Dosage of anti-PD-1 monoclonal antibodies: a cardinal open question

Discovery and clinical development of monoclonal antibodies with the ability to interfere in the regulation of the immune response have significantly changed the landscape of oncology in recent years. Among the active agents licensed by the regulatory agencies, nivolumab and pembrolizumab are paradigmatic as the most relevant ones according to the magnitude of available data derived from the extensive preclinical and clinical experience. Although in both cases the respective data sheets indicate well-defined dosage regimens, a review of the literature permits to verify the existence of many issues still unresolved about dosing the two agents, so it must be considered an open question of potentially important consequences, in which to work to improve the effectiveness and efficiency of use (AU)

Dosage of anti-PD-1 monoclonal antibodies: a cardinal open question.

Discovery and clinical development of monoclonal antibodies with the ability to interfere in the regulation of the immune response have significantly changed the landscape of oncology in recent years. Among the active agents licensed by the regulatory agencies, nivolumab and pembrolizumab are paradigmatic as the most relevant ones according to the magnitude of available data derived from the extensive preclinical and clinical experience. Although in both cases the respective data sheets indicate well-defined dosage regimens, a review of the literature permits to verify the existence of many issues still unresolved about dosing the two agents, so it must be considered an open question of potentially important consequences, in which to work to improve the effectiveness and efficiency of use.

Determining personalized treatment by gene expression profiling in metastatic breast carcinoma patients: a pilot study

Purpose: The present study evaluates the massive study of gene expression in metastatic breast carcinoma (MBC) patients using microarray gene expression profiling (MAGE) complemented with conventional sequencing, immunohistochemistry (IHC) and fluorescent "in situ" hybridization (FISH), seeking to optimize the treatment in a subset of heavily pretreated patients and with limited life expectancy. Patients, material and methods: MBC patients in hormone therapy progression with survival expectancy of at least 3 months (m) have been included. The MAGE contains gene probes representing genes known to potentially interact with available drugs as cited in the literature. Results: Thirty-nine procedures were performed from October 2010 to April 2016. Within the 30 evaluable procedures, considering all hormonal manipulations as a single line, the patients had received a median of 4 treatment lines prior to MAGE (range 1-7). Progression was observed in 6 cases, stable disease (SD) in 7 cases and partial response (PR) in 16 cases, which implies a clinical benefit rate (SD + PR) of 76%. Actuarial median progression-free survival (PFS) was 6 m (95% CI 2.5-9.5) in patients with clinical benefit. The median overall survival (OS) for the entire series was 11 m (95% CI 2.2-19.8). Conclusion: Data presented here indicate that the use of MAGE provides relevant information to establish personalized treatment in frail patients with limited life expectancy in which therapeutic futility is a particularly difficult burden to assume

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Determining personalized treatment by gene expression profiling in metastatic breast carcinoma patients: a pilot study.

PURPOSE: The present study evaluates the massive study of gene expression in metastatic breast carcinoma (MBC) patients using microarray gene expression profiling (MAGE) complemented with conventional sequencing, immunohistochemistry (IHC) and fluorescent "in situ" hybridization (FISH), seeking to optimize the treatment in a subset of heavily pretreated patients and with limited life expectancy. PATIENTS, MATERIAL AND METHODS: MBC patients in hormone therapy progression with survival expectancy of at least 3 months (m) have been included. The MAGE contains gene probes representing genes known to potentially interact with available drugs as cited in the literature. RESULTS: Thirty-nine procedures were performed from October 2010 to April 2016. Within the 30 evaluable procedures, considering all hormonal manipulations as a single line, the patients had received a median of 4 treatment lines prior to MAGE (range 1-7). Progression was observed in 6 cases, stable disease (SD) in 7 cases and partial response (PR) in 16 cases, which implies a clinical benefit rate (SD + PR) of 76%. Actuarial median progression-free survival (PFS) was 6 m (95% CI 2.5-9.5) in patients with clinical benefit. The median overall survival (OS) for the entire series was 11 m (95% CI 2.2-19.8). CONCLUSION: Data presented here indicate that the use of MAGE provides relevant information to establish personalized treatment in frail patients with limited life expectancy in which therapeutic futility is a particularly difficult burden to assume.

Novetats farmacològiques en pediatria a Espanya: any 2012 / No disponible

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Epidermal growth factor receptor (EGFR) mutations in a series of non-small-cell lung cancer (NSCLC) patients and response rate to EGFR-specific tyrosine kinase inhibitors (TKIs).

