Chimiothérapie, immunodépression et cancers secondaires: rapport d'un cas clinique

Nous rapportons ici le cas d'un adénocarcinome colique mucineux de découverte pre-mortem au stade multimétastatique chez un patient présentant un antécédent de myélome multiple. Ce cas permet de discuter la valeur pronostique du typage histo-pathologique du cancer colorectal et le développement des cancers secondaires à la chimiothérapie et/ou à l'immunodépression.

Percutaneous endoscopic gastrostomy in head and neck cancer patients: indications, techniques, complications and results.

The aim of this study was to review our experience in percutaneous endoscopic gastrostomy (PEG) performed in patients with cancer of the upper aerodigestive tract. Descriptive retrospective study of 142 patients (115 males, 27 females), mean age 62.4 years (25-84 years), with head and neck or esophageal cancer, who underwent PEG tube insertion between January 2006 and December 2008. The studied parameters were indications, success rate, rate and type of complications, and their management. Percutaneous endoscopic gastrostomy was inserted before chemoradiation therapy in 80% and during or after cancer treatment in 20% of the patients. PEG placement was possible in 137 patients (96%). Major complications were observed in 9 (7%) and minor complications in 22 (17%) of the 137 patients. Seven of the 9 patients with a major complication needed revision surgery. The mortality directly related to the procedure was 0.7%. Percutaneous endoscopic gastrostomy tube insertion has a high success rate. In patients with upper aerodigestive tract cancer, PEG should be the first choice for enteral nutrition when sufficient oral intake is not possible. Although apparently easy, the procedure may occasionally lead to severe complications. Therefore, a strict technique and knowledge of clinical signs of possible complications are mandatory.

Foxm1 expression in prostate epithelial cells is essential for prostate carcinogenesis.

The treatment of advanced prostate cancer (PCa) remains a challenge. Identification of new molecular mechanisms that regulate PCa initiation and progression would provide targets for the development of new cancer treatments. The Foxm1 transcription factor is highly up-regulated in tumor cells, inflammatory cells, and cells of tumor microenvironment. However, its functions in different cell populations of PCa lesions are unknown. To determine the role of Foxm1 in tumor cells during PCa development, we generated two novel transgenic mouse models, one exhibiting Foxm1 gain-of-function and one exhibiting Foxm1 loss-of-function under control of the prostate epithelial-specific Probasin promoter. In the transgenic adenocarcinoma mouse prostate (TRAMP) model of PCa that uses SV40 large T antigen to induce PCa, loss of Foxm1 decreased tumor growth and metastasis. Decreased prostate tumorigenesis was associated with a decrease in tumor cell proliferation and the down-regulation of genes critical for cell proliferation and tumor metastasis, including Cdc25b, Cyclin B1, Plk-1, Lox, and Versican. In addition, tumor-associated angiogenesis was decreased, coinciding with reduced Vegf-A expression. The mRNA and protein levels of 11β-Hsd2, an enzyme playing an important role in tumor cell proliferation, were down-regulated in Foxm1-deficient PCa tumors in vivo and in Foxm1-depleted TRAMP C2 cells in vitro. Foxm1 bound to, and increased transcriptional activity of, the mouse 11β-Hsd2 promoter through the -892/-879 region, indicating that 11β-Hsd2 was a direct transcriptional target of Foxm1. Without TRAMP, overexpression of Foxm1 either alone or in combination with inhibition of a p19(ARF) tumor suppressor caused a robust epithelial hyperplasia, but was insufficient to induce progression from hyperplasia to PCa. Foxm1 expression in prostate epithelial cells is critical for prostate carcinogenesis, suggesting that inhibition of Foxm1 is a promising therapeutic approach for prostate cancer chemotherapy.

Targeting Notch signaling in pancreatic cancer.

IMPORTANCE OF THE FIELD: With some 220,000 new cases/year in the world, pancreatic adenocarcinoma is the fourth highest cause of death by cancers. Among newly diagnosed patients about 210,000 will die within 9 months following diagnosis. Therefore, effective adjuncts to current treatment strategies are necessary. Because embryological signaling pathways are upregulated in pancreatic adenocarcinoma, they represent potential targets for future therapies. AREAS COVERED IN THIS REVIEW: Our aim is to present the Notch pathway, and to describe its involvement in pancreatic pathophysiology/carcinogenesis. This pathway appeared as a prime target for pancreatic cancer therapy. In the light of the crosstalk of Notch with other survival/embryologic pathways, drugs affecting more than one pathway may have to be combined. WHAT THE READER WILL GAIN: Drugs against gamma-secretases could thus serve in cancer treatment and can be combined with drugs targeting survival pathways interplaying with Notch such as Hedgehog. TAKE HOME MESSAGE: Downregulation of Notch contributes to the inhibition and apoptosis of pancreatic cancer cells whereas Hedgehog inhibition will allow for enhanced delivery of drugs to the tumor. Both pathway inhibitors appear to have synergistic effects for future therapeutics for pancreatic adenocarcinoma, once safety issues of compounds are overcome.

