Carcinomes épidermoïdes de l'hypopharynx et du larynx : prise en charge fondée sur les preuves Squamous cell carcinoma of the hypopharynx and larynx: evidence-based care.

Les carcinomes épidermoïdes de l'hypopharynx et du larynx peuvent être traités par chirurgie et/ou radiothérapie en fonction de la taille tumorale. Pour les petites tumeurs, les résultats sont équivalents. Pour les tumeurs localement avancées, l'approche chirurgicale est mutilante et nécessite une (pharyngo)laryngectomie totale. La chimioradiothérapie exclusive a montré tout son intérêt mais au prix de séquelles tardives. Dans le but de diminuer ces séquelles et les mutilations, la chimiothérapie d'induction par cisplatine, docétaxel et 5FU à visée de préservation d'organe devient le standard de traitement mais il manque des études solides de comparaison de cette approche avec la chimioradiothérapie exclusive. Il n'est pas possible de conclure quant à la supériorité d'un schéma en survie globale. Quand la chimiothérapie d'induction est choisie, les modalités de potentialisation éventuelle de la radiothérapie ne sont pas établies. Squamous cell carcinomas of larynx and hypopharynx can be treated by surgery and/or radiotherapy according to tumor size. For small tumors, the results are similar. For locally advanced tumors, the surgical approach is mutilating and requires a total (pharyngo)laryngectomy. Exclusive chemoradiotherapy has shown its interest at the cost of late sequelae. In order to reduce these effects and mutilation, induction chemotherapy with cisplatin, docetaxel and 5FU for organ preservation becomes the standard treatment but there are no solid studies comparing this approach with the exclusive chemoradiotherapy. And it is not possible to conclude as to the superiority of a scheme in terms of overall survival. When chemotherapy is chosen, the modalities of any potentiation of radiation have not been yet established.

Méta-analyses d'essais randomisés sur données individuelles dans le traitement des cancers ORL non métastatiques : principes, résultats, perspectives [Individual patient data meta-analyses of randomized trials for the treatment of non-metastatic head and neck squamous cell carcinomas: Principles, results and perspectives].

Meta-analyses are considered as an important pillar of evidence-based medicine. The aim of this review is to describe the main principles of a meta-analysis and to use examples of head and neck oncology to demonstrate their clinical impact and methodological interest. The major role of individual patient data is outlined, as well as the superiority of individual patient data over meta-analyses based on published summary data. The major clinical breakthrough of head and neck meta-analyses are summarized, regarding concomitant chemotherapy, altered fractionated chemotherapy, new regimens of induction chemotherapy or the use of radioprotectants. Recent methodological developments are described, including network meta-analyses, the validation of surrogate markers. Lastly, the future of meta-analyses is discussed in the context of personalized medicine.

Quantificação imunofenotípica de células T reguladoras em cães acometidos por linfoma multicêntrico submetidos ao protocolo quimioterápico chop associado ou não a um firocoxib

Pós-graduação em Medicina Veterinária - FCAV

Untersuchungen zu Migration, Homing und Effektor-Funktionen humaner T-Lymphozyten in NOD.Cg-Prkdc scid Il2r gtm1Wjl, SzJ-Mäusen im Rahmen der allogenen hämatopoetischen Stammzelltransplantation

