Risk of colorectal polyps and of malignancies in asymptomatic carriers of mutations in the main DNA mismatch repair genes.

OBJECTIVE: Mutation carriers (Mut+) in DNA mismatch repair genes are predisposed to cancer of various organs and to adenomatous polyps; however, they may remain asymptomatic and cancer or polyp-free for several years. We purposed to analyse the clinical follow-up of individuals carrying constitutional mutations in the MLH1, MSH2 or MSH6 genes who were unaffected by benign polyps or malignant tumours at diagnosis. MATERIAL AND METHODS: Mut + subjects (n.81) were members of Lynch syndromes in whom mutations were detected between 1993 and 2015; all were asymptomatic at diagnosis. They were informed of the cancer risk and surveillance was suggested. As controls, 113 nongene carriers (Mut-) in the same Lynch families were identified. RESULTS: About one-fourth of the mutation carriers developed polyps, mostly adenomas; polyps were less (12%, p < .05) in Mut - subjects, and hyperplastic lesions were the prevalent histology. More polyps were detected in MLH1 vs. MSH2 mutation carriers. In Mut+, 21 malignant tumours developed in 14 carriers vs. 4 tumours in 3 patients among Mut- (p < .001). Tumours were mostly of the Lynch spectrum; however, three glioblastomas were developed, together with neoplasms of various organs (duodenum, thyroid, skin, lung and cervix). Mean age of tumour occurrence was 43.0 years in Mut + vs. 53.0 among Mut-. CONCLUSIONS: Cancer developed more often in Mut+, with no consistent difference between MLH1 and MSH2 carriers. More polyps (mostly adenomas) were detected in MLH1 carriers. The majority (13 of 21) of malignant tumours occurred in organs for which there is no recommended surveillance, and were lethal in three patients.

Novel agent-based salvage autologous stem cell transplantation for relapsed multiple myeloma.

High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is a standard frontline therapy for multiple myeloma (MM). Therapeutic options for patients with relapsed MM after ASCT include novel agents in different combos, salvage ASCT (sASCT), and allogeneic transplant, with no unique standard of care. We retrospectively analyzed 66 MM patients who relapsed after up-front single or double ASCT(s) and received novel agent-based sASCT at five Italian centers. Median event-free survival from up-front ASCT(s) to first relapse (EFS1) was 44 months. Seventy-three percent of patients received sASCT at first disease progression. Re-induction regimens were bortezomib based in 87% of patients. Response to re-induction therapy included complete response (CR) 18%, ≥ very good partial response (VGPR) 48%, and overall response rate (ORR) 83%. Response to sASCT included CR 44%, ≥ VGPR 77%, and ORR 94%. With a median follow-up of 24 months after sASCT, 39 patients experienced disease progression. Median EFS from sASCT (EFS2) was 17 months. Median overall survival from ASCT (OS1) and sASCT (OS2) was 166 and 43 months, respectively. EFS2 and OS2 were significantly shorter in patients with EFS1 ≤ 24 months, in patients who did not receive sASCT at first disease progression and in patients with extramedullary disease (EMD). In multivariate analysis, EFS1 ≤ 24 months was associated with shorter EFS2 and OS2, EMD was associated with shorter EFS2, and < CR after sASCT was associated with shorter OS2. Novel agent-based sASCT is a safe and effective procedure for relapsed MM.

Inverse probability weighting to estimate causal effect of a singular phase in a multiphase randomized clinical trial for multiple myeloma.

BACKGROUND: Randomization procedure in randomized controlled trials (RCTs) permits an unbiased estimation of causal effects. However, in clinical practice, differential compliance between arms may cause a strong violation of randomization balance and biased treatment effect among those who comply. We evaluated the effect of the consolidation phase on disease-free survival of patients with multiple myeloma in an RCT designed for another purpose, adjusting for potential selection bias due to different compliance to previous treatment phases. METHODS: We computed two propensity scores (PS) to model two different selection processes: the first to undergo autologous stem cell transplantation, the second to begin consolidation therapy. Combined stabilized inverse probability treatment weights were then introduced in the Cox model to estimate the causal effect of consolidation therapy miming an ad hoc RCT protocol. RESULTS: We found that the effect of consolidation therapy was restricted to the first 18 months of the phase (HR: 0.40, robust 95 % CI: 0.17-0.96), after which it disappeared. CONCLUSIONS: PS-based methods could be a complementary approach within an RCT context to evaluate the effect of the last phase of a complex therapeutic strategy, adjusting for potential selection bias caused by different compliance to the previous phases of the therapeutic scheme, in order to simulate an ad hoc randomization procedure. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01134484 May 28, 2010 (retrospectively registered) EudraCT: 2005-003723-39 December 17, 2008 (retrospectively registered).

