Adriamycin®), bleomycin, vinblastine, and dacarbazine (ABVD) or equivalent regimens. ABCC1 was expressed in Hodgkin and Reed-Sternberg (HRS) cells in 16 of 82 cases (19.5%) and ABCG2 was expressed by HRS cells in 25 of 77 cases (32.5%). All tumors were negative for ABCB1, ABCC2 and ABCC3. ABCC1 expression was associated with refractory disease (p = 0.01) and was marginally associated with poorer failure-free survival (p = 0.06). Multivariate analysis after adjusting for hemoglobin and albumin levels and age showed that patients with CHL with HRS cells positive for ABCC1 had a higher risk of not responding to treatment (HR = 2.84, 95%, CI: 1.12-7.19 p = 0.028).
CONCLUSIONS: Expression of ABCC1 by HRS cells in CHL patients predicts a higher risk of treatment failure and is marginally associated with poorer failure-free survival using standard frontline chemotherapy regimens.

Moccia AA, Donaldson J, Chhanabhai M, et al.
International Prognostic Score in advanced-stage Hodgkin's lymphoma: altered utility in the modern era.
J Clin Oncol. 2012; 30(27):3383-8 [PubMed]

PURPOSE: The International Prognostic Score (IPS) is the most widely used risk stratification index for Hodgkin's lymphoma (HL). It is based on patients treated before 1992 and predicts 5-year freedom from progression (FFP) and overall survival (OS) ranging from 42% to 84% and 56% to 89%, respectively. The IPS has not been validated in a recently treated population in which outcomes have improved compared with historic results.
PATIENTS AND METHODS: By using the British Columbia Cancer Agency Lymphoid Cancer Database, we identified all patients age ≥ 16 years newly diagnosed with advanced-stage HL (stage III to IV, or stage I to II with "B" symptoms or bulky disease ≥ 10 cm) from 1980 to 2010, treated with curative intent with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) or an ABVD-equivalent regimen with complete clinical information.
RESULTS: In all, 740 patients were identified. Five-year FFP and OS were 78% and 90%, respectively. The IPS was prognostic for both FFP (P < .001) and OS (P < .001), with 5-year FFP ranging from 62% to 88% and 5-year OS ranging from 67% to 98%. Analysis limited to patients age 16 to 65 years (n = 686) demonstrated a narrower range of outcomes, with 5-year FFP ranging from 70% to 88% and 5-year OS ranging from 73% to 98%.
CONCLUSION: The IPS remains prognostic for advanced-stage HL, but the range of outcomes has narrowed considerably. This improvement in outcome with ABVD should be acknowledged before consideration of alternate initial therapies and when comparing results from current trials with those of historic controls.

De Sanctis V, Bolzan C, D'Arienzo M, et al.
Intensity modulated radiotherapy in early stage Hodgkin lymphoma patients: is it better than three dimensional conformal radiotherapy?
Radiat Oncol. 2012; 7:129 [PubMed] Article available free on PMC after 15/12/2013

BACKGROUND: Cure rate of early Hodgkin Lymphoma are high and avoidance of late toxicities is of paramount importance. This comparative study aims to assess the normal tissue sparing capability of intensity-modulated radiation therapy (IMRT) versus standard three-dimensional conformal radiotherapy (3D-CRT) in terms of dose-volume parameters and normal tissue complication probability (NTCP) for different organs at risk in supradiaphragmatic Hodgkin Lymphoma (HL) patients.
METHODS: Ten HL patients were actually treated with 3D-CRT and all treatments were then re-planned with IMRT. Dose-volume parameters for thyroid, oesophagus, heart, coronary arteries, lung, spinal cord and breast were evaluated. Dose-volume histograms generated by TPS were analyzed to predict the NTCP for the considered organs at risk, according to different endpoints.
RESULTS: Regarding dose-volume parameters no statistically significant differences were recorded for heart and origin of coronary arteries. We recorded statistically significant lower V30 with IMRT for oesophagus (6.42 vs 0.33, p = 0.02) and lungs (4.7 vs 0.1 p = 0.014 for the left lung and 2.59 vs 0.1 p = 0.017 for the right lung) and lower V20 for spinal cord (17.8 vs 7.2 p = 0.02). Moreover the maximum dose to the spinal cord was lower with IMRT (30.2 vs 19.9, p <0.001). Higher V10 with IMRT for thyroid (64.8 vs 95, p = 0.0019) and V5 for lungs (30.3 vs 44.8, p = 0.03, for right lung and 28.9 vs 48.1, p = 0.001 for left lung) were found, respectively. Higher V5 and V10 for breasts were found with IMRT (V5: 4.14 vs 20.6, p = 0.018 for left breast and 3.3 vs 17, p = 0.059 for right breast; V10: 2.5 vs 13.6 p = 0.035 for left breast and 1.7 vs 11, p = 0.07 for the right breast.) As for the NTCP, our data point out that IMRT is not always likely to significantly increase the NTCP to OARs.
CONCLUSIONS: In HL male patients IMRT seems feasible and accurate while for women HL patients IMRT should be used with caution.