Die akute myeloische Leukämie (AML) zählt zu den aggressivsten neoplastischen Erkrankungenrnder Hämatopoese. Die Mehrheit der Patienten mit AML erreicht nach Induktions-rnChemotherapie den Zustand der kompletten Remission, jedoch erleiden mehr als die Hälfterndieser Patienten anschließend einen Rückfall und versterben an den Folgen der Erkrankungrn[1]. Die allogene hämatopoetische Stammzelltransplantation (engl.: hematopoietic stem cellrntransplantation, HSCT) stellt die einzig putativ kurative Behandlungsform für rezidierendernPatienten und solche mit schlechter Prognose dar. Jedoch birgt diese Form der Therapiernauch eine Vielzahl an Risiken. Insbesondere das Auftreten einer akuten Transplantat-gegen-rnWirt-Erkrankung (engl.: graft-versus-host disease, GvHD) stellt die Hauptursache für transplantationsassoziierternMortalität und Morbidität dar [2]. Die Depletion von alloreaktiven zytotoxischenrnT Lymphozyten (CTL) aus dem Transplantat ermöglicht zwar die Prävention derrnEntstehung einer GvH-Erkrankung, jedoch häufig unter gleichzeitigem Verlust des förderlichen,rnanti-leukämischen Transplantat-gegen-Leukämie-Effekts (engl.: graft-versus-leukemia,rnGvL) [3]. Um den GvL-Effekt unter Vermeidung einer GvH-Erkrankung zu erhalten, bietetrnsich der gezielte adoptive Transfer von Leukämie-spezifischen, nicht alloreaktiven CTL alsrnattraktive Strategie der Immuntherapie für AML-Patienten nach allogener HSCT an. In derrnvorliegenden Arbeit konnte erfolgreich ein prä-klinisches murines AML-Modell unter Einsatzrndes stark immundefizienten NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ- (NSG-) Mausstamms und primärenrnAML-Blasten durch die Optimierung bereits publizierter Protokolle etabliert werden.rnBei zehn von 17 transplantierten primären AML-Proben konnte ein erfolgreiches Engraftmentrnder humanen Zellen und eine Rekonstitution der humanen Neoplasie in den NSG-Mäusenrnerzielt werden. Die Engraftment-Rate betrug somit 58,82% und lag etwas unter dem aus derrnLiteratur bekannten Wert von 65-70% [4, 5]. Es ließen sich gut, intermediär und schlecht anwachsendernAML-Proben anhand der Engraftment-Stärke und -Reproduzierbarkeit voneinanderrnunterscheiden. Anhand der Analyse von für das Engraftment kritischer Parameter konnternein Zusammenhang zwischen Engraftment-Rate in der Maus und Flt3-Mutationsstatus sowiernFAB-Klassifikation des Patienten hergestellt und somit Angaben aus der Literatur bestätigtrnwerden. Für zwei Patienten-spezifische AML-Modelle, MZ580 und MZ308, konnten in vitrornerfolgreich AML-reaktive, über einzelne bzw. duale HLA-Diskrepanzen restringierte CTLPopulationenrngeneriert und über einen Zeitraum von bis zu 70 Tagen expandiert werden.rnDeren adoptiver Transfer in zuvor mit humanen AML-Blasten inokulierte NSG-Mäuse führternzu einer nahezu vollständigen Eradikation der AML-Blasten und Remission der Versuchstiere.rnAnhand unterschiedlich langer in vitro Kultur-Zeiträume konnte ein für die in vivo ausgeübtenrnEffektor-Funktionen optimaler Reifungszustand der CTL-Populationen von maximalrn28 Tagen bestimmt werden. Die kinetische Analyse der lytischen Aktivität in vivo deutete auf eine relativ schnelle Ausübung der Effektor-Funktionen durch die CTL-Populationen innerhalbrnvon zwei bis 24 Stunden nach adoptivem Transfer hin. Durch die Verwendung von inrnvitro generierten EBV-reaktiven CTL aus einem irrelevanten Spender konnte zudem die Spezifitätrnder in vivo ausgeübten Effektor-Funktionen nachgewiesen werden. Die ex vivo Re-rnIsolation adoptiv transferierter CTL und deren in vitro Analyse in einem IFNγ ELISpot wiesrneine konstante Reaktivität der Zellen ohne Induktion einer Xeno-Reaktivität nach. Die zurrnVerbesserung der Persistenz humaner CTL-Populationen eingesetzten autologen CD4+ TrnZellen zeigten nur im AML MZ308-System eine positive Wirkung. Generell konnte die Persistenzrnin vivo jedoch trotz initialer Substitution mit den Zytokinen IL-2 und IL-7 nicht über einenrnZeitraum von sieben Tagen hinaus aufrechterhalten werden.rnZur Untersuchung des Extravasations-Mechanismus humaner T Zellen über murines Endothelrnwurden sowohl Flusskammer- als auch Transwell-Studien durchgeführt, um die molekularenrnGrundlagen des Adhäsions- und Transmigrationsprozesses aufzuklären. Durch denrnparallelen Einsatz humaner und muriner T Zellen auf murinen Endothelzellen unter Zusatzrnfunktionsblockierender monoklonaler Antikörper konnte gezeigt werden, dass derrnExtravasations-Mechanismus beider Spezies auf Interaktionen homologer Adhäsionsmolekül-rnPaare, nämlich VLA-4–VCAM-1 und LFA-1–ICAM-1, beruht. Für einzelne Moleküle konntenrnin Abhängigkeit der eingesetzten Endothelzellen Unterschiede in der Funktionalität zwischenrnden Spezies identifiziert werden. Der Adhäsionsprozess war durch die Blockade derrnVLA-4–VCAM-1-Interaktion stärker inhibierbar als durch die Blockade von LFA-1–ICAM-1.rnDie Transmigration hingegen war durch die Blockade beider Adhäsionsmolekül-Paare vergleichbarrnstark inhibierbar.