Bortezomib-based therapy combined with high cut-off hemodialysis is highly effective in newly diagnosed multiple myeloma patients with severe renal impairment.

Multiple myeloma (MM) is often associated with renal insufficiency (RI) which adversely influences the prognosis. Several studies demonstrated that bortezomib can improve both renal function and outcome. We prospectively evaluated 21 newly diagnosed MM patients with severe renal impairment secondary to tubular-interstitial damage, most of them due to myeloma kidney, who were primarily treated with bortezomib-based therapy combined with high cut-off hemodialysis (HCOD). The median serum creatinine level at baseline was 6.44 mg dL(-1) and calculated median estimated glomerular filtration rate (eGFR), according to Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation, was 8 mL/min/1.73 m(2) . Serum free light chain (sFLC) median concentration was 6,040 mg L(-1) . Post induction and best stringent complete response rates were 19 and 38%, respectively. Responses were fast, occurring within a median of 1.4 months. The combination of bortezomib and HCOD led to a prompt and remarkable (>90%) decrease in sFLC levels. Sixteen patients (76%) became dialysis independent within a median of 32 days. With a median follow up of 17.2 months, the 3-year PFS and OS were 76 and 67%, respectively. No early deaths were observed. This study demonstrates that incorporation of bortezomib into induction therapy combined with HCOD is a highly effective strategy in rescuing renal function and improving outcomes in patients with MM and RI.

Bortezomib-thalidomide-dexamethasone is superior to thalidomide-dexamethasone as consolidation therapy after autologous hematopoietic stem cell transplantation in patients with newly diagnosed multiple myeloma.

In a randomized, phase 3 study, superior complete/near-complete response (CR/nCR) rates and extended progression-free survival were demonstrated with bortezomib-thalidomide-dexamethasone (VTD) versus thalidomide-dexamethasone (TD) as induction therapy before, and consolidation after, double autologous stem cell transplantation for newly diagnosed myeloma patients (intention-to-treat analysis; VTD, n = 236; TD, n = 238). This per-protocol analysis (VTD, n = 160; TD, n = 161) specifically assessed the efficacy and safety of consolidation with VTD or TD. Before starting consolidation, CR/nCR rates were not significantly different in the VTD (63.1%) and TD arms (54.7%). After consolidation, CR (60.6% vs 46.6%) and CR/nCR (73.1% vs 60.9%) rates were significantly higher for VTD-treated versus TD-treated patients. VTD consolidation significantly increased CR and CR/nCR rates, but TD did not (McNemar test). With a median follow-up of 30.4 months from start of consolidation, 3-year progression-free survival was significantly longer for the VTD group (60% vs 48% for TD). Grade 2 or 3 peripheral neuropathy (8.1% vs 2.4%) was more frequent with VTD (grade 3, 0.6%) versus TD consolidation. The superior efficacy of VTD versus TD as induction was retained despite readministration as consolidation therapy after double autologous transplantation. VTD consolidation therapy significantly contributed to improved clinical outcomes observed for patients randomly assigned to the VTD arm of the study. The study is registered at www.clinicaltrials.gov as #NCT01134484.

Bortezomib and dexamethasone as salvage therapy in patients with relapsed/refractory multiple myeloma: analysis of long-term clinical outcomes.

Bortezomib (bort)-dexamethasone (dex) is an effective therapy for relapsed/refractory (R/R) multiple myeloma (MM). This retrospective study investigated the combination of bort (1.3 mg/m(2) on days 1, 4, 8, and 11 every 3 weeks) and dex (20 mg on the day of and the day after bort) as salvage treatment in 85 patients with R/R MM after prior autologous stem cell transplantation or conventional chemotherapy. The median number of prior lines of therapy was 2. Eighty-seven percent of the patients had received immunomodulatory drugs included in some line of therapy before bort-dex. The median number of bort-dex cycles was 6, up to a maximum of 12 cycles. On an intention-to-treat basis, 55 % of the patients achieved at least partial response, including 19 % CR and 35 % achieved at least very good partial response. Median durations of response, time to next therapy and treatment-free interval were 8, 11.2, and 5.1 months, respectively. The most relevant adverse event was peripheral neuropathy, which occurred in 78 % of the patients (grade II, 38 %; grade III, 21 %) and led to treatment discontinuation in 6 %. With a median follow up of 22 months, median time to progression, progression-free survival (PFS) and overall survival (OS) were 8.9, 8.7, and 22 months, respectively. Prolonged PFS and OS were observed in patients achieving CR and receiving bort-dex a single line of prior therapy. Bort-dex was an effective salvage treatment for MM patients, particularly for those in first relapse.

