High Tumor Load Research Articles

Presence of disseminated tumor cells in bone marrow correlates with tumor stage and nodal involvement in cervical cancer patients

Detection of disseminated tumor cells (DTCs) in the bone marrow (BM) of breast cancer patients is associated with poor outcome. The aim of our study was to evaluate the impact of BM status on survival in a large cohort of cervical cancer patients. Three hundred twenty-five patients with cervical cancer were included into this prospective two-center study (University Hospitals Tuebingen, Munich, Germany). BM was collected preoperatively. DTCs were identified by immunocytochemistry using the pancytokeratin antibody A45B/B3. DTCs were detected in 22% of all BM aspirates. The number of CK-positive cells ranged from 1 to 93 per 2 × 10(6) mononuclear cells. Eighteen percent of patients with T1 stage presented with DTCs in BM compared to 30% in T2 and 45% in T3/4 patients. Among nodal negative patients, 18% had tumor cells in BM compared to 32% of nodal positive patients. Positive DTC status was associated with tumor size (p = 0.007) and nodal status (p = 0.009) but not with grading (p = 0.426). DTC status did not correlate with overall or disease-free survival. In the univariate analysis, tumor stage, nodal status, resection status and grading correlated with OS and DFS. In the multivariate analysis, only tumor stage and nodal status were independent predictors of OS and tumor stage, nodal status and grading of DFS. Tumor cell dissemination into BM is thus a common phenomenon in cervical cancer and correlates with higher tumor load but lacks prognostic relevance. Alternative detection methods may be needed to establish prognostic potential.

Introduction of staging laparoscopy in the management of advanced epithelial ovarian, tubal and peritoneal cancer: Impact on prognosis in a single institution experience

ObjectiveTo evaluate the prognostic impact of routinely use of staging laparoscopy (S-LPS) in patients with primary advanced epithelial ovarian cancer (AEOC). MethodsAll women were submitted to S-LPS before receiving primary debulking surgery (PDS) or neoadjuvant treatment (NACT). The surgical and survival outcome were evaluated by univariate and multivariate analysis. ResultsAmong 300 consecutive patients submitted to S-LPS no complications related to the surgical procedure were registered. The laparoscopic evaluation showed that almost half of the patients (46.3%) had a high tumor load. One-hundred forty-eight (49.3%) women were considered suitable for PDS and the remaining 152 (50.7%) were submitted to NACT. The percentages of complete (residual tumor, RT=0) and optimal (RT<1cm) cytoreduction of PDS and interval debulking surgery (IDS) were 62.1% and 57.5%, 22.5% and 27.7%, respectively, p=0.07. The post-operative complications of NACT/IDS group were lower than PDS group (p=0.01). The median progression free survival in women with RT=0 at PDS was 25months (95% CI, 15.1–34.8), which was statistically significant longer than in all other patients, irrespective of the type of treatment they received (p=0.0001). At multivariate analysis, residual disease (p=0.011) and performance status (p=0.016) maintained an independent association with the PFS. ConclusionsIncluding S-LPS in a tertiary referral center for the management AEOC does not appear to have a negative impact in terms of survival and it may be helpful to individualize the treatment avoiding unnecessary laparotomies and surgical complications.

Aggressive Treatment of Patients with Metastatic Colorectal Cancer Increases Survival: A Scandinavian Single-Center Experience

Background. We examined overall and disease-free survivals in a cohort of patients subjected to resection of liver metastasis from colorectal cancer (CRLM) in a 10-year period when new treatment strategies were implemented. Methods. Data from 239 consecutive patients selected for liver resection of CRLM during the period from 2002 to 2011 at a single center were used to estimate overall and disease-free survival. The results were assessed against new treatment strategies and established risk factors. Results. The 5-year cumulative overall and disease-free survivals were 46 and 24%. The overall survival was the same after reresection, independently of the number of prior resections and irrespectively of the location of the recurrent disease. The time intervals between each recurrence were similar (11 ± 1 months). Patients with high tumor load given neoadjuvant chemotherapy had comparable survival to those with less extensive disease without neoadjuvant chemotherapy. Positive resection margin or resectable extrahepatic disease did not affect overall survival. Conclusion. Our data support that one still, and perhaps to an even greater extent, should seek an aggressive therapeutic strategy to achieve resectable status for recurrent hepatic and extrahepatic metastases. The data should be viewed in the context of recent advances in the understanding of cancer biology and the metastatic process.