Generation of FLT3-ITD-reactive T-cell populations from different sources

Approximately 25% of acute myeloid leukemias (AMLs) carry internal tandem duplications (ITD) of various lengths within the gene encoding the FMS-like tyrosine kinase receptor 3 (FLT3). Although varying duplication sites exist, most of these length mutations affect the protein´s juxtamembrane domain. FLT3-ITDs support leukemic transformation by constitutive phosphorylation resulting in uncontrolled activation, and their presence is associated with worse prognosis. As known form previous work, they represent leukemia- and patient-specific neoantigens that can be recognized by autologous AML-reactive CD8+ T cells (Graf et al., 2007; Graf et al., unpublished). Herein, in patient FL, diagnosed with FLT3-ITD+ AML and in first complete remission after induction chemotherapy, T cells against her leukemia´s individual FLT3-ITD were detected at a frequency up to 1.7x10-3 among peripheral blood CD8+ T lymphocytes. This rather high frequency suggested, that FLT3-ITD-reactive T cells had been expanded in vivo due to the induction of an anti-leukemia response.rnrnCell material from AML patients is limited, and the patients´ anti-leukemia T-cell repertoire might be skewed, e.g. due to complex previous leukemia-host interactions and chemotherapy. Therefore, allogeneic sources, i.e. buffy coats (BCs) from health donors and umbilical cord blood (UCB) donations, were exploited for the presence and the expansion of FLT3-ITD-reactive T-cell populations. BC- and UCB-derived CD8+ T cells, were distributed at 105 cells per well on microtiter plates and, were stimulated with antigen-presenting cells (APCs) transfected with in vitro-transcribed mRNA (IVT-mRNA) encoding selected FTL3-ITDs. APCs were autologous CD8- blood mononuclear cells, monocytes or FastDCs.rnrnBuffy coat lymphocytes from 19 healthy individuals were analyzed for CD8+ T-cell reactivity against three immunogenic FLT3-ITDs previously identified in patients VE, IN and QQ and designated as VE_, IN_ and QQ_FLT3-ITD, respectively. These healthy donors carried at least one of the HLA I alleles known to present an ITD-derived peptide from one of these FLT3-ITDs. Reactivities against single ITDs were observed in 8/19 donors. In 4 donors the frequencies of ITD-reactive T cells were determined and were estimated to be in the range of 1.25x10-6 to 2.83x10-7 CD8+ T cells. These frequencies were 1,000- to 10,000-fold lower than the frequency of autologous FLT3-ITD-reactive T cells observed in patient FL. Restricting HLA I molecules were identified in two donors. In one of them, the recognition of VE_FLT3-ITD was found to be restricted by HLA-C*07:02, which is different from the HLA allele restricting the anti-ITD T cells of patient VE. In another donor, the recognition of IN_FLT3-ITD was restricted by HLA-B*35:01, which also had been observed in patient IN (Graf et al., unpublished). By gradual 3´-fragmentation of the IN_FLT3-ITD cDNA, the 10-mer peptide CPSDNEYFYV was identified as the target of allogeneic T cells against IN_FLT3-ITD. rnLymphocytes in umbilical cord blood predominantly exhibit a naïve phenotype. Seven UCB donations were analyzed for T-cell responses against the FLT3-ITDs of patients VE, IN, QQ, JC and FL irrespective of their HLA phenotype. ITD-reactive responses against all stimulatory FLT3-ITDs were observed in 5/7 UCB donations. The frequencies of T cells against single FLT3-ITDs in CD8+ lymphocytes were estimated to be in the range of 1.8x10-5 to 3.6x10-6, which is nearly 15-fold higher than the frequencies observed in BCs. Restricting HLA I molecules were identified in 4 of these 5 positive UCB donations. They were mostly different from those observed in the respective patients. But in one UCB donation T cells against the JC_FLT3-ITD had exactly the same peptide specificity and HLA restriction as seen before in patient JC (Graf et al., 2007). Analyses of UCB responder lymphocytes led to the identification of the 10-mer peptide YESDNEYFYV, encoded by FL_FLT3-ITD, that was recognized in association with the frequent allele HLA-A*02:01. This peptide was able to stimulate and enrich ITD-reactive T cells from UCB lymphocytes in vitro. Peptide responders not only recognized the peptide, but also COS-7 cells co-transfected with FL_FLT3-ITD and HLA-A*02:01.rnrnIn conclusion, T cells against AML- and individual-specific FLT3-ITDs were successfully generated not only from patient-derived blood, but also from allogeneic sources. Thereby, ITD-reactive T cells were detected more readily and at higher frequencies in umbilical cord blood than in buffy coat lymphocytes. It occurred that peptide specificity and HLA restriction of allogeneic, ITD-reactive T cells were identical to autologous patient-derived T cells. As shown herein, allogeneic, FLT3-ITD-reactive T cells can be used for the identification of FLT3-ITD-encoded peptides, e.g. for future therapeutic vaccination studies. In addition, these T cells or their receptors can be applied to adoptive transfer.

