Cobimetinib plus atezolizumab in BRAFV600 wild-type melanoma: primary results from the randomized phase III IMspire170 study.

BACKGROUND: Emerging data suggest that the combination of MEK inhibitors and immunotherapeutic agents may result in improved efficacy in melanoma. We evaluated whether combining MEK inhibition and immune checkpoint inhibition was more efficacious than immune checkpoint inhibition alone in patients with previously untreated BRAFV600 wild-type advanced melanoma. PATIENTS AND METHODS: IMspire170 was an international, randomized, open-label, phase III study. Patients were randomized 1 : 1 to receive cobimetinib (60 mg, days 1-21) plus anti-programmed death-ligand 1 atezolizumab (840 mg every 2 weeks) in 28-day cycles or anti-programmed death-1 pembrolizumab (200 mg every 3 weeks) alone until loss of clinical benefit, unacceptable toxicity, or consent withdrawal. The primary outcome was progression-free survival (PFS), assessed by an independent review committee in the intention-to-treat population. RESULTS: Between 11 December 2017, and 29 January 2019, 446 patients were randomized to receive cobimetinib plus atezolizumab (n = 222) or pembrolizumab (n = 224). Median follow-up was 7.1 months [interquartile range (IQR) 4.8-9.9] for cobimetinib plus atezolizumab and 7.2 months (IQR 4.9-10.1) for pembrolizumab. Median PFS was 5.5 months [95% confidence interval (CI) 3.8-7.2] with cobimetinib plus atezolizumab versus 5.7 months (95% CI 3.7-9.6) with pembrolizumab [stratified hazard ratio 1.15 (95% CI 0.88-1.50); P = 0.30]. Hazard ratios for PFS were consistent across prespecified subgroups. In exploratory biomarker analyses, higher tumor mutational burden was associated with improved clinical outcomes in both treatment arms. The most common grade 3-5 adverse events (AEs) were increased blood creatine phosphokinase (10.0% with cobimetinib plus atezolizumab versus 0.9% with pembrolizumab), diarrhea (7.7% versus 1.9%), rash (6.8% versus 0.9%), hypertension (6.4% versus 3.7%), and dermatitis acneiform (5.0% versus 0). Serious AEs occurred in 44.1% of patients with cobimetinib plus atezolizumab and 20.8% with pembrolizumab. CONCLUSION: Cobimetinib plus atezolizumab did not improve PFS compared with pembrolizumab monotherapy in patients with BRAFV600 wild-type advanced melanoma.

Baseline neutrophils and derived neutrophil-to-lymphocyte ratio: prognostic relevance in metastatic melanoma patients receiving ipilimumab.

BACKGROUND: Clinical responses to ipilimumab are variable in terms of onset, magnitude and duration. Upfront identification of patients who are more likely or unlikely to benefit from treatment is a major need. PATIENTS AND METHODS: Prospectively collected data from 720 advanced melanoma patients treated with ipilimumab 3 mg/kg within the Italian expanded access program were analyzed. The derived neutrophil-to-lymphocyte ratio (dNLR) was calculated from baseline peripheral blood cell counts, and receiver operating characteristic curve was used to evaluate the best cutoff for this marker. Patients were stratified according to dichotomized baseline absolute neutrophil counts (ANC), dNLR and their combination. The prognostic values of ANC and dNLR for survival were assessed using multivariate Cox proportional hazard models. A subgroup analysis including LDH in the models was also carried out. RESULTS: The median follow-up was 16.5 months. The optimal cutoff for dNLR was 3. Baseline ANC and dNLR were significantly associated with the outcome of ipilimumab-treated melanoma patients, in terms of disease progression and death (P < 0.0001 for all). Furthermore, for each elevated variable, prognosis worsened. Patients with both ANC ≥ 7500 and dNLR ≥ 3 had a significantly and independently increased risk of death [hazard ratio(HR) = 5.76; 95% confidence interval (CI) 4.29-7.75] and of progression (HR = 4.10; 95% CI 3.08-5.46) compared with patients with both lower ANC and dNLR. Patients with one of the two factors elevated displayed an intermediate risk of progression and death. The 1- and 2-year survival rates were 2% and 0%, respectively, for patients with ANC ≥ 7500 and dNLR ≥ 3, and 43% and 24%, respectively, for patients with both lower ANC and dNLR. CONCLUSIONS: Although these findings need to be confirmed and validated, we suggest that a neutrophil-based index may help risk-group stratification and assist disease-management strategies. Furthermore, the potential predictive value of this index for response to ipilimumab should be investigated in randomized clinical trials.