Congenital high airway obstruction syndrome and airway reconstruction: an evolving paradigm.

OBJECTIVES: To refine the classic definition of, and provide a working definition for, congenital high airway obstruction syndrome (CHAOS) and to discuss the various aspects of long-term airway reconstruction, including the range of laryngeal anomalies and the various techniques for reconstruction. DESIGN: Retrospective chart review. PATIENTS: Four children (age range, 2-8 years) with CHAOS who presented to a single tertiary care children's hospital for pediatric airway reconstruction between 1995 and 2000. CONCLUSIONS: To date, CHAOS remains poorly described in the otolaryngologic literature. We propose the following working definition for pediatric cases of CHAOS: any neonate who needs a surgical airway within 1 hour of birth owing to high upper airway (ie, glottic, subglottic, or upper tracheal) obstruction and who cannot be tracheally intubated other than through a persistent tracheoesophageal fistula. Therefore, CHAOS has 3 possible presentations: (1) complete laryngeal atresia without an esophageal fistula, (2) complete laryngeal atresia with a tracheoesophageal fistula, and (3) near-complete high upper airway obstruction. Management of the airway, particularly in regard to long-term reconstruction, in children with CHAOS is complex and challenging.

Colorectal cancer metastasis: the DNA repair inhibitor Dbait increases sensitivity to hyperthermia and improves efficacy of radiofrequency ablation.

PURPOSE: To assess the usefulness of combining hyperthermia with a DNA repair inhibitor (double-strand break bait [Dbait]) and its potential application to radiofrequency ablation (RFA) in a preclinical model of human colorectal cancer. MATERIALS AND METHODS: The local ethics committee of animal experimentation approved all investigations. First, the relevance was assessed by studying the survival of four human colorectal adenocarcinoma cell cultures after 1 hour of hyperthermia at 41°C or 43°C with or without Dbait. Human colon adenocarcinoma cells (HT-29) were grafted subcutaneously into nude mice (n = 111). When tumors reached approximately 500 mm(3), mice were treated with Dbait alone (n = 20), sublethal RFA (n = 21), three different Dbait schemes and sublethal RFA (n = 52), or a sham treatment (n = 18). RFA was performed to ablate the tumor center alone. To elucidate antitumor mechanisms, 39 mice were sacrificed for blinded pathologic analysis, including assessment of DNA damage, cell proliferation, and tumor necrosis. Others were monitored for tumor growth and survival. Analyses of variance and log-rank tests were used to evaluate differences. RESULTS: When associated with mild hyperthermia, Dbait induced cytotoxicity in all tested colon cancer cell lines. Sublethal RFA or Dbait treatment alone moderately improved survival (median, 40 days vs 28 days for control; P = .0005) but combination treatment significantly improved survival (median, 84 days vs 40 days for RFA alone, P = .0004), with approximately half of the animals showing complete tumor responses. Pathologic studies showed that the Dbait and RFA combination strongly enhances DNA damage and coagulation areas in tumors. CONCLUSION: Combining Dbait with RFA sensitizes the tumor periphery to mild hyperthermia and increases RFA antitumor efficacy.

International Society of Urological Pathology (ISUP) Consensus Conference on Handling and Staging of Radical Prostatectomy Specimens. Working group 4: seminal vesicles and lymph nodes.

The 2009 International Society of Urological Pathology Consensus Conference in Boston made recommendations regarding the standardization of pathology reporting of radical prostatectomy specimens. Issues relating to the infiltration of tumor into the seminal vesicles and regional lymph nodes were coordinated by working group 4. There was a consensus that complete blocking of the seminal vesicles was not necessary, although sampling of the junction of the seminal vesicles and prostate was mandatory. There was consensus that sampling of the vas deferens margins was not obligatory. There was also consensus that muscular wall invasion of the extraprostatic seminal vesicle only should be regarded as seminal vesicle invasion. Categorization into types of seminal vesicle spread was agreed by consensus to be not necessary. For examination of lymph nodes, there was consensus that special techniques such as frozen sectioning were of use only in high-risk cases. There was no consensus on the optimal sampling method for pelvic lymph node dissection specimens, although there was consensus that all lymph nodes should be completely blocked as a minimum. There was also a consensus that a count of the number of lymph nodes harvested should be attempted. In view of recent evidence, there was consensus that the diameter of the largest lymph node metastasis should be measured. These consensus decisions will hopefully clarify the difficult areas of pathological assessment in radical prostatectomy evaluation and improve the concordance of research series to allow more accurate assessment of patient prognosis.

NY-ESO-1-specific circulating CD4+ T cells in ovarian cancer patients are prevalently T(H)1 type cells undetectable in the CD25+ FOXP3+ Treg compartment.