INTRODUCTION Epidermal growth factor receptor (EGFR) mutation related to tyrosine kinase inhibitors' (TKIs) responsiveness in non-small cell lung cancer (NSCLC) has become an important issue for therapeutic decision-making in NSCLC patients. MATERIAL AND METHODS Sixty-nine Caucasian NSCLC patients were screened for mutations in the tyrosine kinase (TK) domain of EGFR by direct sequencing from December 2005 to September 2010. RESULTS Activating mutations in the EGFR TK domain were found in 8 of 69 (11.6%) (7 deletions in exon 19 and one L858R mutation in exon 21). Seven of those mutations were found in adenocarcinoma and one mutation in bronchiolo-alveolar carcinoma; five of them in females (one smoker) and three of them in males (one smoker). All patients carrying activating mutations in the TK domain of EGFR were treated with TKIs. Ten patients not carrying an activating mutation in EGFR, who progressed after chemotherapy, were also treated with compassionate use of EGFR-specific TKIs (gefitinib or erlotinib). An objective response (partial response) was observed in all patients carrying an activating mutation in EGFR that received TKIs. Median overall survival for these patients has not been reached, however mean survival has been estimated at 39.5 months (95% CI, 22-57). CONCLUSIONS As previously reported, EGFR TK mutational analysis was a predictive test for response to targeted therapy with EGFR TKIs. The early identification of these patients consistently attains disease response and clearly improves outcomes.

Epidermal growth factor receptor (EGFR) mutations in a series of non-small-cell lung cancer (NSCLC) patients and response rate to EGFR-specific tyrosine kinase inhibitors (TKIs)

INTRODUCTION Epidermal growth factor receptor (EGFR) mutation related to tyrosine kinase inhibitors' (TKIs) responsiveness in non-small cell lung cancer (NSCLC) has become an important issue for therapeutic decision-making in NSCLC patients. MATERIAL AND METHODS Sixty-nine Caucasian NSCLC patients were screened for mutations in the tyrosine kinase (TK) domain of EGFR by direct sequencing from December 2005 to September 2010. RESULTS Activating mutations in the EGFR TK domain were found in 8 of 69 (11.6%) (7 deletions in exon 19 and one L858R mutation in exon 21). Seven of those mutations were found in adenocarcinoma and one mutation in bronchiolo-alveolar carcinoma; five of them in females (one smoker) and three of them in males (one smoker). All patients carrying activating mutations in the TK domain of EGFR were treated with TKIs. Ten patients not carrying an activating mutation in EGFR, who progressed after chemotherapy, were also treated with compassionate use of EGFR-specific TKIs (gefitinib or erlotinib). An objective response (partial response) was observed in all patients carrying an activating mutation in EGFR that received TKIs. Median overall survival for these patients has not been reached, however mean survival has been estimated at 39.5 months (95% CI, 22-57). CONCLUSIONS As previously reported, EGFR TK mutational analysis was a predictive test for response to targeted therapy with EGFR TKIs. The early identification of these patients consistently attains disease response and clearly improves outcomes (AU)

Cytoreductive surgery and perioperative intraperitoneal chemotherapy in patients with peritoneal carcinomatosis of colonic origin: outcomes after 7 years' experience of a new centre for peritoneal surface malignancies

INTRODUCTION: Peritoneal carcinomatosis is a relatively frequent situation in the natural history of colorectal cancer and is associated with a dismal prognosis. Promising results have been shown after radical cytoreduction followed by intraperitoneal chemohyperthermic perfusion. The aim our study was to assess the outcomes after treating patients with peritoneal carcinomatosis of colonic origin by means of cytoreductive surgery and intraoperative hyperthermic intraperitoneal chemotherapy (HIPEC) followed by early postoperative intraperitoneal chemotherapy (EPIC). METHODS: Tumour resection was performed in accordance with the guidelines for oncologic surgery. Selective peritonectomies and remnant nodule electroevaporation were performed with the aim of achieving a complete cytoreduction. Peritoneal perfusion was carried out according to the Coliseum technique at 0.5-1 L/min, and chemotherapy was administered at 42oC for 40-90 min. Mitomycin C 10-12.5 mg/m(2) or oxaliplatin 360 mg/m(2) was used. Postoperative intraperitoneally administered 5-fluorouracil (5-FU) (650 mg/m(2) per day) was given for 5 consecutive days. RESULTS: Twenty patients were treated from 2001 to 2008. The mean peritoneal cancer index was 11 (range 2-39). Fifteen patients had undergone complete cytoreductive surgery. The morbidity was 40%. There was one case of death due to bone marrow aplasia. Ten patients had recurrence; five of them underwent salvage surgery. Two patients were treated with a second HIPEC. Actuarial overall survival and progression-free survival were 36% and 30% at 5 years, respectively, with a median follow-up of 18 (range 8-28) months. CONCLUSIONS: Cytoreductive surgery combined with HIPEC is a feasible technique that might increase patient survival. It represents a potential cure for selected patients who have no other alternatives (AU)

Fototoxicidad asociada al voriconazol / Voriconazole-associated phototoxicity

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Carcinomatosis peritoneal. Quimioterapia intraperitoneal con hipertermia / No disponible

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Fixed higher dose schedule of suramin plus hydrocortisone in patients with hormone refractory prostate carcinoma a multicenter Phase II study.