Risk of second primary malignancies among 1537 melanoma patients and risk of second primary melanoma among 52 354 cancer patients in Northern Italy.

BACKGROUND: The number of melanoma survivors has been increasing for decades due to early diagnosis and improved survival. These patients have an increased risk of developing a second primary cancer (SPC); also, melanoma is frequently diagnosed among patients firstly diagnosed with an extracutaneous malignancy. OBJECTIVE: We evaluated the risk of developing a SPC among 1537 melanoma patients, and the risk of second primary melanoma (SPM) in 52 354 extracutaneous cancer patients, who were treated at the European Institute of Oncology in Milan, Italy, during 2000-2010. MATERIAL AND METHODS: We calculated standardized incidence ratios (SIR) by applying gender-, age-, year- and region-specific reference rates to the follow-up time accrued between the diagnosis of the first and the second primary malignancies. RESULTS: Seventy-six SPC were diagnosed during a median follow-up of 4 years, of which 49 (64%) during the first 2 years upon melanoma diagnosis. The SIR was increased for cancer of breast (4.10, 95% CI 2.79-6.03), thyroid (4.67, 95% CI 1.94-11.22), brain (6.13, 95% CI 2.30-16.33) and for non-Hodgkin lymphoma (3.12, 95% CI 1.30-7.50). During a median follow-up of 4 years, 127 SPM were diagnosed: thick lesions were less frequent than for melanoma diagnosed as first cancer. The SIR was increased for cancer of breast (5.13, 95%CI 3.91-6.73), thyroid (16.2, 95%CI: 5.22-50.2), head and neck (5.62, 95%CI 1.41-22.50), soft tissue (8.68, 95%CI 2.17-34.70), cervix (12.5, 95% CI 3.14-50.20), kidney (3.19, 95%CI 1.52-6.68), prostate (4.36, 95%CI 2.63-7.24) and acute myeloid leukaemia (6.44, 95%CI 2.42-17.20). CONCLUSIONS: The most likely causes of these associations are the clustering of lifestyle risk factors in the same subgroups of population, mainly on a sociocultural basis and surveillance bias. This raises important questions about how to best follow cancer survivors by avoiding an inefficient use of resources and an excessive medicalization of these patients' lives.

Baseline neutrophil-to-lymphocyte ratio is associated with outcome of ipilimumab-treated metastatic melanoma patients.

BACKGROUND: Ipilimumab improves the survival of metastatic melanoma patients. Despite documented, durable objective responses, a significant number of patients fails to benefit from treatment. The aim of this study was to identify an upfront marker for treatment benefit. METHODS: A total of 187 metastatic melanoma patients treated in three Italian Institutions with 3 mg kg(-1) ipilimumab, and 27 patients treated with 10 mg kg(-1) ipilimumab, were evaluated. Neutrophil-to-lymphocyte ratio (NLR) was calculated from pre-therapy full blood counts. Progression-free survival (PFS) and overall survival (OS) were assessed using the Kaplan-Meier method, and multivariate Cox models were applied, adjusting for confounders and other prognostic factors. RESULTS: In the training cohort of 69 patients treated at European Institute of Oncology, pre-therapy NLR was identified as the strongest and independent marker for treatment benefit in multivariate analyses. Patients with baseline NLR<5 had a significantly improved PFS (HR=0.38; 95% CI: 0.22-0.66; P=0.0006) and OS (HR=0.24; 95% CI: 0.13-0.46; P<0.0001) compared with those with a NLR⩾5. Associations of low NLR with improved survival were confirmed in three validation cohorts of patients. CONCLUSION: Our findings show that baseline NLR is strongly and independently associated with outcome of patients treated with ipilimumab, and may serve to identify patients most likely to benefit from this therapy.

Ipilimumab retreatment in patients with pretreated advanced melanoma: the expanded access programme in Italy.

