Cancer-Related Fatigue and Circulating Biomarkers in Breast Cancer Survivors.

PURPOSE: Cancer-related fatigue (CRF) is the most common and disruptive symptom experienced by cancer survivors and because of its frequency and severity is especially worrisome in breast cancer survivors (BCS). Despite a great deal of research, the mechanisms underlying CRF have not been determined. The present study aims to describe associations between CRF in BCS and different blood biomarkers. METHODS: A descriptive and cross-sectional study was conducted. A set of biomarkers assessing inflammation were measured in BCS: C-reactive protein (CRP), neutrophil-lymphocyte ratio (NLR), IL-1ß, IL-6, IL-8, IL-10, tumor necrosis factor (TNF); HPA axis dysfunction (cortisol), autonomic dysfunction (noradrenaline); oxidative stress (8-OH deoxyguanosine); insulin resistance markers (insulin, IGF-I, IGFBP3) and sexual hormones (estrogens, progesterone, testosterone). RESULTS: NLR (p = .00) and cortisol (p = .02) were positive and negatively associated with CRF, respectively. The rest of the blood markers were not associated with CRF. CONCLUSION: Our results increase the evidence on pathophysiological mechanisms driving CRF in BCS. However, longitudinal studies are needed to explore the role of these factors as potential causal mechanisms.

Sexual dysfunction in patients with cancer, a challenge in oncology practice: results of the CLARIFY project.

BACKGROUND: Sexual dysfunction (SD) associated with oncological treatment is a common and understudied disorder. Our aim was to characterize SD in a cohort of Spanish patients. METHODS: Analytic observational study in patients included in the CLARIFY H2020 project at the Hospital Universitario Puerta de Hierro. Clinical variables and validated measures of sexual function were collected from October 2020 to May 2022. Frequency and quality of sexual activity were assessed. Descriptive, trend associations, and logistic regression analyses were performed. RESULTS: A total of 383 patients were included: breast cancer 68.14% (261), lung cancer 26.37% (101), and lymphoma 5.50% (21). Mean age was 56.5 years (range 33-88). 19.58% (75) were men and 80.42% (308) were women. 69% and 31% of men and women, respectively, reported being sexually active. The absolute frequency of overall sexual dissatisfaction was 76% in women and 24% in men. Women with breast cancer were most likely to have severe sexual dysfunction. Those with early disease had resolved complaints after 5 years. In multinomial logistic regression, significant associations were found in women with metastatic breast cancer and severe disorders of arousal (p 0.000), lubrication (p 0.002), orgasm (p 0.000), as well as dissatisfaction with sexual performance (p 0.000) and global sexual dissatisfaction (p 0.000). Women with lung cancer have severe arousal dysfunction (p 0.016) and global sexual dissatisfaction (p 0.044). CONCLUSIONS: Our population has a high prevalence of SD, which supports the need to increase awareness of this disorder among the medical oncology team and the importance of including sexual health assessment in oncological patient follow-up.

Patterns and outcome of unplanned care in lung cancer patients: an observational study in a medical oncology department.

Background: There is increasing interest in unplanned care utilization among lung cancer patients and its evaluation should allow the identification of areas for quality improvement. Being a major priority for transformation in oncology, we aim to measure the risk and burden of unplanned care in a medical oncology department and identify factors that determine acute care. Methods: This was an observational retrospective cohort study that included all lung cancer patients treated at Puerta de Hierro-Majadahonda University Hospital between January 1st 2016 and December 31st 2020. Data cut off: June 30th, 2021. The main objective was to assess the incidence of unplanned care, emergency department (ED) visits and unplanned hospital admissions, from the first visit to the medical oncology service and its potential conditioning variables, considering patient death as a competitive event. As secondary objectives, a description and a quality of unplanned care evaluation was carried out. Results: A total of 821 lung cancer patients, all histologies and stages, were included (median follow-up: 32.8 months). Six hundred and eighty-one patients required consultation in the ED (82.9%), and 558 required an unplanned admission (68%). Eighty-six percent of ED consultations and 80.9% of unplanned hospital admissions were related to cancer or its treatment. The 1-year cumulative incidence for ED consultation and for unplanned hospital admission was 71.3% (95% CI: 67.8-74.5%) and 56.7% (95% CI: 53-60%), respectively. In the multivariable analysis, a higher tumor stage increased the risk of consultation in the ED, while a higher stage, Eastern Cooperative Oncology Group performance status (ECOG PS) 2 compared to ECOG PS 0, male sex, opioid or steroid use at first consultation increased the risk of unplanned admission. Conclusions: Our study shows that lung cancer patients have an extremely high demand for unplanned care. It is an early need and related to cancer in the majority of consultations and admissions and therefore a key issue for the management of oncology departments. We must optimize the follow-up of patients with a higher risk of unplanned care, advanced lung cancer or symptomatic patients, incorporating remote monitoring strategies and early interventions, as developing specific urgent care pathways for a better comprehensive cancer care.