Bortezomib- and thalidomide-induced peripheral neuropathy in multiple myeloma: clinical and molecular analyses of a phase 3 study.

A subanalysis of the GIMEMA-MMY-3006 trial was performed to characterize treatment-emergent peripheral neuropathy (PN) in patients randomized to thalidomide-dexamethasone (TD) or bortezomib-TD (VTD) before and after double autologous transplantation (ASCT) for multiple myeloma (MM). A total of 236 patients randomized to VTD and 238 to TD were stratified according to the emergence of grade ≥2 PN. Gene expression profiles (GEP) of CD138+ plasma cells were analyzed in 120 VTD-treated patients. The incidence of grade ≥2 PN was 35% in the VTD arm and 10% in the TD arm (P < 0.001). PN resolved in 88 and 95% of patients in VTD and TD groups, respectively. Rates of complete/near complete response, progression-free and overall survival were not adversely affected by emergence of grade ≥2 PN. Baseline characteristics were not risk factors for PN, while GEP analysis revealed the deregulated expression of genes implicated in cytoskeleton rearrangement, neurogenesis, and axonal guidance. In conclusion, in comparison with TD, incorporation of VTD into ASCT was associated with a higher incidence of PN which, however, was reversible in most of the patients and did not adversely affect their outcomes nor their ability to subsequently receive ASCT. GEP analysis suggests an interaction between myeloma genetic profiles and development of VTD-induced PN.

Prognostic relevance of 18-F FDG PET/CT in newly diagnosed multiple myeloma patients treated with up-front autologous transplantation.

We prospectively analyzed the prognostic relevance of positron emission tomography-computed tomography (PET/CT) at diagnosis, after thalidomide-dexamethasone (TD) induction therapy and double autotransplantation (ASCT) in 192 newly diagnosed multiple myeloma (MM) patients. Presence at baseline of at least 3 focal lesions (FLs; 44% of cases), a standardized uptake value (SUV) > 4.2 (46%), and extramedullary disease (EMD; 6%) adversely affected 4-year estimates of progression-free survival (PFS; ≥ 3 FLs: 50%; SUV > 4.2: 43%; presence of EMD: 28%). SUV > 4.2 and EMD were also correlated with shorter overall survival (OS; 4-year rates: 77% and 66%, respectively). Persistence of SUV > 4.2 after TD induction was an early predictor for shorter PFS. Three months after ASCT, PET/CT was negative in 65% of patients whose 4-year rates of PFS and OS were superior to those of PET-positive patients (PFS: 66% and OS: 89%). In a multivariate analysis, both EMD and SUV > 4.2 at baseline and persistence of fluorodeoxyglucose (FDG) uptake after ASCT were independent variables adversely affecting PFS. PET/CT involvement at diagnosis, after novel agent-based induction and subsequent ASCT is a reliable predictor of prognosis in MM patients. This study is registered at www.clinicaltrials.gov as NTC01341262.

Lymph node micrometastasis and survival of patients with Stage I (Dukes' A) colorectal carcinoma.

OBJECTIVE: Although patients with Stage I colorectal cancer show an excellent prognosis, a few of them die of metastatic disease. In this subgroup of individuals, the search of occult metastasis might reveal that early dissemination of tumor cells could be the cause of cancer progression. MATERIAL AND METHODS: Through a Cancer Registry, we selected all patients with Stage I disease who died of metastatic tumor; a total of 32 patients were identified and in 25 of them paraffin-embedded material was available. The group was matched to 70 Stage I patients with favorable prognosis (controls). In cases and controls resected lymph nodes were cut, and micrometastases were searched using pan-cytokeratin antibodies. RESULTS: Micrometastases were detected in 18 of 25 (72%) Stage I patients who died of the disease, while they were almost absent among controls (1 of 70, p < 0.001 by χ(2) test). Vascular invasion and tumor budding were more frequent among Stage I patients with an unfavorable prognosis than in controls. By regression analyses, micrometastases (HR 12.3, CI 4.8-32) and vascular invasion (HR 3.5, CI 1.4-8.5) maintained an independent association with prognosis (cancer-specific survival). CONCLUSION: Micrometastasis in the lymph nodes can be revealed in the majority of patients with early colorectal cancer who die of tumor progression, while they appear extremely rare in Stage I individuals with good prognosis. The selection of patients through histology (vascular invasion) and search of occult metastatic cells might represent a way to identify individuals who might benefit from adjuvant chemotherapy.