BACKGROUND: Retreatment with ipilimumab has been shown to re-establish disease control in some patients with disease progression. Here, we report the efficacy and safety of retreatment with ipilimumab 3 mg kg(-1) among patients participating in an expanded access programme in Italy. METHODS: Patients who achieved disease control during induction therapy were retreated with ipilimumab upon progression (3 mg kg(-1) every 3 weeks for up to four doses), providing they had not experienced toxicity that precluded further dosing. Tumour assessments were conducted after retreatment, and patients were monitored throughout for adverse events. RESULTS: Of 855 patients treated with ipilimumab, 51 were retreated upon disease progression. Of these, 28 (55%) regained disease control upon retreatment and 42% were alive 2 years after the first induction dose of ipilimumab; median overall survival was 21 months. Eleven patients (22%) had a treatment-related adverse event of any grade during retreatment. These were generally mild-to-moderate and resolved within a median of 4 days. No new types of toxicity were reported. CONCLUSIONS: For patients who meet predefined criteria, retreatment with ipilimumab is generally well tolerated and can translate into clinical benefit. This strategy should be compared with other therapeutic options in randomised controlled trials.

Baseline neutrophil-to-lymphocyte ratio (NLR) is associated with outcome of patients treated with BRAF inhibitors.

PURPOSE: The aim of this study is to verify if baseline hematological markers, in patients with advanced melanoma receiving BRAF inhibitor (BRAFi)-based therapies, are independently associated with progression free survival (PFS) and overall survival (OS). METHODS: We retrospectively analyzed 90 patients with metastatic melanoma harboring BRAF V600 mutation, who received treatment with either BRAFi alone or combined with a MEK inhibitor (MEKi) at the recommended dosages. Study population included 28 women and 62 men. Median age was 53 years. Seventy-three (82%) patients presented with M1c disease, 49 (56%) had elevated LDH and 54 (60%) had three or more metastatic sites. RESULTS: The median PFS was 9.1 and 3.5 months, respectively, for patients with baseline NLR < 5 and NLR ≥ 5, while median OS was 17.2 and 5.5 months, respectively, for patients with NLR < 5 and NLR ≥ 5. Multivariate analysis confirmed that baseline NLR < 5 was significantly associated with half risk of relapse (HR = 0.49; 95% CI = 0.28-0.85; p = 0.01) and half risk of death (HR = 0.46; 95% CI = 0.23-0.76; p = 0.004), independent of age, sex, stage, LDH > 2xULN, previous treatments, concomitant use of steroids and type of therapy. In patients with LDH ≥ ULN, NLR < 5 remained significantly and independently associated with improved PFS (HR = 0.28; 95% CI = 0.13-0.62; p = 0.002,) and OS (HR = 0.23; 95% CI = 0.10-0.55; p = 0.001). CONCLUSIONS: These biomarkers are easily reproducible, affordable and costless and NLR could help to identify patients who have the best benefit from BRAF inhibitors.

A new comprehensive gene expression panel to study tumor micrometastasis in patients with high-risk breast cancer.

The incidence and prognostic relevance of bone marrow (BM) and leukapheresis (PBPC) tumor cell contamination (TCC) in breast cancer patients is still to be circumstantiated. We developed a new comprehensive gene expression panel to study cytokeratins (CK), maspin (MAS) and mammaglobin (MAM) as possible predictors of prognosis. Forty-eight patients undergoing high dose chemotherapy (HDCT) and PBPC support were enrolled and analyzed for TCC on 116 PBPC apheresis and 96 BM obtained at basal conditions. All of the patients were evaluated by reverse transcriptase nested PCR (RT-PCR) for MAM and MAS gene expression and by immunocytochemistry (ICC) and nested RT-PCR to evaluate CK expression. PBPC and BM frequency of CK-positive (+) cells was 12-13% by ICC and 71-73% by RT-PCR respectively. Sixty-seven percent of CK ICC+ samples were MAM RT-PCR+ and 89% of them were MAS RT-PCR+. PBPC and BM frequency of MAM+ cells was 21% and 31% respectively, while for MAS+ cells it was 48% and 52% respectively by RT-PCR. After 71 mo median FU, 16 patients (33%) relapsed and 14 (88%) had BM/PBPC TCC. No marker had an impact on overall survival (OS) but MAS expression on BM and MAM expression on PBPC correlated with a statistically significant improved (p=0.05) and worsened RFS (p=0.06) respectively. These data confirm the activity of MAM as a negative prognostic factor and show for the first time that MAS could work as a tumor suppressor gene even in a clinical setting, since it protects from recurrence.