Relevance of rise in CA15.3 during fulvestrant therapy in advanced breast cancer patients.

e11567 Background: Serum CA15.3 (assay for MUC1 mucin, a membrane glycoprotein of breast ductal epithelium) is elevated in 50-70% of patients with metastatic disease. Transient initial rise (i.e., spike) of CA15.3 due to partial agonistic or cytotoxic effects of tamoxifen and chemotherapy is known. We report differential expression of spike in ER+ breast cancer showing clinical benefit (CB) or progressive disease (PD) on fulvestrant therapy (250mg). Methods: Serial serum CA15.3 measured at therapy initiation (Rx), 1, 3, 6, 9, 12 months and at progression were correlated with clinical outcome (CB/PD). Results: 112 patients (median age=71.4 years) with DOR=10.7+ (median duration of response in months, range) showed 63%CB (DOR=19.2+, 7-120.8+; MBC=48, LAPC=23) and 37%PD (DOR=3, 1-6; MBC=38, LAPC=3). Conclusions: CA15.3 spike was a common feature during therapy regardless of baseline level or clinical outcome (2nd row). However, in those with abnormal baseline (3rd row), %rise was higher in CB than PD patients reflecting greater tumour lyses (and perhaps therapy effectiveness) suggesting continuing therapy beyond early months (1-2 months) even with rising CA15.3. However, on analysis of only patients with spike, the majority of either CB or PD (4th row) were patients with MBC (perhaps reflecting higher tumour load) but with much larger %change in PD. Therefore, though therapy may not be stopped at early rise of CA15.3 but additional interim imaging may be required in MBC patients. [Table: see text]

Comparison of three molecular assays for the detection and molecular characterization of circulating tumor cells in breast cancer

IntroductionComparison studies between different analytical methodologies for circulating tumor cells (CTC) detection and molecular characterization are urgently needed, since standardization of assays is essential before their use in clinical practice.MethodsWe compared three different CTC molecular assays. To avoid discrepancies due to pre-analytical errors we used the same cDNAs throughout our study. CTC were isolated using anti-EpCAM and anti-MUC1 coated magnetic beads from 2 × 5 ml of peripheral blood of 254 early and 51 metastatic breast cancer patients and 30 healthy individuals. The same cDNAs were analyzed by: a) singleplex RT-qPCR assay for CK-19; b) multiplex RT-qPCR for CK-19, HER-2, MAGE- A3, and PBGD; and c) a commercially available molecular assay (AdnaTest BreastCancer) for GA733-2, MUC-1, HER-2 and beta-actin.ResultsIn early breast cancer, CK-19 RT-qPCR, multiplex RT-qPCR and the AdnaTest, were positive for the presence of CTC in 14.2%, 22.8% and 16.5% subjects, respectively. The concordance between the AdnaTest and CK-19 RT-qPCR was 72.4% while between the AdnaTest and multiplex RT-qPCR was 64.6%. In patients with overt metastasis, CK-19 RT-qPCR, multiplex RT-qPCR and the AdnaTest were positive in 41.2%, 39.2% and 54.9% patients, respectively. The concordance between the AdnaTest and CK-19 RT-qPCR was 70.6% while between the AdnaTest and multiplex RT-qPCR was 68.6%.ConclusionsAll CTC assays gave similar results in about 70% of cases. Better agreement was found in the metastatic setting, possibly explained by the higher tumor load in this group. Discordances could be attributed to the different gene transcripts used to evaluate CTC positivity. Our results indicate the importance of CTC heterogeneity for their detection by different analytical methodologies.