Assessing the risk of cardiovascular events in patients receiving immune checkpoint inhibitors.

Background: Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment. However, despite their excellent therapeutic effect, these medications typically result in a broad spectrum of toxicity reactions. Immune-related cardiotoxicity is uncommon but can be potentially fatal, and its true incidence is underestimated in clinical trials. The aim of this study is to assess the incidence and identify risk factors for developing a cardiac event in patients treated with ICIs. Methods: We conducted a single-institution retrospective study, including patients treated with ICIs in our center. The main outcomes were cardiac events (CE) and cardiovascular death. Results: A total of 378 patients were analyzed. The incidence of CE was 16.7%, during a median follow-up of 50.5 months. The multivariable analysis showed that age, a history of arrhythmia or ischemic heart disease, and prior immune-related adverse events were significantly associated with CE. Conclusion: CE during ICI treatment are more common than currently appreciated. A complete initial cardiovascular evaluation is recommended, especially in high-risk patients, being necessary a multidisciplinary approach of a specialized cardio-oncology team.

Chronodisruption and Ambulatory Circadian Monitoring in Cancer Patients: Beyond the Body Clock.

PURPOSE OF REVIEW: Circadian rhythms impose daily rhythms a remarkable variety of metabolic and physiological functions, such as cell proliferation, inflammation, and DNA damage response. Accumulating epidemiological and genetic evidence indicates that circadian rhythms' disruption may be linked to cancer. The integration of circadian biology into cancer research may offer new options for increasing cancer treatment effectiveness and would encompass the prevention, diagnosis, and treatment of this disease. RECENT FINDINGS: In recent years, there has been a significant development and use of multi-modal sensors to monitor physical activity, sleep, and circadian rhythms, allowing, for the very first time, scaling accurate sleep monitoring to epidemiological research linking sleep patterns to disease, and wellness applications providing new potential applications. This review highlights the role of circadian clock in tumorigenesis, cancer hallmarks and introduces the state-of-the-art in sleep-monitoring technologies, discussing the eventual application of insights in clinical settings and cancer research.

C-Reactive Protein Is Associated with Physical Fitness in Breast Cancer Survivors.

Background: Physical fitness (PF) is an expression of the physiological functioning of multiple body components. PF is an important prognostic factor in terms of cardiovascular mortality, cancer mortality, and all-cause mortality. PF has been related to some biomarkers in the general population but not in breast cancer survivors (BCS). Purpose: To evaluate the effects of PF on biomarkers potentially related to physical activity (PA) in a sample of BCS. Methods: Cross-sectional study. A total of 84 BCS (mean age 54) who had finished their treatment were recruited. Different components of PF were evaluated, namely body composition (anthropometry), cardiorespiratory fitness (one-mile walk test), muscular (handgrip and sit-to-stand timed test), and motor (gait speed) components. Sexual hormones, inflammation, and insulin resistance biomarkers were measured. Results: C-Reactive Protein (CRP) was associated with every component of physical fitness: cardiorespiratory fitness (p-value = 0.002), muscular (sit-to-stand timed test, p-value = 0.002) and motor (gait speed, p-value = 0.004) components, and body composition (body mass index, p-value = 0.003; waist, p-value < 0.000; and waist-to-hip index, p-value = 0.012). CRP also was associated with "poor physical condition," a constructed variable that encompasses all components of physical fitness (p-value < 0.001). Insulin was associated with cardiorespiratory fitness and gait speed (p-values = 0.002 and 0.024, respectively). Insulin-like Growth Factor-1 was negatively associated with waist perimeter and waist-to-hip ratio. Conclusions: CRP can also be considered an indicator of poor PF in BCS. Implications for cancer survivors: in case of elevation of CRP indicating cardiovascular risk, health professionals should recommend lifestyle changes to improve BCS physical condition.