Relative role of APC and MUTYH mutations in the pathogenesis of familial adenomatous polyposis.

OBJECTIVE: Familial adenomatous polyposis (FAP) is an interesting model for the study of colorectal tumour. Two genes contribute to the FAP phenotype - APC and MUTYH - but their relative role is still undefined. The objective of this study was to evaluate the contribution of the two genes to the pathogenesis of FAP by means of a series of FAP families. MATERIAL AND METHODS: Sixty-one unrelated families with a diagnosis of FAP and a total of 187 affected individuals were evaluated. After extracting DNA, APC and MUTYH genes were sequenced. RESULTS: In the whole series of patients, colectomy with ileorectal anastomosis was the most frequent surgery, although the number of patients treated by total proctocolectomy and ileoanal anastomosis was increasing. Duodenal and jejunal-ileal adenomas were present in more than half of the patients. Constitutional mutations were detected in 37 of the 45 families (82.2%); there were 33 families with APC and 4 with MUTYH alterations. Age at onset of polyposis and age at surgery were 10-15 years delayed for carriers of MUTYH mutations; cancer at diagnosis was frequent, and extracolonic manifestations were diagnosed in the majority of MUTYH-positive families. MUTYH-associated polyposis showed the horizontal transmission expected for recessive inheritance (at variance with the dominant pattern seen with APC mutations). CONCLUSIONS: At least two genes are associated with the FAP phenotype. APC mutations account for the majority of cases, while MUTYH mutations can be observed in 10% of patients. There are few but definite differences between APC- and MUTYH-associated FAP, such as age at diagnosis and pattern of transmission.

Survival, surgical management and perioperative mortality of colorectal cancer in the 21-year experience of a specialised registry.

BACKGROUND AND AIMS: A general improvement of colorectal cancer prognosis has been observed. Reasons of this more favourable trend are diffusion of screening, advancements in molecular biology, new developments in chemotherapy and surgical techniques. Through the data of a colorectal cancer registry, we purposed to evaluate changes in surgical procedures for colorectal neoplasms and to analyse trends of perioperative mortality. PATIENTS AND METHODS: Patients with colorectal cancer were registered from 1984 to 2004. The main surgical procedures were recorded and classified. Perioperative mortality was defined as death of patients within 1 month since the operation. RESULTS: Regression analysis showed an increase over time of right and left hemicolectomy. Both colectomy and endoscopic polypectomy showed significant rise over time. In contrast, abdominoperineal operations dropped during the study period. A similar decrease was observed for palliative surgery. Perioperative mortality declined from 7-11% to 3-6% of all operations; main factors associated with perioperative mortality were presence of comorbidities, increasing age and advanced stage. CONCLUSION: The better prognosis of patients with colorectal cancer was associated with changes of surgical techniques, with a tendency to prefer large operations over limited resections. Perioperative mortality showed a gradual decrease and is at present in the order of 3% to 6% of all operations.

Myeloperoxidase-positive cell infiltration in colorectal carcinogenesis as indicator of colorectal cancer risk.