BACKGROUND: Using a fixed higher-dose schedule, the efficacy and toxicity of suramin plus hydrocortisone were assessed in patients with metastatic hormone-refractory prostate carcinoma (HRPC). METHODS: Fifty consecutive patients with HRPC (including those in whom hormonotherapy was withdrawn) and an Eastern Cooperative Oncology Group performance status of 0-2 were recruited. Treatment was comprised of a bolus intravenous infusion of 200 mg of suramin followed by suramin (500 mg/m(2) intravenously [i.v.] over 24 hours) given daily over 5 days as a loading course, followed by suramin (350 mg/m(2) i.v. over 2 hours) administered weekly for 12 weeks. This 12-week course was repeated at 6-month intervals. All patients received concomitant hydrocortisone. RESULTS: Five hundred fifty weekly doses of therapy were delivered over the course of the entire study. A partial response, based on a > 50% decrease in the prostate specific antigen (PSA) level, was achieved in 27 patients (54%; 95% confidence interval [95% CI], 44.7-65.0%), 16 of whom (32%; 95%CI, 23.9-43.2%) had a > 75% decrease in their PSA levels. The measurable disease objective response rate was 18% (95% CI, 2.3-51.8%). Of the 37 patients with bone pain requiring analgesia, 27 patients (73%; 95% CI, 55.9-86.2%) reduced their medication consumption to a lower level on the World Health Organization analgesic ladder. The median duration of response was 15.5 weeks (range, 6-70 weeks), the median time to disease progression was 13 weeks, and the median overall survival time was 11 months. Treatment generally was well tolerated. Fatigue and severe lymphopenia were the most commonly reported significant toxicities. In addition, there was 1 septic toxic death reported, and 10% of the patients were found to have NCI Grade 3-4 neurotoxicity. CONCLUSIONS: The results of the current study demonstrated that the fixed-dose suramin regimen administered herein showed high, although short-lived, activity and a good tolerance profile in HRPC patients.

[Neonatal screening for sickle cell disease in the Consorci Sanitari de Mataro. Rationale and first results]. / Screening neonatal de drepanocitosis en el Consorci Sanitari de Mataró. Justificación y primeros resultados.

OBJECTIVE: Neonatal screening for sickle cell disease in prevalent population permits its early detection and provides the possibility of starting early prophylactic measures that will greatly reduce the high mortality of the disease. METHODS: We expose the preliminary results of a neonatal screening for sickle cell disease, with alkaline and acid hemoglobin electrophoresis, selective for the black population coming from subsaharian Africa ad immigrated to our area. They are 82 black neonates born in our hospital between July 1995 and July 1997. RESULTS: Despite they are too few, we can talk about a gene prevalence (S, C) of 10.98% (95% IC 4.21-17.74), and a disease prevalence (SS, CC, SC, S-betathalassemia) of 1.22% (95% IC 0.00-3.60) which is slightly lower that what we expected. CONCLUSIONS: Neonatal screening for sickle cell disease in the black immigrated is necessary, and alkaline and acid hemoglobin electrophoresis is an appropriate technique.

CD34+ cell dose and CD33- subsets: collection and engraftment kinetics in autologous peripheral blood stem cells transplantation.

BACKGROUND AND OBJECTIVE: We analyzed the factors that affected the number and quality of peripheral blood stem cells (PBSC) collected for transplant in order to establish a minimum threshold for rapid hematopoietic recovery. DESIGN AND METHODS: From January 1995 to November 1996, a consecutive series of 67 patients, with hematologic and solid tumors underwent autologous PBSC transplantation. Collection of PBSC was performed after mobilization with granulocyte-colony stimulating factor (G-CSF) or with chemotherapy (CT) plus G-CSF. We calculated the factors that influenced PBSC collection, the kinetics of granulocyte and platelet recovery and the threshold value of CD34+ cells for a rapid recovery. The data were analyzed by means of multivariate Cox regression model and the receiver operating characteristic (ROC) methodology. RESULTS: Our results showed that mobilization with chemotherapy plus G-CSF was associated with a higher yield of PBSC in comparison with mobilization with G-CSF alone. Disease status, fewer cycles of conventional prior chemotherapy and absence of prior radiation therapy also influenced the yield of PBSC. The number of CD34+ cells, CD34+CD33- cell subsets, the mobilization schedule, and the conditioning regimen correlated significantly with time to hematopoietic recovery. In the multivariate analysis only the CD34+CD33- cell content and the total number of CD34+ were related with rapid neutrophil and platelet recovery, respectively. Use of G-CSF after transplant significantly shortened the neutrophil recovery time only in patients transplanted with suboptimal dose of PBSC. INTERPRETATION AND CONCLUSIONS: These data suggest the utility of quantitation of CD34+ cells subsets to predict quick engraftment.