6q Deletion Helps in the Discrimination Between Symptomatic Waldenström’s Macroglobulinemia and Asymptomatic Forms of IgM Monoclonal Gammopathies

AbstractAbstract 4566Cytogenetic abnormalities are present in virtually all cases of Waldenström’s macroglobulinemia (WM). Among them, deletion of the long arm of chromosome 6 (6q-) is the most frequently reported in the literature, but the potential impact on disease evolution has not been completely elucidated. In this study we have analyzed the prevalence of this aberration in 203 patients with B-cell lymphoproliferative disorders (B-LPD) producing a monoclonal IgM component. Detection was evaluated by In Situ Fluorescence Hybridization in CD19+ separated cells and results were correlated with disease characteristics. The frequency of 6q21 deletion varied according to the type of B-LPD: 1/42 (2%) in IgM-MGUS, 5/69 (7%) in asymptomatic WM (aWM), 25/83 (30%) in symptomatic WM (sWM) and 0/9 in other IgM B-LPD. Within MGUS and aWM, patients with deletion of 6q displayed a high frequency of adverse prognostic features and required treatment earlier than patients with normal 6q (37 mo vs. +120 mo, p<0.05) although they finally displayed a similar overall survival. Within the sWM, those patients with del(6q) displayed parameters of high tumor burden, such as high levels of b2M and monoclonal paraprotein and more frequent anemia and hypoalbuminemia. Interestingly, there was a correlation between the presence of 6q deletion and the ISS prognostic index (frequency of 6q- among patients stratified in stages 1, 2 and 3 was 24%, 42% and 67% respectively). However, overall survival analysis did not show any difference between patients with and without 6q-, independently if the overall survival was considered globally or free of specific disease mortality. In summary, in IgM monoclonal gammopathies, 6q deletion is associated with more symptomatic forms, higher probability of treatment requirement and high tumor load, although the presence of this abnormality does not represent necessarily an adverse prognosis for OS. [Display omitted] Disclosures:Ocio:PharmaMar: Patents & Royalties, Research Funding. San Miguel:Celgene: Honoraria; Millenium: Honoraria; Janssen: Honoraria.

Daratumumab, a Novel Therapeutic Human CD38 Monoclonal Antibody, Induces Killing of Refractory Patient-Derived Multiple Myeloma Cells, Growing in a Novel Humanized Mouse MM Model

AbstractAbstract 940The evolution of multiple myeloma (MM) is a multi-step process during which mature B cells acquire genetic mutations in multiple genes, which typically takes place in the bone marrow (BM) microenvironment. This, together with the difficulty to culture MM in vitro or to grow MM in vivo in animal models has been the main reason during past decades for poor progress in preclinical research with patient-derived myeloma (pMM) cells. Recently, we developed a unique human-mouse hybrid model that allows engraftment and outgrowth of pMM cells by implementing a technology that is based on first generating a human bone environment in immune deficient mice (Groen et al. 2012) and that is subsequently capable of supporting growth of injected pMM cells. The model offers the opportunity (1) to study the pathobiology of myeloma, and (2) to evaluate, preclinically, new therapeutics for MM treatment, including antibody testing against pMM cells, obtained from patients who acquired resistance to conventional and novel drugs.Daratumumab (DARA) is a human CD38 antibody with broad-spectrum killing activity. Daratumumab induces effective killing of MM tumor cells via complement dependent cytolysis (CDC), ADCC (antibody dependent cellular cytolysis) and ADCP (antibody-dependent phagocytosis). DARA represents a novel promising treatment for MM and other hematological malignancies and is currently tested in Phase I/II clinical trials. In these clinical studies the adverse events have been manageable and marked reductions in paraprotein and bone marrow plasma cells have been observed. In the current study, we asked whether DARA was able to inhibit growth of refractory tumor cells in our human-mouse hybrid model.To this end, immune-deficient RAG2−/−gc−/−-mice were implanted subcutaneously with biphasic calcium phosphate (BCP) particles (2–3 mm) loaded with culture expanded human mesenchymal stromal cells (MSCs). Eight weeks later, the humanized scaffolds in mice (n=45) were injected with 0.5–5×106 pMM cells obtained from different refractory, MM patients. The pMM cells were gene-marked with a GFP-luciferase lentiviral construct for imaging of viable tumor cells. Bioluminescent imaging (BLI) was used to follow myeloma outgrowth in time and to visualize the effect of treatment. The pMM cells were obtained from patients at diagnosis (type 1); at end stage disease, after a history of MPT (melphalan, prednisone, thalidomide, type 2); or from a patient refractory to chemotherapy with bortezomib (BORT), adriamycine and dexamethasone (DEX) (type 3).Mice carrying the pMM cells received similar treatment as the patients or were treated with DARA in a dose range of 1x 50 μg (low dose (LD)) or 2 to 3x 200 μg/mouse (high dose (HD)). BLI showed that the type 1 pMM-bearing mice responded well to all treatments, including DARA; type 2-bearing pMM mice showed no reduction in tumor growth after chemotherapy, but DARA treatment (LD) resulted in an almost complete elimination of circulating MM cells, as assessed with a CD138 antibody, in blood and BM. In a second experiment, type 2-pMM bearing mice were treated with a high DARA dose early (day 34, 50 and 72, 3 times HD, tumor size/BLI signal <200 cmp/cm2) or late (day 50 and 72, 2 times HD, tumor size/BLI signal >8000 cpm/cm2). A significant reduction of overall tumor load, as measured with BLI was observed, which interestingly did not differ between the high and low tumor load group. A reduction of circulating tumor cells (CD138+) was observed for both conditions, which was most obvious in the early treated mice and in agreement with the observations in the first experiment. Type 3 (resistant) pMM-bearing mice showed only a minor response to DEX and BORT, but were highly sensitive to melphalan. When DEX- and BORT-treated mice were treated with a single injection of DARA, this resulted in a complete remission in 3 out of 4 mice and a reduction of the tumor load by 50% in the fourth BORT-treated mouse.In conclusion, our results demonstrate that DARA is effective against multiple myeloma cells derived from therapy- naïve or -refractory patients grafted in a humanized mouse model. In addition, this humanized MM model can be used to study the potential and mechanism of action of DARA in vivo. This novel MM model might be used to predict responsiveness of myeloma patients to particular treatments. Disclosures:Groen:Genmab BV: Research Funding. Raymakers:Novartis: Consultancy. Lammerts van Bueren:Genmab BV: Employment. Parren:genmab: Employment. Mutis:genmab: Research Funding. Martens:Genmab BV: Research Funding.