Prevalence and correlates of cancer-related fatigue in breast cancer survivors.

PURPOSE: To identify potential correlates of cancer-related fatigue (CRF) after curative breast cancer (BC) treatment. The hypothesis was that fatigue would be more severe among women treated with cardiotoxic drugs, with poor physical condition and those who exercised less. METHODS: Observational cross-sectional design. Fatigue was evaluated through PERFORM Questionnaire (multi-item, multi-dimensional). Patient-reported assessments and objective information regarding clinical data, physical activity (PA) and physical condition were analysed as potential correlates of CRF. RESULTS: One hundred eighty women who remained free of disease were recruited. The prevalence of fatigue interfering with quality of life was 43%. Weight, resting and recovery heart rate were positively associated with fatigue. Age and time from diagnosis were negatively associated. Previous therapies, objectively assessed weekly PA, cardiorespiratory condition, muscular strength and adherence to Mediterranean diet were not associated with CRF. CONCLUSIONS: CRF is a prevalent problem after BC treatment. Objectively assessed PA, cardiorespiratory fitness and muscular strength did not predict CRF. The association of heart rate and fatigue deserves a further insight. Future research should include longitudinal studies and determination of biomarkers. IMPLICATIONS FOR CANCER SURVIVORS: BC survivors, especially younger and overweight women, should be informed about fatigue as a potential persistent symptom through all stages of the cancer trajectory and into survivorship. They also should be routinely screened for CRF.

Concurrent Exercise Interventions in Breast Cancer Survivors with Cancer-related Fatigue.

This study compared the effects of two supervised concurrent training interventions in breast cancer survivors with cancer-related fatigue at baseline. Twenty-three female breast cancer survivors (50±8 years) were randomized to a high- (n=13) or a moderate-intensity (n=10) training program. Both interventions lasted 16 weeks and included the same resistance exercises, but the aerobic component was supervised and more intense in the former (i.e., rating of perceived exertion of 7-8 vs. 6 on a 1-10 scale for the high and moderate-intensity intervention, respectively). The primary endpoint was fatigue perception. Endpoints were assessed at baseline and after 16 weeks. The p-value for statistical significance was set at 0.004 after Bonferroni correction for multiple comparisons. The high-intensity training program increased lower-limb muscle strength significantly (p=0.002) and tended to improve fatigue perception (p=0.006), waist circumference (p=0.013), neutrophil-to-lymphocyte ratio (p=0.028) and some quality of life items (p=0.011). Although the moderate-intensity training program did not provide such benefits in general (i.e., higher p-values for pre vs post-intervention comparisons), no significant differences were found between interventions (all p>0.004). Further research is needed to elucidate if the benefits provided by high-intensity concurrent training are superior to those elicited by moderate-intensity training in breast cancer survivors.

A Pilot, Phase II, Randomized, Open-Label Clinical Trial Comparing the Neurotoxicity of Three Dose Regimens of Nab-Paclitaxel to That of Solvent-Based Paclitaxel as the First-Line Treatment for Patients with Human Epidermal Growth Factor Receptor Type 2-Negative Metastatic Breast Cancer.