Colorectal mucosa is targeted by toxic agents, which can initiate or promote colon cancer. The mechanism of damage might be a focal irritation with loss of normal epithelial cell barrier function. Genetic alterations in tumors may also affect host inflammatory response. The aim of this study was to define the extent of inflammation in colorectal mucosa, along colorectal carcinogenesis, and in microsatellite stable and unstable colorectal carcinomas. We collected 103 samples of normal colorectal mucosa from 65 patients (35 with colorectal cancer or adenoma, 8 with inflammatory bowel diseases, and 22 controls with normal colonoscopy). We also examined 24 aberrant crypt foci, 14 hyperplastic polyps, 16 adenomas, and 67 samples of colorectal carcinoma. Immunohistochemistry was used to count myeloperoxidase (MPO)-positive cells (neutrophils and monocytes) in x100 optical fields under a light microscope. Patients with colorectal tumors had a higher mean number of MPO-positive cells in normal mucosa than controls (mean +/- SD, 2.7 +/- 2.0 versus 1.4 +/- 1.4; P = 0.017). MPO-positive cell number was tightly linked to dysplasia in aberrant crypt foci and adenomas, and it was higher in carcinomas microsatellite unstable than those microsatellite stable (21.6 +/- 15.5 versus 11.9 +/- 8.0; P < 0.01). MPO immunohistochemistry is a simple and reliable technique for the quantification of inflammation in colorectal mucosa., and it may be a potential marker of colorectal cancer risk. Microsatellite instability seems to influence host immune responses to colorectal carcinoma. These observations strongly support a key role of inflammation in colorectal carcinogenesis.

Extracellular ATP induces apoptosis through P2X7R activation in acute myeloid leukemia cells but not in normal hematopoietic stem cells.

Recent studies have shown that high ATP levels exhibit direct cytotoxic effects on several cancer cells types. Among the receptors engaged by ATP, P2X7R is the most consistently expressed by tumors. P2X7R is an ATP-gated ion channel that could drive the opening of a non-selective pore, triggering cell-death signal. We previously demonstrated that acute myeloid leukemia (AML) cells express high level of P2X7R. Here, we show that P2X7R activation with high dose ATP induces AML blast cells apoptosis. Moreover, P2X7R is also expressed on leukemic stem/progenitor cells (LSCs) which are sensitive to ATP-mediated cytotoxicity. Conversely, this cytotoxic effect was not observed on normal hematopoietic stem/progenitor cells (HSCs). Notably, the antileukemic activity of ATP was also observed in presence of bone marrow stromal cells and its addition to the culture medium enhanced cytosine arabinoside cytotoxicity despite stroma-induced chemoresistance. Xenotransplant experiments confirmed ATP antineoplastic activity in vivo.Overall, our results demonstrate that P2X7R stimulation by ATP induced a therapeutic response in AML at the LSC level while the normal stem cell compartment was not affected. These results provide evidence that ATP would be promising for developing innovative therapy for AML.

Attenuated polyposis of the large bowel: a morphologic and molecular approach.

Attenuated polyposis could be defined as a variant of familial adenomatous polyposis (FAP) in which synchronous polyps of the large bowel range between 10 and 99. We analysed all cases of attenuated polyposis observed over the last 30 years with the objectives: (A) to classify the disease according to different type and proportion of polyps; (B) To ascertain the contribution of APC and MutYH genes; (C) to discover features which could arise the suspicion of mutations; (D) To obtain indications for management and follow-up. 84 individuals in 82 families were studied. Polyps were classified into four groups as adenoma, hyperplastic, other serrated lesions or others; APC and MutYH mutations were assessed. Mean age at diagnosis was 54 ± 14 years in men and 48 ± 13 in women (P = 0.005). Polyps were more numerous in women (37 ± 26 vs 29 ± 22). Sixty % of patients underwent bowel resection, mainly for cancer; the remaining were managed through endoscopy. A total of 2586 polyps were detected at diagnostic endoscopy: 2026 (80 %) were removed and analysed. Adenomas were diagnosed in 1445 (70 %), hyperplastic polyps in 541 (26 %), other serrated lesions in 61 (2.9 %). Adenomas and hyperplastic lesions were detected in the majority of patients. In 68 patients (81 %) in whom studies were executed, APC mutations were found in 8 and MutYH mutations in 10. Genetic variants were more frequent in women (12 vs 6, P = 0.039). Taking into consideration the prevalent (>50 %) histology and presence of mutations, patients could be subdivided into four groups: (1) APC mutated polyposis (AFAP), when adenomas were >50 % and APC mutations detected (no. 8, 10 %); (2) MutYH mutated polyposis (MAP), adenomas >50 % and biallelic MutYH mutations (no. 10, 12 %); (1) attenuated polyposis without detectable mutations, prevalence of adenomas, 48 cases (57 %); (1) hyperplastic-serrated polyposis, with prevalence (>50 %) of hyperplastic/other serrated lesions and no constitutional mutation (no. 18, 21 %). Aggregation of tumors, cancer in probands, distribution of polyps and other clinical characteristics showed no difference among the four groups. In conclusions, AFAP and MAP, the polyposis labeled by constitutional mutations, represented about 25 % of all attenuated polyposis. Mutation-associated cases showed an earlier age of onset of polyps and were more frequent in the female sex.