1352 - Clinical Profile and Patterns of Progression (PD) of Patients (PTS) with Advanced Non-Squamous Non-Small Cell Lung Cancer (NSNSCLC) Treated with First Line Bevacizumab (B): Avva Study

ABSTRACT Background B in combination with platinum doublets prolongs survival and delays PD in chemo-naive pts with advanced nsNSCLC and its safety profile has been widely described in clinical trials. In this study we aim to evaluate the behavior, clinical profile and patterns of PD of real-life nsNSCLC pts treated with B in 44 Spanish institutions. Methods AVVA is a multicenter, epidemiological study to define the clinical profile (gender, age, PS, histology, stage, comorbidities, tumor load, Tx, response and tolerability) and describe the patterns of PD. Pts diagnosed with advanced nsNSCLC and evidence of PD after treatment (Tx) with standard chemotherapy (CT) plus B up to 6 cycles followed by maintenance B were included. Results Data of 158 pts are presented. Clinical profile was: median age 58 years (range 34-79); male 65%; stage IV 91%; adenocarcinoma 77%; ECOG PS 0/1/ ≥ 2 (%): 35/56/9; never/current/former smokers (%): 23/40/37. 64% of pts presented relevant concomitant disease at baseline (27% cardiovascular disease, 24% pulmonary disease). Tx received: B plus carboplatin-doublet/cisplatin-doublet/other (%) 70/25/5. Median no. of cycles for CT/B: 6/9. Patterns of PD: 44% presented high tumor load (tumor diameter ≥55mm and ≥5 lesions); 97% of pts presented intra-thoracic disease, 53% presented extra-thoracic disease and 13% only pulmonary disease. High tumor load was associated with extra-thoracic disease (p Conclusions B was effective in this real-life patients' population, irrespective of tumor load and location of the disease. These results confirm the well-established safety profile and the efficacy of B as frontline Tx in nsNSCLC. Disclosure All authors have declared no conflicts of interest.