Gemtuzumab ozogamicin as postremission treatment in AML at 60 years of age or more: results of a multicenter phase 3 study

In older patients with acute myeloid leukemia (AML), the prevention of relapse has remained one of the major therapeutic challenges, with more than 75% relapses after complete remission. The anti-CD33 immunotoxin conjugate gemtuzumab ozogamicin (GO) has shown antileukemic remission induction activity in patients with relapsed AML. Patients with AML or refractory anemia with excess blasts in first complete remission attained after intensive induction chemotherapy were randomized between 3 cycles of GO (6 mg/m(2) every 4 weeks) or no postremission therapy (control) to assess whether GO would improve outcome. The 2 treatment groups (113 patients receiving GO vs 119 control patients) were comparable with regard to age (60-78 years, median 67 years), performance status, and cytogenetics. A total of 110 of 113 received at least 1 cycle of GO, and 65 of 113 patients completed the 3 cycles. Premature discontinuation was mainly attributable to incomplete hematologic recovery or intercurrent relapse. Median time to recovery of platelets 50 x 10(9)/L and neutrophils 0.5 x 10(9)/L after GO was 14 days and 20 days. Nonhematologic toxicities were mild overall, but there was 1 toxic death caused by liver failure. There were no significant differences between both treatment groups with regard to relapse probabilities, nonrelapse mortality, overall survival, or disease-free survival (17% vs 16% at 5 years). Postremission treatment with GO in older AML patients does not provide benefits regarding any clinical end points. The HOVON-43 study is registered at The Netherlands Trial Registry (number NTR212) and at http://www.controlled-trials.com as ISRCTN77039377.

High-grade supraclavicular soft tissue sarcoma as secondary malignancy after successful treatment of acute myeloid leukemia: case report and literature review

It is well known that the treatment protocols for hematopoetic neoplasms carry a high risk of long-term oncogenicity. However, few reports have been published of sarcomas as secondary malignancies. An unusual case report of a soft tissue sarcoma appearing as a secondary cancer is presented, with a review of the published data. The present report involves a soft tissue sarcoma of the neck that occurred 18 years after curative treatment of acute myeloid leukemia by induction chemotherapy and bone marrow transplantation. Consecutive graft-versus-host disease affected the cervical skin. Soft tissue sarcomas appearing as secondary tumors are rare in oncology. The presented case describes the appearance of a sarcoma 18 years after curative treatment of acute myeloid leukemia. This is only the second case of this type reported in published studies.