Forero-Torres A, Fanale M, Advani R, et al.
Brentuximab vedotin in transplant-naive patients with relapsed or refractory hodgkin lymphoma: analysis of two phase I studies.
Oncologist. 2012; 17(8):1073-80 [PubMed] Article available free on PMC after 01/08/2013

BACKGROUND: Brentuximab vedotin is an antibody-drug conjugate designed to selectively deliver monomethyl auristatin E, a microtubule-disrupting agent, to CD30-expressing cells. Brentuximab vedotin induces durable objective responses in patients with relapsed or refractory Hodgkin lymphoma (HL) after autologous stem cell transplantation (ASCT). The objective of this post-hoc analysis was to characterize the safety and efficacy of brentuximab vedotin for patients with relapsed or refractory HL who refused or were ineligible for ASCT.
METHODS: This case series included 20 transplant-naïve patients who were enrolled in two phase I multicenter studies. Patients received brentuximab vedotin intravenously every 3 weeks or every week for 3 out of 4 weeks.
RESULTS: The majority of patients were transplant-naïve because of chemorefractory disease. Median age was 31.5 years (range, 12-87 years). Treatment-emergent adverse events in >20% of patients were peripheral neuropathy, fatigue, nausea, pyrexia, diarrhea, weight decreased, anemia, back pain, decreased appetite, night sweats, and vomiting; most events were grade 1 or 2. Six patients obtained objective responses: two complete remissions and four partial remissions. Median duration of response was not met; censored durations ranged from >6.8 to >13.8 months. Three of six responders subsequently received ASCT.
CONCLUSION: Brentuximab vedotin was associated with manageable adverse events in transplant-naïve patients with relapsed or refractory HL. The objective responses observed demonstrate that antitumor activity is not limited to patients who received brentuximab vedotin after ASCT. The promising activity observed in this population warrants further study.

Omura Y, O'Young B, Jones M, et al.
Newly discovered quick, non-invasive screening method of bone marrow malignancies including various leukemias, Hodgkin's lymphoma, non-Hodgkin's lymphoma, & multiple myeloma by abnormality of small rectangular area within bone marrow organ representation areas of the face.
Acupunct Electrother Res. 2012; 37(1):13-47 [PubMed]

Diagnoses of bone marrow associated malignancies such as Acute & Chronic Lymphocytic Leukemia, Acute & Chronic Myelogenous (Myeloid) Leukemia, Hodgkin's Lymphoma & Non-Hodgkin's Lymphoma, and Multiple Myeloma are often missed without a blood test. However, in 2008, Omura Y reported several newly discovered organ representation areas that exist between the lower end of the eyebrows and upper end of the upper eyelid. This space was divided into 5 organ representation areas. The first space (more than 1/4 of entire space) near the side of the face (temple) is the bone marrow representation area (BMRA). Therefore, we examined the bone marrow representation areas non-invasively using the Bi-Digital O-Ring Test (BDORT). When the small rectangular shaped part of the BMRA is strong negative (-) with more than -2, often there is a malignancy associated with bone marrow. In this area, we found 1) Integrin alpha5beta1 & Oncogen C-fos Ab2 increased very significantly between 125-300 ng BDORT units; 2) very high Chrysotile Asbestos (0.11-0.14 mg); 3) markedly reduced Acetylcholine of less than 1 ng; 4) significantly reduced telomere of less than 1 yg (= 10(-24) g); and 5) Increased 8-OH-dG (often more than 5 ng). Once the abnormal small rectangular area is localized by BDORT, by detecting the specific microscope slide which produces EMF (electromagnetic field) resonance, one can diagnose these malignancies non-invasively in about 10 minutes. When a subject has any one of the above 7 types of bone marrow associated malignancies, the 5 aforementioned abnormal parameters can be detected. When Acetylcholine is markedly reduced to 0.25 ng or less, 8-OH-dG is 10 ng or higher, and Sirtuin 1 (one of the 7 mammalian longevity genes products) in both the Hippocampus and the body is 0.025 pg or less, most of the patients have a very poor prognosis. However, we found that increasing normal cell telomere & longevity gene product Sirtuin 1 can often improve both pathology & prognosis. All measurements are in BDORT units (the weight required to produce maximum EMF resonance).