Successful selective internal radiotherapy (SIRT) in a patient with a malignant solid pseudopapillary pancreatic neoplasm (SPN)

Solid pseudopapillary neoplasms of the pancreas (SPNs, Gruber-Frantz-Tumor) are a rare entity representing 1–5% of all exocrine pancreatic tumors. The pseudocystic lesions preferentially affect young females <30 years, are mostly benign (∼90%) and normally present with unspecific symptoms.We describe the case of a 16-years-old Asian woman that was initially diagnosed with an SPN in the pancreatic head with mesenterial and hepatic metastases. After diagnosis, an extensive tumor resection was performed including pyloric-preserving pancreatic head resection followed by sequential resection of all hepatic metastases. After the patient was diagnosed with a hepatic recurrence and high intrahepatic tumor load, we chose a multimodal procedure and performed a selective internal radiotherapy (SIRT). Four years after SIRT and 10 years after initial diagnosis of metastatic SPN, the patient is in a good condition without any evidence for hepatic recurrence.This case represents a rare clinical course of a malignant and invasive SPN with an exceptionally long survival despite of high initial tumor burden. The selective internal radiotherapy is a suitable approach for inducing long-term remissions of the strongly vascularized liver metastases.

Functional MRI for radiotherapy dose painting

Modern radiation therapy techniques are exceptionally flexible in the deposition of radiation dose in a target volume. Complex distributions of dose can be delivered reliably, so that the tumor is exposed to a high dose, whereas nearby healthy structures can be avoided. As a result, an increase in curative dose is no longer invariably associated with an increased level of toxicity. This modern technology can be exploited further by modulating the required dose in space so as to match the variation in radiation sensitivity in the tumor. This approach is called dose painting.For dose painting to be effective, functional imaging techniques are essential to identify regions in a tumor that require a higher dose. Several techniques are available in nuclear medicine and radiology. In recent years, there has been a considerable research effort concerning the integration of magnetic resonance imaging (MRI) into the external radiotherapy workflow motivated by the superior soft tissue contrast as compared to computed tomography. In MRI, diffusion-weighted MRI reflects the cell density of tissue and thus may indicate regions with a higher tumor load. Dynamic contrast-enhanced MRI reflects permeability of the microvasculature and blood flow, correlated to the oxygenation of the tumor. These properties have impact on its radiation sensitivity.New questions must be addressed when these techniques are applied in radiation therapy: scanning in treatment position requires alternative solutions to the standard patient setup in the choice of receive coils compared to a diagnostic department. This standard positioning also facilitates repeated imaging. The geometrical accuracy of MR images is critical for high-precision radiotherapy. In particular, when multiparametric functional data are used for dose painting, quantification of functional parameters at a high spatial resolution becomes important.In this review, we will address these issues and describe clinical developments in MRI-guided dose painting.

Delay of Cytoreductive Surgery and Heated Intraperitoneal Chemotherapy in Patients with Appendiceal Neoplasm

Cytoreductive surgery/heated intraperitoneal chemotherapy (CRS/HIPEC) has been shown to be effective for selected patients with advanced appendiceal cancer. We propose that delaying CRS/HIPEC leads to disease progression and affects outcome. A retrospective analysis of a prospective database was carried out. Patients were divided into two groups based on time from diagnosis to CRS/HIPEC (less than 6 months = early, greater than 6 months = delayed). Comparison was made of Peritoneal Cancer Index (PCI), Prior Surgery Score (PSS), complete cytoreduction (CC), and lymph node status. Overall survival (OS) was calculated using Kaplan-Meier estimates. Of 127 patients, 50 had disseminated peritoneal adenomucinosis and 77 had peritoneal mucinous carcinomatosis (PMCA). Of patients with PMCA, 41 had early CRS/HIPEC and 36 delayed. PCI was less than 20 in 46 and 17 per cent (P = 0.007) of the early and delayed groups, respectively. CC was achieved in 88 and 61 per cent (P = 0.009) of the early and delayed groups, respectively. PSS was (2 of 3) in 51 and 91 per cent (P = 0.001) of the early and delayed groups, respectively. Five-year OS was 54 per cent for the early group and 45 per cent for the delayed group (P = 0.2). Delaying CRS/HIPEC was associated with higher tumor load and lower chance for complete cytroreduction. Longer follow-up and larger numbers are needed to determine if OS difference will reach statistical significance.