Limited predictive value of FDG-PET for response assessment in the preoperative treatment of esophageal cancer: results of a prospective multi-center trial (SAKK 75/02)

BACKGROUND: Only responding patients benefit from preoperative therapy for locally advanced esophageal carcinoma. Early detection of non-responders may avoid futile treatment and delayed surgery. PATIENTS AND METHODS: In a multi-center phase ll trial, patients with resectable, locally advanced esophageal carcinoma were treated with 2 cycles of induction chemotherapy followed by chemoradiotherapy (CRT) and surgery. Positron emission tomography with 2[fluorine-18]fluoro-2-deoxy-d-glucose (FDG-PET) was performed at baseline and after induction chemotherapy. The metabolic response was correlated with tumor regression grade (TRG). A decrease in FDG tumor uptake of less than 40% was prospectively hypothesized as a predictor for histopathological non-response (TRG > 2) after CRT. RESULTS: 45 patients were included. The median decrease in FDG tumor uptake after chemotherapy correlated well with TRG after completion of CRT (p = 0.021). For an individual patient, less than 40% decrease in FDG tumor uptake after induction chemotherapy predicted histopathological non-response after completion of CRT, with a sensitivity of 68% and a specificity of 52% (positive predictive value 58%, negative predictive value 63%). CONCLUSIONS: Metabolic response correlated with histopathology after preoperative therapy. However, FDG-PET did not predict non-response after induction chemotherapy with sufficient clinical accuracy to justify withdrawal of subsequent CRT and selection of patients to proceed directly to surgery.

TP53 as a Biomarker in Head and Neck Squamous Cell Carcinoma

Currently, there are no molecular biomarkers that guide treatment decisions for patients with head and neck squamous cell carcinoma (HNSCC). Several retrospective studies have evaluated TP53 in HNSCC, and results have suggested that specific mutations are associated with poor outcome. However, there exists heterogeneity among these studies in the site and stage of disease of the patients reviewed, the treatments rendered, and methods of evaluating TP53 mutation. Thus, it remains unclear as to which patients and in which clinical settings TP53 mutation is most useful in predicting treatment failure. In the current study, we reviewed the records of a cohort of patients with advanced, resectable HNSCC who received surgery and post-operative radiation (PORT) and had DNA isolated from fresh tumor tissue obtained at the time of surgery. TP53 mutations were identified using Sanger sequencing of exons 2-11 and the associated splice regions of the TP53 gene. We have found that the group of patients with either non-disruptive or disruptive TP53 mutations had decreased overall survival, disease-free survival, and an increased rate of distant metastasis. When examined as an independent factor, disruptive mutation was strongly associated with the development of distant metastasis. As a second aim of this project, we performed a pilot study examining the utility of the AmpliChip® p53 test as a practical method for TP53 sequencing in the clinical setting. AmpliChip® testing and Sanger sequencing was performed on a separate cohort of patients with HNSCC. Our study demonstrated the ablity of the AmpliChip® to call TP53 mutation from a single formalin-fixed paraffin-embedded slide. The results from AmpliChip® testing were identical with the Sanger method in 11 of 19 cases, with a higher rate of mutation calls using the AmpliChip® test. TP53 mutation is a potential prognostic biomarker among patients with advanced, resectable HNSCC treated with surgery and PORT. Whether this subgroup of patients could benefit from the addition of concurrent or induction chemotherapy remains to be evaluated in prospective clinical trials. Our pilot study of the p53 AmpliChip® suggests this could be a practical and reliable method of TP53 analysis in the clinical setting.

Post-remission treatment with allogeneic stem cell transplantation in patients aged 60 years and older with acute myeloid leukaemia: a time-dependent analysis