[Spontaneous tumor regression. Report of 2 cases]. / Regresión tumoral espontánea. A propósito de dos casos.

Two cases of spontaneous tumor regression (STR) occurring in a patient with non Hodgkin lymphoma and in another patient with squamous carcinoma of the lung are presented. Both cases fulfill the criteria of STR defined by Everson and Cole. Recent results obtained in basic and clinical studies have indicated that immunological mechanisms could play an important role in STR. The mediator effects more frequently referred are: 1) generation of antineoplastic cytotoxic cells; 2) production of immunoregulatory cytokines by lymphocytes and monocytes, and 3) possible cross reaction between tumor and bacterial antigens. These mechanisms of action are discussed in relation to the presented cases.

[Intensive chemotherapy with 1-3 drugs and support with autologous myelopoietic cells extracted from the peripheral blood: the preliminary results]. / Quimioterapia intensiva con 1-3 fármacos y soporte con células mielopoyéticas autólogas extraídas de la sangre periférica: resultados preliminares.

UNLABELLED: Fourteen patients with different solid tumors have been treated with high-dose combination chemotherapy followed by autologous PBSC support. A total of 15 procedures have been done. 4,5-7 x 10(10) mononuclear cells were obtained through 1-4 leukapheresis using a CS-3.000 continuous flow blood cell separator. Cells were maintained in standard culture conditions for 3-5 days prior to infusion. Chemotherapy consisted in the administration of 1-3 agents: CPA 80 mg/kg; VP-16, 800 mg/m2; BCNU 700-800 mg/m2, CBDCA 1.000 mg/m2. APBSC were infused 48 hours after the last chemotherapy was given. Patients were maintained in single-bed rooms with standard prophylactic antibiotics, including gentamycin, piperacillin, vancomycin and amphotericin B during the period of aplasia. Currently 5 procedures are available for response and all patients are evaluable for toxicity. Responses have been: 2 complete responses and 3 partial response. All patients entered in aplasia, with 12 infections (73%), 8 bleeding (53%), 4 diarrhea (27%), 2 stomatitis (13%) and 3 renal failure (16%). CONCLUSIONS: 1. Bone marrow recovery after high dose chemotherapy can be shortened with APBSC support. 2. APBSC can be safely maintained using standard culture techniques, thus avoiding the freezing procedure.

[Intra-arterial chemotherapy, using the hepatic artery, in metastases of colorectal carcinoma]. / Quimioterapia intra-arterial hepática en las metástasis del carcinoma colorrectal.

Hepatic metastasis is the major cause of death in advanced cancer of the colon and rectum. Various modes of therapy have been attempted with only partial success. Infusion of cytotoxic agents into the hepatic artery has allowed a higher concentration of drug into the tumor capillary bed than is achievable with intravenous administration. We review the data on therapeutic outcome, administration techniques and toxicity of hepatic arterial chemotherapy for colorectal cancer metastatic to the liver.

[Bone marrow lymphoid follicles in myelofibrosis compared with chronic myelogenous leukaemia (author's transl)]. / Les nodules lymphoïdes de la moelle dans la splénomégalie myéloïde: comparaison avec la leucémie myéloïde chronique.

The trephine bone marrow biopsies of 51 patients with myeloproliferative syndromes were revised searching for lymphoid follicles and lymphoplasmocytosis: 18 of these had idiopathic myelofibrosis and 33 chronic myelogenous leukaemia. Six of the 18 biopsies on patients with myelofibrosis showed lymphoid follicles but only one of the 33 with chronic meylogenous leukaemia did (P = 0.01, Fisher exact test). In addition, four of the six myelofibrosis having follicles had two or more of them. When the pathological pattern of myelofibrosis was considered according to the Lennert and al. classification we found significantly more follicles in the cellular phase of the disease than in the advanced phases (P = 00.4, Fisher exact test). These findings can be considered as a morphological argument supporting the idea of an immunological mechanism in the development of myelofibrosis.