Prognostic impact of serial measurements of serum-free light chain assay throughout the course of newly diagnosed multiple myeloma treated with bortezomib-based regimens.

We retrospectively investigated the role of serial serum-free light chain (sFLC) evaluations in 150 multiple myeloma (MM) patients treated with first-line bortezomib-based regimens. Baseline sFLC ratio (sFLCR) identified three groups of patients - normal, lightly abnormal (<100), and highly abnormal (≥100) - with different progression-free survival (PFS: 3-year estimate 72% versus 61% versus 44%, respectively, p = 0.03). Moreover, the achievement of a normal sFLCR correlated with extended PFS (49 versus 17 months, p < 0.0001) and overall survival (75 versus 43 months, p < 0.0001) as compared with abnormal sFLCR, a gain maintained in a multivariate analysis for PFS. At relapse, a high sFLCR was associated with earlier start of salvage therapy compared with sFLCR <100 (3-month probability: 89% versus 64%, p = 0.0426). In 20% of patients, sFLC escape preceded the conventional relapse by a median of 3.8 months. Our results highlight the role of sFLC assay in the prognosis and follow-up of MM.

The genetic and genomic background of multiple myeloma patients achieving complete response after induction therapy with bortezomib, thalidomide and dexamethasone (VTD).

The prime focus of the current therapeutic strategy for Multiple Myeloma (MM) is to obtain an early and deep tumour burden reduction, up to the level of complete response (CR). To date, no description of the characteristics of the plasma cells (PC) prone to achieve CR has been reported. This study aimed at the molecular characterization of PC obtained at baseline from MM patients in CR after bortezomib-thalidomide-dexamethasone (VTD) first line therapy.One hundred and eighteen MM primary tumours obtained from homogeneously treated patients were profiled both for gene expression and for single nucleotide polymorphism genotype. Genomic results were used to obtain a predictor of sensitivity to VTD induction therapy, as well as to describe both the transcription and the genomic profile of PC derived from MM with subsequent optimal response to primary induction therapy.By analysing the gene profiles of CR patients, we identified a 5-gene signature predicting CR with an overall median accuracy of 75% (range: 72%-85%). In addition, we highlighted the differential expression of a series of genes, whose deregulation might explain patients' sensitivity to VTD therapy. We also showed that a small copy number loss, covering 606Kb on chromosome 1p22.1 was the most significantly associated with CR patients.

PET/CT Improves the Definition of Complete Response and Allows to Detect Otherwise Unidentifiable Skeletal Progression in Multiple Myeloma.

PURPOSE: To evaluate the role of 18F-FDG PET/CT in 282 symptomatic multiple myeloma patients treated up-front between 2002 and 2012. EXPERIMENTAL DESIGN: All patients were studied by PET/CT at baseline, during posttreatment follow-up, and at the time of relapse. Their median duration of follow-up was 67 months. RESULTS: Forty-two percent of the patients at diagnosis had >3 focal lesions, and in 50% SUVmax was >4.2; extramedullary disease was present in 5%. On multivariate analysis, ISS stage 3, SUVmax >4.2, and failure to achieve best complete response (CR) were the leading factors independently associated with shorter progression-free survival (PFS) and overall survival (OS). These 3 variables were used to construct a prognostic scoring system based on the number of risk factors. After treatment, PET/CT negativity (PET-neg) was observed in 70% of patients, whereas conventionally defined CR was achieved in 53%. Attainment of PET-neg favorably influenced PFS and OS. PET-neg was an independent predictor of prolonged PFS and OS for patients with conventionally defined CR. Sixty-three percent of patients experienced relapse or progression; in 12%, skeletal progression was exclusively detected by systematic PET/CT performed during follow-up. A multivariate analysis revealed that persistence of SUVmax >4.2 following first-line treatment was independently associated with exclusive PET/CT progression. CONCLUSIONS: PET/CT combined with ISS stage and achievement or not of CR on first-line therapy sorted patients into different prognostic groups. PET/CT led to a more careful evaluation of CR. Finally, in patients with persistent high glucose metabolism after first-line treatment, PET/CT can be recommended during follow-up, to screen for otherwise unidentifiable progression.