Opposite effects of the acute promyelocytic leukemia PML-retinoic acid receptor alpha (RAR alpha) and PLZF-RAR alpha fusion proteins on retinoic acid signalling.

Fusion proteins involving the retinoic acid receptor alpha (RAR alpha) and the PML or PLZF nuclear protein are the genetic markers of acute promyelocytic leukemias (APLs). APLs with the PML-RAR alpha or the PLZF-RAR alpha fusion protein are phenotypically indistinguishable except that they differ in their sensitivity to retinoic acid (RA)-induced differentiation: PML-RAR alpha blasts are sensitive to RA and patients enter disease remission after RA treatment, while patients with PLZF-RAR alpha do not. We here report that (i) like PML-RAR alpha expression, PLZF-RAR alpha expression blocks terminal differentiation of hematopoietic precursor cell lines (U937 and HL-60) in response to different stimuli (vitamin D3, transforming growth factor beta1, and dimethyl sulfoxide); (ii) PML-RAR alpha, but not PLZF-RAR alpha, increases RA sensitivity of hematopoietic precursor cells and restores RA sensitivity of RA-resistant hematopoietic cells; (iii) PML-RAR alpha and PLZF-RAR alpha have similar RA binding affinities; and (iv) PML-RAR alpha enhances the RA response of RA target genes (those for RAR beta, RAR gamma, and transglutaminase type II [TGase]) in vivo, while PLZF-RAR alpha expression has either no effect (RAR beta) or an inhibitory activity (RAR gamma and type II TGase). These data demonstrate that PML-RAR alpha and PLZF-RAR alpha have similar (inhibitory) effects on RA-independent differentiation and opposite (stimulatory or inhibitory) effects on RA-dependent differentiation and that they behave in vivo as RA-dependent enhancers or inhibitors of RA-responsive genes, respectively. Their different activities on the RA signalling pathway might underlie the different responses of PML-RAR alpha and PLZF-RAR alpha APLs to RA treatment. The PLZF-RAR alpha fusion protein contains an approximately 120-amino-acid N-terminal motif (called the POZ domain), which is also found in a variety of zinc finger proteins and a group of poxvirus proteins and which mediates protein-protein interactions. Deletion of the PLZF POZ domain partially abrogated the inhibitory effect of PLZF-RAR alpha on RA-induced differentiation and on RA-mediated type II TGase up-regulation, suggesting that POZ-mediated protein interactions might be responsible for the inhibitory transcriptional activities of PLZF-RAR alpha.

PML/RAR alpha+ U937 mutant and NB4 cell lines: retinoic acid restores the monocytic differentiation response to vitamin D3.

We have analyzed the differentiation program of a U937 promonocytic leukemia clone transduced with the acute promyelocytic leukemia specific PML/RAR alpha fusion gene, the expression of which is under the control of the inducible metallothionine (MT) I promoter (MTPR9 clone). MTPR9 cells treated with Zn2+ hence exhibit levels of PML-RAR alpha protein as high as fresh acute promyelocytic leukemia blasts. In the absence of Zn2+, i.e., upon low level PML/RAR alpha expression, 1,25-dihydroxyvitamin D3 (D3) and particularly D3 plus transforming growth factor beta 1 (TGF-beta 1) induced terminal differentiation of MTPR9 cells (as observed in "wild-type" U937 cells), on the basis of morphology, membrane antigen pattern, and functional criteria. Conversely, in the presence of Zn2+, D3 and D3 plus TGF-beta 1 failed to induce terminal differentiation, as evaluated by the above parameters. Interestingly, retinoic acid (RA) treatment suppresses the differentiation blockade induced by high level PML-RAR alpha protein; indeed, Zn(2+)-treated MTPR9 cells incubated with RA plus D3 exhibited significant terminal monocytic maturation, comparable to that of cells treated with D3 alone or combined with RA in absence of Zn2+. Similar observations were made in NB4, a PML-RAR+ human acute leukemic line. As expected RA treatment of NB4 cells causes granulocytic differentiation. Interestingly, the cell line is only scarcely induced to mature monocytic cells by D3 or D3 plus TGF-beta 1 treatment, whereas it is effectively induced to monocytic maturation by combined treatment with D3 and RA. Accordingly, the rate of NB4 cell proliferation is only slightly affected by D3 or D3 plus TGF-beta 1 treatment, mildly inhibited by RA, and markedly decreased by D3 plus RA. These results indicate that in both U937 and NB4 cells high level PML/RAR alpha expression inhibits the monocytic terminal differentiation program triggered by D3 or D3 plus TGF-beta 1, whereas RA treatment effectively antagonizes this inhibitory PML-RAR alpha action and restores the D3 differentiative effect.