BACKGROUND: This study aimed to characterize the neurotoxicity of three different regimens of nab-paclitaxel compared with a standard regimen of solvent-based (sb) paclitaxel for the first-line treatment of HER2-negative metastatic breast cancer based on the Total Neurotoxicity Score (TNS), a tool specifically developed to assess chemotherapy-induced neurotoxicity. MATERIALS AND METHODS: This was a randomized, open-label study testing 4-week cycles of 80 mg/m2 sb-paclitaxel (PACL80/w) on days 1, 8, and 15; 100 mg/m2 nab-paclitaxel on days 1, 8, and 15 (NAB100/w); 150 mg/m2 nab-paclitaxel on days 1, 8, and 15 (NAB150/w); and 150 mg/m2 nab-paclitaxel on days 1 and 15 (NAB150/2w). In addition to the TNS, neuropathy was assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE). Tumor response and quality of life were also evaluated. RESULTS: Neurotoxicity, as evaluated by the TNS, did not significantly differ between the sb-paclitaxel group and any of the nab-paclitaxel groups. The frequency of (any grade) polyneuropathy, as measured by the NCI-CTCAE, was lower in the PACL80/w (n = 7, 50%) and NAB150/2w (n = 10, 62.5%) groups than in the NAB100/w (n = 13, 81.3%) or NAB150/w (n = 11, 78.6%) group. Although the differences were not statistically significant, compared with the other groups, in the NAB150/w group, the time to occurrence of grade ≥2 polyneuropathy was shorter, and the median time to recovery from grade ≥2 polyneuropathy was longer. Dose delays and reductions due to neurotoxicity and impact of neurotoxicity on the patients' experience of symptoms and functional limitations was greater with NAB150/w. Among the seven polymorphisms selected for genotyping, the variant alleles of EPHA5-rs7349683, EPHA6-rs301927, and EPHA8-rs209709 were associated with an increased risk of paclitaxel-induced neuropathy. CONCLUSION: The results of this exploratory study showed that, regardless of the dose, nab-paclitaxel did not differ from sb-paclitaxel in terms of neurotoxicity as evaluated with the TNS. However, results from NCI-CTCAE, dose delays and reductions, and functional tools consistently indicate that NAB150/w regimen is associated with a greater risk of chemotherapy-induced neuropathy. Thus, our results question the superiority of the TNS over NCI-CTCAE for evaluating chemotherapy-induced neuropathy and guiding treatment decisions in this context. The selection of the nab-paclitaxel regimen should be individualized based on the clinical context and potentially supported by pharmacogenetic analysis. Registry: EudraCT, 2012-002361-36; NCT01763710 IMPLICATIONS FOR PRACTICE: The results of this study call into question the superiority of the Total Neurotoxicity Score over the National Cancer Institute Common Terminology Criteria for Adverse Events for evaluating chemotherapy-induced neuropathy and guiding treatment decisions in this context and suggest that a regimen of 150 mg/m2 nab-paclitaxel administered on days 1, 8, and 15 is associated with a greater risk of chemotherapy-induced neuropathy and hematological toxicity compared with other lower-dose nab-paclitaxel regimens or a standard regimen of solvent-based paclitaxel. The selection of the nab-paclitaxel regimen should be individualized based on the clinical context and could benefit from pharmacogenetics analysis.

Cardiorespiratory fitness and adiposity in breast cancer survivors: is meeting current physical activity recommendations really enough?

PURPOSE: Breast cancer (BC) survivors are becoming increasingly predisposed to cardiovascular disease (CVD) mortality. Low cardiorespiratory fitness and physical activity (PA) levels, as well as high values of adiposity indices, contribute to CVD risk. We evaluated adiposity, cardiorespiratory profile, and PA levels in two independent cohorts of BC survivors. METHODS: Data were collected from two groups (99% women) from different areas of Madrid (Spain): group 1, n = 110, age 51.4 ± 9.7 years, median time from diagnosis 365 days (95% confidence interval [CI], 354-401), and group 2, n = 93, age 54.7 ± 8.9 years, 1714 days (95% CI, 1502-1938). We estimated peak oxygen uptake (VO2peak) and measured body mass index (BMI), waist circumference (WC), waist-to-hip index, and accelerometry-determined PA. RESULTS: Both groups had values of BMI in the overweight range (25.3 ± 4.3 and 27.1 ± 5.1 kg/m2, p = 0.003). Estimated VO2peak levels were lower in group 2 than in group 1 (28.1 ± 9.1 and 23.7 ± 8.8 ml/kg/min, p < 0.001), although levels in both groups were low. Yet, the majority of participants in both groups (81 and 88%, p = 0.234) met international PA recommendations (235 ± 196 and 351 ± 173 min/week of moderate-vigorous PA, p < 0.001). Both groups had very low levels of vigorous PA. These results were essentially independent of type of treatment (anthracycline/radiotherapy). CONCLUSIONS: We found a poor cardiorespiratory profile in two independent BC cohorts that differed in median time from diagnosis (as well in socioeconomic status), supporting the notion that implementation of PA (possibly focusing on vigorous PA) and dietary intervention is urgently needed in this patient population.

mRNA in exosomas as a liquid biopsy in non-Hodgkin Lymphoma: a multicentric study by the Spanish Lymphoma Oncology Group.