Clinical profile and patterns of progression (PD) of patients (pts) with advanced nonsquamous non-small cell lung cancer (nsNSCLC) treated with first-line bevacizumab (B): AVVA study.

e18015 Background: B in combination with platinum doublets prolongs survival and delays PD in chemo-naïve pts with advanced nsNSCLC and its safety profile has been widely described in clinical trials. In this study we aim to evaluate the behavior, clinical profile and patterns of PD of real-life nsNSCLC pts treated with B in 44 Spanish institutions. Methods: AVVA is a multicenter, epidemiological study to define the clinical profile (gender, age, PS, histology, stage, comorbidities, tumor load, Tx, response and tolerability) and describe the patterns of PD. Pts diagnosed with advanced nsNSCLC and evidence of PD after treatment (Tx) with standard chemotherapy (CT) plus B up to 6 cycles followed by maintenance B were included. Results: Data of 158 pts are presented. Clinical profile was: median age 58 years (range 34-79); male 65%; stage IV 91%; adenocarcinoma 77%; ECOG PS 0/1/≥2 (%): 35/56/9; never/current/former smokers (%): 23/40/37. 64% of pts presented relevant concomitant disease at baseline (27% cardiovascular disease, 24% pulmonary disease). Tx received: B plus carboplatin-doublet/cisplatin-doublet/other (%) 70/25/5. Median no. of cycles for CT/B: 6/9. Patterns of PD: 44% presented high tumor load (tumor diameter ≥55mm and ≥5 lesions); 97% of pts presented intra-thoracic disease, 53% presented extra-thoracic disease and 13% only pulmonary disease. High tumor load was associated with extra-thoracic disease (p&lt;0.05). ORR was 53% (95% CI: 45-61) and disease control rate was 85%. Best response was achieved after a median of 4 cycles (range 1-16). ECOG 0/1 at PD (%): 15/50. Median PFS was 7.7 months (95% CI: 7.3-8.1). No differences were found in ORR or PFS according to tumor load and intra/extra-thoracic disease. Grade 3/4 toxicities were: venous thrombosis (3.2%/0), proteinuria (0.6%/0), hemoptysis (0.6%/0), pulmonary embolism (0/0.6%) and mucositis (0.6%/0). Conclusions: B was effective in this real-life patients’ population, irrespective of tumor load and location of the disease. These results confirm the well-established safety profile and the efficacy of B as frontline Tx in nsNSCLC.

Improving T-cell Immunotherapy for Melanoma Through a Mathematically Motivated Strategy

T-cell mediated immunotherapy for malignant diseases has become an effective treatment option, especially in malignant melanoma. Recent advances have enabled the transfer of high T-cell numbers with high functionality. However, with more T cells becoming technically available for transfer, questions about dose, treatment schedule, and safety become most relevant. Mathematical oncology can simulate tumor characteristics in silico and predict the tumor response to novel therapeutics. Using similar methods to classical pharmacokinetics/pharmacodynamics-type models, mathematical oncology translates the findings into a multiparameter model system and simulates T-cell therapy for malignant diseases. The tumor and immune system dynamics model can provide minimal requirements (in terms of T-cell dose and T-cell functionality) depending on the tumor characteristics (growth rate, residual tumor size) for a clinical study, and help select the best treatment schedule (repetitive doses, minimally required duration, etc.). Here, we present a new mathematical model developed for modeling cellular immunotherapy for melanoma. Computer simulations based on the new model offer an explanation for the observed finding from clinical trials that the patients with the smallest tumor load respond better. We simulate different parameters critical for improvement of cellular therapy for patients with high tumor load of fast-growing tumors. We show that tumor growth rate and tumor load are crucial in predicting the outcome of T-cell therapy. Rather than intuitively extrapolating from experimental data, we demonstrate how mathematical oncology can assist in rational planning of clinical trials.

Delineation of the clinical phenotype associated with non-mosaic type-2 NF1 deletions: two case reports