Dabrafenib in metastatic melanoma: a monocentric 'real life' experience.

Dabrafenib is a potent BRAF-kinase inhibitor. Its activity was evaluated on 40 consecutive metastatic melanoma patients (pts) harboring the V600BRAF mutations. Dabrafenib was administered orally at the dosage of 150 mg b.i.d. daily. ORR was 82%, with 7% CR, 62% PR, 13% SD and 18% PD. The median PFS and OS were seven and 17 months, respectively (median follow-up: 8.5 months). Increased risk of progression was found in pts with elevated LDH, ECOG PS >1 and more than two metastatic sites. Grade 3-4 adverse events were recorded in 4 pts. In this retrospective analysis, Dabrafenib confirmed its role as the standard clinical option in metastatic melanoma pts.

Cooperation between the RING + B1-B2 and coiled-coil domains of PML is necessary for its effects on cell survival.

PML/RARalpha is the abnormal protein product of the Acute Promyelocytic Leukemia-specific 15;17 translocation. Both the PML and RARalpha components are required for the PML/RARalpha biological activities, namely its capacity to block differentiation and to increase survival of haematopoietic precursors. The physiological role of PML and its contribution to the function of the fusion protein are unknown. PML localizes to the cytoplasm and within specific nuclear bodies (NBs). In vitro, overexpression of PML correlates with suppression of cell transformation. The PML aminoterminal portion retained within the PML/RARalpha protein contains the RING finger, two newly defined cystein/histidine-rich motifs called B-boxes (B1 and B2) and a coiled-coil region. We report here that PML has a growth suppressive activity in all the cell lines tested, regardless of their transformed phenotype, and that the cellular basis for the PML growth suppression is induction of apoptotic cell death. Analysis of various nuclear and cytoplasmic PML isoforms showed that the PML growth suppressive activity correlates with its nuclear localization. Analysis of the localization and growth suppressive activity demonstrated that: (i) the Ring + B1-B2 and coiled-coil regions are both indispensable and sufficient to target PML to the NBs; (ii) individual deletions of the various PML domains have no effect on its growth suppressor activity; (iii) the Ring + B1-B2 region exerts a partial growth suppressor activity but its fusion with the coiled-coil region is sufficient to recapitulate the suppressive function of wild type PML. These results indicate that PML is involved in cell survival regulation and that the PML component of the fusion protein (Ring + B1-B2 and coiled-coil regions) retains intact biological activity, thereby suggesting that the effects of PML/RARalpha on survival derive from the activation of the incorporated PML sequence.

Effect of the acute promyelocytic leukemia PML/RAR alpha protein on differentiation and survival of myeloid precursors.

Acute promyelocytic leukaemia is characterized by an expansion of haematopoietic precursors arrested at the promyelocytic stage (1). The differentiation block can be reversed by retinoic acid, which induces blast differentiation both in vitro (2) and in vivo (3-4). Acute promyelocytic leukaemia is also characterized by a 15;17 chromosome translocation (5) with breakpoints within the retinoic acid alpha receptor (RAR alpha) gene on 17 and within the PML gene, that encodes a putative transcription factor of unknown function (6-7), on 15 (8-10). As a consequence of the translocation a PML/RAR alpha gene is formed. It is transcriptionally active and encodes a PML/RAR alpha fusion protein detectable in all APL cases (11-14). We expressed the PML/RAR alpha protein in U937 myeloid precursor cell line and show that they: 1) lose the capacity to differentiate under the action of different stimuli (vitamin D3, transforming growth factor beta 1); ii) acquire enhanced sensitivity to retinoic acid; iii) exhibit a higher growth rate that is due to a reduction in apoptotic cell death. These results provide the first evidence of biological activity of PML/RAR alpha and recapitulate critical features of the promyelocytic leukemia phenotype.