PURPOSE: To determine the feasibility of mRNAs (C-MYC, BCL-XL, BCL-6, NF-κß, PTEN and AKT) in exosomes of plasma as a liquid biopsy method for monitoring and prognostic evolution in B-cell lymphomas. PATIENTS AND METHODS: Exosomes were isolated from 98 patients with B-cell Lymphoma and 68 healthy controls. mRNAs were analyzed by quantitative PCR. An additional 31 post-treatment samples were also studied. RESULTS: In the general and follicular lymphoma series, the presence of AKT mRNA was associated with poor response to rituximab-based treatment. Patients with first relapse or disease progression showed a lower percentage of PTEN and BCL-XL mRNA. The presence of BCL-6 mRNA was associated with a high death rate. The absence of PTEN mRNA in the general series, and presence of C-MYC mRNA in follicular lymphomas, were associated with short progression-free survival. BCL-6 and C-MYC mRNA were independent prognostic variables of overall survival. C-MYC mRNA may provide prognostic information with respect to overall survival. BCL-XL mRNA and increase of BCL-6 mRNA in post-treatment samples could serve as molecular monitoring markers. CONCLUSIONS: This is the first large study to evaluate the prognostic and predictive values of pretreatment tumor-associated mRNA in exosomes. BCL-6 and C-MYC mRNA positivity in pretreatment samples were predictors of worse PFS compared to patients with mRNA negativity. C-MYC mRNA positivity was also a statistically significant predictor of inability to obtain complete response with first-line therapy.

Cisplatin plus vinorelbine as induction treatment in stage IIIA non-small cell lung cancer.

Survival rates in patients with stage IIIA non-small cell lung cancer (NSCLC) remain low despite curative treatment. This is due to tumor recurrence at distant sites. The aim of neoadjuvant chemotherapy (NA-CT) is to eradicate occult micrometastatic disease and improve survival in patients that are not candidates for surgery following induction therapy. A total of 21 patients with ipsilateral mediastinal node involvement (N2) with potentially resectable disease, who had been diagnosed with stage IIIA (T1-3 N1-2 and T4N0) NSCLC and who had received cisplatin and vinorelbine as induction treatment were included in this retrospective study. Patients who responded to the treatment underwent surgery, and those who were unresponsive received radical radiotherapy. Follow-up was conducted between March 2008 and April 2014. The median age of patients was 61 years, and all patients exhibited a good Eastern Cooperative Oncology Group performance status. The majority of patients were histologically diagnosed with adenocarcinoma (48%) or squamous cell carcinoma (38%), which was a poor prognostic factor for overall survival (OS). A total of 7 patients underwent surgery (of which 6 were down-staged), with a 3-year survival rate of 42.8%. The most significant factor associated with response to induction treatment was multistation nodal involvement. The complete resection rate for surgical patients was 85.7%. Unresectable patients had a 3-year survival rate of 25.8%. OS time for the whole cohort was 28.5 months, and the 3- and 5-year OS rates were 28.5% and 4.7%, respectively. CT-induced toxicity did not affect any treatment regime or surgical procedures. In conclusion, the use of cisplatin plus vinorelbine is feasible in a neoadjuvant setting, with good response rates and acceptable toxicity. Multistation N2 involvement is the main prognostic factor for a poor response to induction treatment.

Sentinel lymph node biopsy in breast cancer: the role of micrometastasis.

Intraoperative sentinel lymph node biopsy is widely used in patients with early-stage breast cancer for staging the axilla. The conventional analysis of the SLN has classically been performed by frozen section or touch imprint with a rapid H&E (hematoxylin and eosin) staining. Because of the risk of false-negative results, it has been replaced by the one-step acid amplification (OSNA) assay, a molecular diagnostic assay for the detection of cytokeratin 19 mRNA expression. Due to the controversial for the use of OSNA to evaluate the SLN because of its cost-effective and the lack of consensus to perform or avoid a lymphadenectomy when there is micrometastasis, we analyze 410 patients subjected to SLN biopsy in Hospital Puerta de Hierro, Madrid (Spain). Of the total of nodes, 223 (54.4 %) were processed throughout frozen-section examination and imprint cytology and 187 (45.6 %) throughout OSNA. The specificity of the frozen-section histological examination was of 100 %, with a sensitivity of 83.33 % (95 % CI 73.07-93.60). Of the 40 patients with definitive micrometastasis in the SLN, axillary dissection was performed in 90 % of the patients, with subsequent positive affectation in four of them (11.11 %). Based on our result and taking into account that 10 % of the lymphadenectomy performed after micrometastasis are positive, we do not believe that lymphadenectomy should be avoided after N(mi+) is detected in a SLN.