BACKGROUND Acute myeloid leukaemia mainly affects elderly people, with a median age at diagnosis of around 70 years. Although about 50-60% of patients enter first complete remission upon intensive induction chemotherapy, relapse remains high and overall outcomes are disappointing. Therefore, effective post-remission therapy is urgently needed. Although often no post-remission therapy is given to elderly patients, it might include chemotherapy or allogeneic haemopoietic stem cell transplantation (HSCT) following reduced-intensity conditioning. We aimed to assess the comparative value of allogeneic HSCT with other approaches, including no post-remission therapy, in patients with acute myeloid leukaemia aged 60 years and older. METHODS For this time-dependent analysis, we used the results from four successive prospective HOVON-SAKK acute myeloid leukaemia trials. Between May 3, 2001, and Feb 5, 2010, a total of 1155 patients aged 60 years and older were entered into these trials, of whom 640 obtained a first complete remission after induction chemotherapy and were included in the analysis. Post-remission therapy consisted of allogeneic HSCT following reduced-intensity conditioning (n=97), gemtuzumab ozogamicin (n=110), chemotherapy (n=44), autologous HSCT (n=23), or no further treatment (n=366). Reduced-intensity conditioning regimens consisted of fludarabine combined with 2 Gy of total body irradiation (n=71), fludarabine with busulfan (n=10), or other regimens (n=16). A time-dependent analysis was done, in which allogeneic HSCT was compared with other types of post-remission therapy. The primary endpoint of the study was 5-year overall survival for all treatment groups, analysed by a time-dependent analysis. FINDINGS 5-year overall survival was 35% (95% CI 25-44) for patients who received an allogeneic HSCT, 21% (17-26) for those who received no additional post-remission therapy, and 26% (19-33) for patients who received either additional chemotherapy or autologous HSCT. Overall survival at 5 years was strongly affected by the European LeukemiaNET acute myeloid leukaemia risk score, with patients in the favourable risk group (n=65) having better 5-year overall survival (56% [95% CI 43-67]) than those with intermediate-risk (n=131; 23% [19-27]) or adverse-risk (n=444; 13% [8-20]) acute myeloid leukaemia. Multivariable analysis with allogeneic HSCT as a time-dependent variable showed that allogeneic HSCT was associated with better 5-year overall survival (HR 0·71 [95% CI 0·53-0·95], p=0·017) compared with non-allogeneic HSCT post-remission therapies or no post-remission therapy, especially in patients with intermediate-risk (0·82 [0·58-1·15]) or adverse-risk (0.39 [0·21-0·73]) acute myeloid leukaemia. INTERPRETATION Collectively, the results from these four trials suggest that allogeneic HSCT might be the preferred treatment approach in patients 60 years of age and older with intermediate-risk and adverse-risk acute myeloid leukaemia in first complete remission, but the comparative value should ideally be shown in a prospective randomised study. FUNDING None.

Disseminated Scedosporium prolificans infection and survival of a child with acute lymphoblastic leukemia

Scedosporium prolificans is a saprophytic fungus responsible for an increasing number of infections among immumocompromised hosts. Historically, disseminated infection with this organism has resulted in death. We report on a pediatric patient who developed overwhelming S. prolificans sepsis after induction chemotherapy for acute lymphoblastic leukemia. She is well 18 months after the diagnosis of fungal sepsis and continues to receive chemotherapy for leukemia, which remains in remission.

Emergency emicolectomy for intestinal primary Aspergillosis in acute myeloid leukemia

ntestinal aspergillosis is an infection with a very high death rate especially in leukemic patients. Here we describe a case of a 46 years old woman with acute myeloid leukemia (LAM M5) who developed intestinal primary aspergillosis. This patient was diagnosed with LAM M5 through bone marrow aspiration and bone biopsy in March 2004. Symptoms of the disease were slight persistent fever, weight loss, asthenia, anemia, thrombocytopenia,and leukocytosis with high number of blasts in peripheral blood. After induction chemotherapy with ICE (Ifosfamide, Carboplatin, Etoposide), she developed neutropenia and high fever without apparent infective foci. She was treated with empiric antibiotic therapy, nevertheless she developed an intense diarrhea and ileo-cecal distention. Diagnostic exams didn’t show signs of a focal lesion. Despite the change in antibiotic treatment and the transfusions of granulocytes and blood cells, the patient developed extremely critical conditions with persistence of neutropenia and abdominal distention. A surgical treatment was decided at the time. We treated the patient with a two steps surgical procedure. The first step was a right abdominal ileostomy followed by improvement of general conditions and then the second step a right colectomy. The histological morphology confirmed necrotizing colitis with Aspergillus ife. At that time , treatment with voriconazole was started. The general conditions of the patient improved rapidly and we were able to treat the patient with other medical anti-leukemic therapies. The patient is now cured and in healthy state. We obtained a good clinical result as only in other few cases described in literature.