Personalised medicine: Development and external validation of a prognostic model for metastatic melanoma patients treated with ipilimumab.

PURPOSE: The purpose of this study was to set up a prognostic model for the identification of survival predictors specific for melanoma patients treated with ipilimumab. EXPERIMENTAL DESIGN: The following prospectively collected data were utilised: patient and primary tumour characteristics, relapse-free-interval, site and number of metastases, previous therapies and level of serum biomarkers (lactic dehydrogenase (LDH), C-reactive protein, ß2-microglobulin, vascular endothelial growth factor (VEGF), IL2, IL6, S-100, alkaline phosphatase (ALP), transaminases, leucocyte count, lymphocytes subpopulations). A multivariate prognostic model was developed using the Cox regression model fitted to the data of 113 consecutive metastatic patients treated with ipilimumab (3 mg/kg, q3w) at Veneto Institute of Oncology (IOV). External validation was obtained using the data of 69 and 34 patients treated at European Oncology Institute (IEO) and University of Torino (UT), respectively. RESULTS: Median survival was 8.3, 4.9 and 7.1 months from first ipilimumab administration at IOV, IEO and UT, respectively. Both higher baseline levels of LDH (Hazard Ratio [HR] v=1.36, 95% Confidence Interval [CI] 1.16-1.58, P<.001) and neutrophils (HR=1.76, 95% CI 1.41-2.10, P<.001) were associated with worse prognosis. Model performance was satisfactory both upon internal validation (Dxy=0.42) and external validation (Dxy=0.40). Serum LDH and neutrophil count discriminated patients who lived more (low neutrophils and low LDH) or less (high LDH or neutrophils) than 24 months. CONCLUSION: Serum LDH and neutrophil count were significant independent prognostic factors. This externally validated prognostic nomogram, could help clinicians to identify the patients who would benefit most from ipilimumab and consequently to improve resource allocation. These easily available biomarkers deserve further validation.

The molecular genetics of acute promyelocytic leukemia.

The chromosome breakpoints of the acute promyelocytic leukemia (APL)-specific 15;17 translocation have recently been isolated. They are localized on a previously unknown gene, PML, on chromosome 15 and in the gene that encodes the alpha retinoic acid receptor (RAR alpha) on 17. The translocation, which is balanced and reciprocal, leads to the formation of two fusion genes, PML/RAR alpha and RAR alpha/PML. Both are expressed in APL. The PML/RAR alpha gene codes for two abnormal proteins: the PML/RAR alpha fusion protein and an abnormal PML protein, the RAR alpha/PML gene encodes the RAR alpha/PML fusion protein. Experiments to investigate the biological activity of the abnormal translocation products are in progress. Preliminary results suggest that the PML/RAR alpha fusion protein is responsible for two important properties of the APL phenotype: the differentiation block characteristic of the leukemic blasts and the high sensitivity of the blasts to the differentiative action of retinoic acid (RA) both in vivo and in vitro. The mechanism through which PML/RAR alpha exerts its biological function remains unknown. However, there is accumulating evidence that it acts by interfering with normal endogenous pathways of both RAR alpha and PML. The RAR alpha receptor is implicated in regulating the myeloid differentiation induced by RA. Although the physiological function of PML is not known, it is probably a transcription factor. Definition of the molecular architecture of the t(15;17) has furnished further tools for: (1) molecular diagnosis of APL and (2) highly sensitive evaluation of the neoplastic clone during antileukaemic therapy. The molecular identification of residual APL disease after anti-leukaemia therapy allows patients at risk of relapse to be identified.

Totally implantable central venous access ports for high-dose chemotherapy administration and autologous stem cell transplantation: analysis of overall and septic complications in 68 cases using a single type of device.