IntroductionLarge deletions of the NF1 gene and its flanking regions are frequently associated with a severe clinical manifestation. Different types of gross NF1 deletion have been identified that are distinguishable both by their size and the number of genes included within the deleted regions. Type-1 NF1 deletions encompass 1.4 Mb and include 14 genes, whereas the much less common type-2 NF1 deletions span 1.2 Mb and contain 13 genes. Genotype-phenotype correlations in patients with large NF1 deletions are likely to be influenced by the nature and number of the genes deleted in addition to the NF1 gene. Whereas the clinical phenotype associated with type-1 NF1 deletions has been well documented, the detailed clinical characterization of patients with non-mosaic type-2 NF1 deletions has not so far been reported.Case presentationIn the present report we characterized two Caucasian European patients with non-mosaic (germline) type-2 NF1 deletions. Our first patient was a 13-year-old girl with dysmorphic facial features, mild developmental delay, large hands and feet, hyperflexibility of the joints, macrocephaly and T2 hyperintensities in the brain. A whole-body magnetic resonance imaging scan indicated two internal plexiform neurofibromas. Our second patient was an 18-year-old man who exhibited dysmorphic facial features, developmental delay, learning disability, large hands and feet, hyperflexibility of the joints, macrocephaly and a very high subcutaneous and internal tumor load as measured volumetrically on whole-body magnetic resonance imaging scans. At the age of 18 years, he developed a malignant peripheral nerve sheath tumor and died from secondary complications. Both our patients exhibited cardiovascular malformations.ConclusionsOur two patients with non-mosaic type-2 NF1 deletions exhibited clinical features that have been reported in individuals with germline type-1 NF1 deletions. Therefore, a severe disease manifestation is not confined to only patients with type-1 NF1 deletions but may also occur in individuals with type-2 NF1 deletions. Our findings support the concept of an NF1 microdeletion syndrome with severe clinical manifestation that is caused by type-1 as well as type-2 NF1 deletions.

The in vivo mechanism of action of CD20 monoclonal antibodies depends on local tumor burden

CD20 monoclonal antibodies are widely used in clinical practice. Antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity and direct cell death have been suggested to be important effector functions for CD20 antibodies. However, their specific contributions to the in vivo mechanism of action of CD20 immunotherapy have not been well defined. Here we studied the in vivo mechanism of action of type I (rituximab and ofatumumab) and type II (HuMab-11B8) CD20 antibodies in a peritoneal, syngeneic, mouse model with EL4-CD20 cells using low and high tumor burden. Interestingly, we observed striking differences in the in vivo mechanism of action of CD20 antibodies dependent on tumor load. In conditions of low tumor burden, complement was sufficient for tumor killing both for type I and type II CD20 antibodies. In contrast, in conditions of high tumor burden, activating FcγR (specifically FcγRIII), active complement and complement receptor 3 were all essential for tumor killing. Our data suggest that complement-enhanced antibody-dependent cellular cytotoxicity may critically affect tumor killing by CD20 antibodies in vivo. The type II CD20 antibody 11B8, which is a poor inducer of complement activation, was ineffective against high tumor burden. Tumor burden affects the in vivo mechanism of action of CD20 antibodies. Low tumor load can be eliminated by complement alone, whereas elimination of high tumor load requires multiple effector mechanisms.

Acute painful lumbosacral paresthesia after intrathecal rituximab

Acute painful lumbosacral paresthesia after intrathecal rituximab

Functional MRI for tumor delineation in prostate radiation therapy

A unique property of radiation therapy is the capacity for a differential treatment, in which a high dose can be delivered to tissue with a high tumor load, whereas a lower dose is applied to treat microscopic disease around the primary tumor. This approach is termed ‘dose painting’ and is currently tested in the radiation therapy of prostate cancer. Functional MRI techniques, such as dynamic contrast-enhanced MRI and diffusion-weighted MRI, are well established for tumor localization and staging. However, application for target delineation in radiotherapy raises some specific issues: at what spatial resolution can these techniques be used reliably? What is the detection limit of the techniques? Do different techniques identify the same regions as suspicious or do they provide complimentary information? In this article we address these issues and explore how functional MRI techniques can be used for radiotherapy dose painting.

TPF Sequential Therapy: When and for Whom?

Concurrent chemoradiation is a standard approach for the treatment of locally advanced squamous cell carcinoma of the head and neck. However, sequentially administered chemotherapy and radiotherapy/chemoradiation may be an effective alternative for some patients. Although chemoradiation is a highly effective treatment approach, it is associated with high incidences of severe acute toxicities, including mucositis. In addition, late toxicities can cause long-term morbidity in a substantial proportion of patients. In a retrospective analysis of three Radiation Therapy Oncology Group trials, pharyngeal dysfunction was seen in 27% of patients and feeding tube dependence and laryngeal dysfunction were each seen in approximately 12% of patients. Sequential administration of chemotherapy and radiotherapy, with a doublet cisplatin and 5-fluorouracil (PF) induction chemotherapy regimen, is associated with less acute severe mucositis than concomitantly administered cisplatin and radiotherapy. The addition of the taxane docetaxel to PF has resulted in the highly active triplet induction regimen TPF. Data from randomized trials indicate that TPF sequential therapy may be an effective alternative to concurrent chemoradiation for some patients. TPF is well tolerated, although it is associated with a higher incidence of hematologic adverse events than with PF, including neutropenia and neutropenia-related complications. This may be managed by the use of prophylactic G-CSF and/or antibiotics. Patients suitable for treatment with a TPF-based sequential administration approach include those with a good performance status, no contraindication to cisplatin or taxanes, and locally advanced oropharyngeal, hypopharyngeal, or laryngeal cancer with a high tumor load.