Surgery after biological therapy in locally advanced NSCLC with molecular driver: feasibility and effectiveness of a new multidisciplinary approach

Introduction: Surgical outcomes after biological therapy have not been investigated yet and no information about timing, postoperative complications and survival have been recorded. Methods: This is a prospective study which compares a group of stage IIIA and IIIB NSCLC patients treated with biological therapy with patients undergoing standard induction chemotherapy. Data reported are preliminary results on the safety and effectiveness of surgery after target therapy. Results: We compared 22 patients treated with standard chemotherapy (Group 1) and 6 patients who received target therapy (Group 2). No differences were observed with an important bias due to the limited number of cases. The median time of resection was 159.8 ± 62.8 for group 1 and 201 ± 57.8 for group 2 (p=0.194). Complete resection was obtained in all Group 1-cases. Post-operative complication rate was 22% vs 16% (p=1). Pathologists reported necrosis >50% in 13% in group 1, Fibrosis >50% was presents respectively in 27% and 33% of patients (p=1). Residual vital tumor was >50% in 77% of patients undergone CT and in 66% of patients undergone TT (p=0.622). A total of 6 (31%) patients in the CT-group developed recurrence, 3 in the TT- group (64.2%), p was 0.634. No difference was observed both in terms of OS (P=0.29, Figure 3) and in term of DFS (P=0.106, Figure 4). Discussion: There is no consensus in the use of target therapy for advanced tumor in association with surgery. EGFR-tyrosine kinase inhibitors showed higher and more rapid response and our study wants to demonstrate that surgery after target therapy gives full access to the advantage of definitive local treatment. In our series, despite fibrosis, radical surgery has been achieved in all patients operated. The intraoperative blood loss, operation time, postoperative hospital stay and postoperative complication rate seems to be similar.

Treatment of pleural malignancies by photo-induction combined to systemic chemotherapy: Proof of concept on rodent lung tumors and feasibility study on porcine chest cavities.

BACKGROUND: Low-dose, Visudyne®-mediated photodynamic therapy (photo-induction) was shown to selectively enhance tumor vessel transport causing increased uptake of systemically administered chemotherapy in various tumor types grown on rodent lungs. The present experiments explore the efficacy of photo-induced vessel modulation combined to intravenous (IV) liposomal cisplatin (Lipoplatin®) on rodent lung tumors and the feasibility/toxicity of this approach in porcine chest cavities. MATERIAL AND METHODS: Three groups of Fischer rats underwent orthotopic sarcoma (n = 14), mesothelioma (n = 14), or adenocarcinoma (n = 12) implantation on the left lung. Half of the animals of each group had photo-induction (0.0625 mg/kg Visudyne®, 10 J/cm(2) ) followed by IV administration of Lipoplatin® (5 mg/kg) and the other half received Lipoplatin® without photo-induction. Then, two groups of minipigs underwent intrapleural thoracoscopic (VATS) photo-induction (0.0625 mg/kg Visudyne®; 30 J/cm(2) hilum; 10 J/cm(2) apex/diaphragm) with in situ light dosimetry in combination with IV Lipoplatin® administration (5 mg/kg). Protocol I (n = 6) received Lipoplatin® immediately after light delivery and Protocol II (n = 9) 90 minutes before light delivery. Three additional animals received Lipoplatin® and VATS pleural biopsies but no photo-induction (controls). Lipoplatin® concentrations were analyzed in blood and tissues before and at regular intervals after photo-induction using inductively coupled plasma mass spectrometry. RESULTS: Photo-induction selectively increased Lipoplatin® uptake in all orthotopic tumors. It significantly increased the ratio of tumor to lung Lipoplatin® concentration in sarcoma (P = 0.0008) and adenocarcinoma (P = 0.01) but not in mesothelioma, compared to IV drug application alone. In minipigs, intrapleural photo-induction combined to systemic Lipoplatin® was well tolerated with no toxicity at 7 days for both treatment protocols. The pleural Lipoplatin® concentrations were not significantly different at 10 and 30 J/cm(2) locations but they were significantly higher in protocol I compared to II (2.37 ± 0.7 vs. 1.37 ± 0.7 ng/mg, P  < 0.001). CONCLUSION: Visudyne®-mediated photo-induction selectively enhances the uptake of IV administered Lipoplatin® in rodent lung tumors. Intrapleural VATS photo-induction with identical treatment conditions combined to IV Lipoplatin chemotherapy is feasible and well tolerated in a porcine model. Lasers Surg. Med. 47:807-816, 2015. © 2015 Wiley Periodicals, Inc.