Sixty-eight patients suffering from breast cancer, ovarian cancer, lymphoma or multiple myeloma were treated with high-dose chemotherapy and autologous stem cell transplantation. They underwent placement of a central venous port via the subclavian vein for delivery of chemotherapy and reinfusion of stem cells. All patients were followed prospectively for device-related and overall complications, comprising a total of 18,213 days in situ (median: 267 days, range: 90-480). One patient experienced a pneumothorax (1.4%) spontaneously resolved, as an acute toxicity. Two patients (2.8%, 0.1 episodes/1000 days of use) were forced to have the port removed due to infection, caused by Streptococcus mitis in one case, while the causative agent was not identified by laboratory tests in the second. The other 66 patients completed the therapeutic programme, including peripheral stem cell reinfusions and supportive care, such as i.v. antibiotics, antiemetics or fluid administration and blood sample collection, without additional complications. In conclusion, the use of totally implantable central venous access ports has resulted in good long-term access to central veins, in spite of the severe neutropenia and increased septic risk of this category of oncology patients.

Evaluation of acute toxicities associated with autologous peripheral blood progenitor cell reinfusion in patients undergoing high-dose chemotherapy.

Peripheral blood progenitor cell reinfusion (PBPC) in patients undergoing high-dose chemotherapy (HDC) for poor prognosis malignancies, has been described as causing possible acute gastrointestinal (nausea, vomiting), allergic (oedema, bronchospasm, anaphyl- axis), renal (proteinuria, haematuria) and/or cardiovascular (hypotension, arrhythmia, conduction disturbances, transient ischaemic phenomena) toxicities. To establish the clinical relevance of these observations and the possible relationship with different HDC regimens used, we performed a clinical and instrumental evaluation on 33 patients with advanced breast cancer, non-Hodgkin's lymphoma, Hodgkin's disease, relapsed ovarian cancer, Ewing's sarcoma, extragonadal germinal tumour and small cell lung cancer. They underwent at least one reinfusion each for a total of 51 studied procedures. No patient had a previous history of cardiovascular disease or significant intercurrent illness such as diabetes or liver, renal or neurologic impairment. All patients had totally implanted central venous catheters, through which the transplants had been collected and reinfused without technical consequences. To evaluate cardiovascular function, we continuously monitored 12-lead ECGs, with arterial pressure (AP) measurements every 5 min from the beginning of the procedure to 15 min after the reinfusion ended. We did not observe any significant differences between basal and subsequent steps in AP, heart rate, PQ and QTc time, P wave and QRS complex duration or P wave and QRS electrical axes. No patient showed any ST-T tract pathological abnormality, but one patient developed a transient ectopic atrial rhythm, without any haemodynamic disfunction and with spontaneous reversion to sinus rhythm. No patient complained of symptoms of haemodynamic failure. Gastrointestinal side-effects appeared to be strictly related to speed of reinfusion and to the number of packs reinfused, probably reflecting on the amount of dimethylsulphoxide infused. In one patient a tonic-clonic seizure occurred during a vomiting episode, but no patient developed allergic or renal toxicities. We conclude that PBPC reinfusion, if managed according to the procedure we propose in patients without organic impairment, is a safe procedure not associated either with increased risk of acute arrhythmias or ischaemic or significant systemic acute toxicities. Bone Marrow Transplantation (2000) 25, 173-177.

ACOD, a modified CHOP regimen for elderly patients with aggressive non-Hodgkin's lymphoma.