Papel del moxifloxacino en la profilaxis de la endoftalmitis posquirúrgica

The ideal treatment approach for colorectal cancer (CRC) with synchronous liver metastases (SCRLM) remains debated. We performed a network meta-analysis (NMA) comparing the ‘bowel-first’ approach (BFA), simultaneous resection (SIM), and the ‘liver-first’ approach (LFA).A systematic search of comparative studies in CRC with SCRLM was undertaken using the Embase, PubMed, Web of Science, and CENTRAL databases. Outcome measures included postoperative complications, 30- and 90-day mortality, chemotherapy use, treatment completion rate, 3- and 5-year recurrence-free survival, and 3- and 5-year overall survival (OS). Pairwise and network meta-analysis were performed to compare strategies. Heterogeneity was assessed using the Higgins I2 statistic.One prospective and 43 retrospective studies reporting on 10 848 patients were included. Patients undergoing the LFA were more likely to have rectal primaries and a higher metastatic load. The SIM approach resulted in a higher risk of major morbidity and 30-day mortality. Compared to the BFA, the LFA more frequently resulted in failure to complete treatment as planned (34% versus 6%). Pairwise and network meta-analysis showed a similar 5-year OS between LFA and BFA and a more favorable 5-year OS after SIM compared to LFA (odds ratio 0.25–0.90, p = 0.02, I2 = 0%), but not compared to BFA.Despite a higher tumor load in LFA compared to BFA patients, survival was similar. A lower rate of treatment completion was observed with LFA. Uncertainty remains substantial due to imprecise estimates of treatment effects. In the absence of prospective trials, treatment of stage IV CRC patients should be individually tailored.

Combined treatment of rapidly progressing neuroendocrine tumors by transcatheter arterial chemoembolisation of the liver and peptide-receptor radiotherapy is save and effective: Report of 30 consecutive patients.

e14634 Background: Patients with rapidly progressing neuroendocrine tumors presenting with high tumor load and/or severe clinical syndromes are clinically challenging with limited life expectany. Peptide receptor radiotherapy (PRRT) and transcatheter arterial chemoembolisation (TACE) have demonstrated efficacy in the treatment of neuroendocrine tumors. However, there are no reports that both therapies have been applied in combination. Methods: We treated thirty consecutive patients (19 male and 11 female, mean age 55.2) years with rapidly progressing neuroendorine tumors with high tumor load or severe functional syndromes by sequential PRRT and TACE. The treatment was well tolerated by all patients except for one patient suffering from hepatic encephalopathy grade 3 for 12 hours after TACE. One patient showed hepatic failure attributed to progression. 28 of 30 patients could be discharged. Severe functional syndromes were present in 9 patients Sequential TACE and PRRT was performed in 29 patients. One patient intended to treat sequentially died after the first cycle of TACE due to progression and ectopic Cushing's syndrome. A mean of 2.8 cycles (1-10) of TACE was performed and a mean of 4.03 cycles of PRRT (1-7) with 90-Yttrium or 177- Lutetium. Results: In 7/9 patients functional syndromes could be controlled. Two of the nine patients died due to functional syndromes and progression. Response to combined treatment was evaluated after the last treatment, either TACE or PRRT. Stable disease was noted in 16/30 with a mean of 7 months, partial remission in 2/30 patients with a mean of 5 months (4-6) and progressive disease in 12/30 patients after a mean of 2.7 months (0.5-6). Nine deaths occurred, all in the progressive disease group. Conclusions: Initial experience with combined treatment of PRRT and TACE is safe and effective in controlling severe functional syndromes. A subgroup of patients responds with stable disease of partial remission although prognosis remains poor for most of the patients. No significant financial relationships to disclose.