Does the presence of hepatitis virus B and C influence the evolution of diffuse large B-cell lymphoma?

Hepatitis infection has a high prevalence in patients with non-Hodgkin lymphoma. Our objective was to evaluate clinical characteristics and survival of patients diagnosed with diffuse large B-cell lymphoma (DLBCL) who were hepatitis B and/or C (HBV/HCV) positive. We reviewed 224 patents diagnosed with DLBCL and found 21 to be HBV/HCV positive (9.3%). Significant differences were found in the number of nodal regions affected, four in HBV/HCV positive versus two in virus negative patients, and in liver involvement, which was greater in HBV/HCV positive patients (28.6% vs. 10%, p = 0.028). No significant differences were found in the two groups with respect to the number of relapses or the probability of overall or progression-free survival. Despite the finding of differences with respect to stage, total number of nodal regions affected and liver involvement, HBV/HCV positive and negative patients with DLBCL should receive the same treatment, and the disease responds and evolves equally.

¿Puede la calidad del cuidado del paciente oncológico ser mejorada?: resultados de la puesta en marcha de una línea de atención telefónica en la enfermería oncológica / Can quality care of the oncology patient be improved? Results of the introduction of a healthcare help line in Oncological Nursing

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PET-CT in the staging and treatment of non-small-cell lung cancer.

Positron emission tomography with 2-((18)F)-fluoro- 2-deoxy-D-glucose (FDG-PET) is a metabolic imaging technique. FDG-PET is more accurate than CT for the evaluation of mediastinal involvement in patients with nonsmall- cell lung cancer, offering a high negative predictive value. It can detect occult metastases in 11% of patients, although the etiology of the extrathoracic isolated uptakes needs confirmation. Theoretically, FDG-PET can influence the planning volume for radiotherapy, primarily in patients with atelectasis. Quantification of metabolic activity using FDG-PET is influenced by the size of the lesion, glucose levels and the time elapsed since the isotope injection. More clinical trials are required to standardize the methods for performing PET, assess its use as a prognostic factor and for the evaluation of treatment response.

Activity of trabectidin in desmoplastic small round cell tumor.

Desmoplastic small round cell tumor (DSRCT) is a rare and aggressive cancer that typically arises in teenage boys. As a result of its low prevalence, there have been few studies of its treatment and impact on survival. Here, we report the case of a patient who was refractory to multiple drugs but remains stable with trabectedin. To our knowledge, this is the first published report that supports antitumoral activity of trabectedin in DSRCT.

Inoperable stage III non-small cell lung cancer: Current treatment and role of vinorelbine.

Most lung cancer patients are diagnosed with a non-resectable disease; and around 40% in advanced stages. Stage III non-small cell lung cancer (NSCLC) is a heterogeneous disease with great variations in its clinical extent which presents a major therapeutic challenge. Although chemo-radiotherapy treatment has become the most widely used, there is currently no consensus on the best standard treatment and the experience of the therapy team plays an important role in the decision taking. We review the treatment of inoperable stage III NSCLC and the role of concomitant vinorelbine in this clinical scenario.

Late relapses in Hodgkin lymphoma: a clinical and immunohistochemistry study.

Survival in Hodgkin lymphoma (HL) has significantly increased, and most relapses occur in the first 2 years. We analyzed the proportion of relapses occurring after 5 years, the method of detection, and survival in the database of patients with HL in our hospital (1967-2005). We undertook a retrospective study of clinical and molecular characteristics with the use of 12 different antibodies (Abs): CD30, CD15, CD20, CD3, BCL-2, BCL-6, CD57, EMA, p53, Ki-67, Aurora kinase A, and PAX-5. We studied 534 patients with HD and found 150 relapses (28%), 30 of which occurred 5 years after the end of treatment. The relapses were detected during a scheduled appointment in 16 (54%) asymptomatic patients. Seven of 30 patients relapsed with a different histological type. There were no statistically significant differences in survival between those patients with a late relapse and new remission and those who never relapsed. None of the molecular markers were associated with relapse. Long-term survival was not significantly different in relapsed patients with remission after treatment compared with patients who never relapsed. We need to maintain active follow-up in order to detect late and recoverable relapses.