The aim of this study is to verify the feasibility and the clinical activity of a new CHOP-like schedule (ACOD) with a fractionated days 1 and 8 administration in elderly patients. This regimen was chosen in the attempt to allow a sufficient dose intensity (DI) of each drug with better compliance. Fifty-two patients, (74 years, median age), with diffuse large B cell non-Hodgkin's lymphoma were retrospectively evaluated. Patients received ADM 25 mg/sqm, CTX 500 mg/sqm, VCR 1.2 mg/sqm (max 2 mg intravenously) days 1 and 8 and PDN 50 mg orally, days 1-8. Results showed that 54% of patients reached a complete remission, 21% a partial remission with an overall response rate of 75%. Two-thirds of the patients received at least 70% of the planned dose of cyclophosphamide and doxorubicin and 50% of vincristine and prednisone. The median duration of follow up was 12.6 months (range 0.7-61.4). The estimated median OS was 15.2 months (95%CI = [11.6, not estimable]); the estimated median PFS was 5.7 months (95%CI = [5.12, not estimable]). After 2 years, the proportion of patients alive was 47% (95%CI = 34-64%) and the proportion of patients free from progression was 39% (95%CI = 27-57%). Grade 3-4 leukopenia was observed in 61% of patients with 11% of febrile neutropenia. In conclusion, the ACOD chemotherapy regimen seems safe and feasible in elderly patients. This schedule allowed a sufficient DI of chemotherapic agents with clinical results very similar to those recorded with the standard CHOP regimen in young adults.

Chemosaturation with percutaneous hepatic perfusions of melphalan for hepatic metastases: experience from two European centers.

PURPOSE: Chemosaturation with percutaneous hepatic perfusion (PHP; Hepatic CHEMOSAT(®) Delivery System; Delcath Systems Inc, USA) is a minimally invasive, repeatable regional therapy for unresectable hepatic metastases. It uses a system of catheters and filters to isolate hepatic venous blood from the systemic circulation, allowing delivery of high-dose chemotherapy to the hepatic artery. Effluent hepatic venous blood is filtered before being returned to the systemic circulation, thereby reducing exposure to chemotherapy. We describe our experiences with chemosaturation-PHP at 2 European centers. MATERIALS AND METHODS: 14 patients presented unresectable hepatic metastases from solid tumors; 13 received 1 - 3 sessions of chemosaturation-PHP. Melphalan 2.0 (n = 1) or 3.0 (n = 12) mg/kg was given as a 30-minute infusion into the hepatic artery. 12 patients were evaluable for tumor response. RESULTS: One complete (cholangiocarcinoma, n = 1) and 6 partial responses (ocular, n = 3 or cutaneous melanoma, n = 3) were observed, 5 patients had stable disease (ocular melanoma, n = 3; breast cancer, n = 1; gastric cancer, n = 1). Mild to moderate filter-related toxicity (i. e. thrombocytopenia, anemia) was observed immediately post-procedure. Grade 3/4 melphalan-related pancytopenia developed after 1 - 2 weeks. All hematological events were managed effectively with transfusions and/or other supportive measures. The new high-efficiency filter showed milder toxicity and faster recovery. In one case, chemosaturation-PHP was abandoned prematurely due to heparin-induced vaginal bleeding, and one patient died due to retroperitoneal hemorrhage from heparin anti-coagulation. CONCLUSION: Chemosaturation-PHP for non-resectable liver metastases is a feasible treatment option when performed by an experienced multi-disciplinary team. It may be a promising regional therapy for patients with no effective treatment options.

Newly identified tumor antigens as promising cancer vaccine targets for malignant melanoma treatment.

Immunogenicity of tumour cells, immunomodulation and direct targeting of signalling pathways are promising avenues and matter of dated and innovative research in melanoma. Unfortunately, tumour cells are considered to be antigenic, but not immunogenic, either due to presentation of weakly recognized antigens or to the inability of the immune system to recognize them. However, spontaneous complete remission can be rarely observed in patients affected by melanoma, which are mainly attributed to the immune response against the tumour. Also, an elevated frequency of spontaneous humoral immune responses against tumour antigens was occasionally found in patients. These data confirm the existence of an interaction of the immune system with the tumour which can be used as a promising pathway for intervention and incorporates all portions of the immune system. The cancer immunotherapy approach is based on artificial activation of the immune system against the tumour and groups several types of treatments including immunization/vaccination but also modulation of immunity by cytokines or antibodies. Immunization approaches could either be based on undefined tumour antigens (e.g. whole tumour cells, tumour cell lysates, or tumour-antigen enriched fractions) or aimed at eliciting T-cell responses against specific tumour antigens. Novel and contemporary antigen-targeted therapy strategies, mainly directed to Cancer Testis and Heat Shock Proteins, leading to a possible active immunization against melanoma through T-cell specific activation, are discussed in this review.