Spontaneous CD4(+) T-cell responses to the tumor-specific antigen NY-ESO-1 (ESO) are frequently found in patients with epithelial ovarian cancer (EOC). If these responses are of effector or/and Treg type, however, has remained unclear. Here, we have used functional approaches together with recently developed MHC class II/ESO tetramers to assess the frequency, phenotype and function of ESO-specific cells in circulating lymphocytes from EOC patients. We found that circulating ESO-specific CD4(+) T cells in EOC patients with spontaneous immune responses to the antigen are prevalently T(H)1 type cells secreting IFN-γ but no IL-17 or IL-10 and are not suppressive. We detected tetramer(+) cells ex vivo, at an average frequency of 1:25,000 memory cells, that is, significantly lower than in patients immunized with an ESO vaccine. ESO tetramer(+) cells were mostly effector memory cells at advanced stages of differentiation and were not detected in circulating CD25(+)FOXP3(+)Treg. Thus, spontaneous CD4(+) T-cell responses to ESO in cancer patients are prevalently of T(H)1 type and not Treg. Their relatively low frequency and advanced differentiation stage, however, may limit their efficacy, that may be boosted by immunogenic ESO vaccines.

Deoxyribonucleic acid content as an indicator of progression of squamous cell carcinogenesis in the esophagus: comparative analysis on imprint-cytospin and tissue section preparation.

BACKGROUND: The purpose of this study was to explore the potential use of image analysis on tissue sections preparation as a predictive marker of early malignant changes during squamous cell (SC) carcinogenesis in the esophagus. Results of DNA ploidy quantification on formalin-fixed, paraffin-embedded tissue using two different techniques were compared: imprint-cytospin and 6 microm thick tissue sections preparation. METHODS: This retrospective study included 26 surgical specimens of squamous cell carcinoma (SCC) from patients who underwent surgery alone at the Department of Surgery in CHUV Hospital in Lausanne between January 1993 and December 2000. We analyzed 53 samples of healthy tissue, 43 tumors and 7 lymph node metastases. RESULTS: Diploid DNA histogram patterns were observed in all histologically healthy tissues, either distant or proximal to the lesion. Aneuploidy was observed in 34 (79%) of 43 carcinomas, namely 24 (75%) of 32 early squamous cell carcinomas and 10 (91%) of 11 advanced carcinomas. DNA content was similar in the different tumor stages, whether patients presented with single or multiple synchronous tumors. All lymph node metastases had similar DNA content as their primary tumor. CONCLUSIONS: Early malignant changes in the esophagus are associated with alteration in DNA content, and aneuploidy tends to correlate with progression of invasive SCC. A very good correlation between imprint-cytospin and tissue section analysis was observed. Although each method used here showed advantages and disadvantages; tissue sections preparation provided useful information on aberrant cell-cycle regulation and helped select the optimal treatment for the individual patient along with consideration of other clinical parameters.

Transanal endoscopic microsurgery versus conventional transanal excision for patients with early rectal cancer.

OBJECTIVE: To compare transanal endoscopic microsurgery (TEMS) with conventional transanal excision (TAE) in terms of the quality of resection, local recurrence, and survival rates in patients with stage I rectal cancer. BACKGROUND: Although TEMS is often considered a superior surgical technique to TAE, it is poorly suited for excising tumors in the lower third of the rectum. Such tumors may confer a worse prognosis. METHODS: We retrospectively reviewed information on all patients with stage pT1 and pT2 rectal adenocarcinoma who underwent local excision from 1997 through mid-2006. We excluded patients with node-positive, metastatic, recurrent, previously irradiated, or snare-excised tumors. RESULTS: Our study included 42 TEMS and 129 TAE patients. We found no significant differences in patient characteristics, adjuvant therapy, tumor stage, or adverse histopathologic features. In the TAE group, 52 (40%) of tumors were <5 cm from the anal verge (AV); in the TEMS group, only 1 (2%) (P = 0.0001). Surgical margins were less often positive in the TEMS group (2%) than in the TAE group (16%) (P = 0.017). For patients with tumors > or =5 cm from the AV, the estimated 5-year disease-free survival (DFS) rate was similar between the TEMS group (84.1%) and the TAE group (76.1%) (P = 0.651). But within the TAE group, the estimated 5-year DFS rate was better for patients with tumors > or =5 cm from the AV (76.1%) vs. <5 cm from the AV (60.5%) (P = 0.029). In our multivariate analysis, the tumor distance from the anal verge, the resection margin status, the T stage, and the use of adjuvant therapy--but not the surgical technique (i.e., TEMS or TAE) itself--were independent predictors of local recurrence and DFS. CONCLUSIONS: The quality of resection is better with TEMS than with TAE. However, the apparently better oncologic outcomes with TEMS can be partly explained by case selection of lower-risk tumors of the upper rectum.

Apport de la pH-impédancemétrie au diagnostic du reflux gastro- oesophagien et de la dysphagie [Advantages of pH-impedance monitoring in gastroesophageal reflux and dysphagia investigations]

Les manifestations ORL du reflux gastro-œsophagien sont fréquentes. La pH-impédancemétrie permet d’évaluer des reflux acides ou non acides et de déterminer leur extension proximale. A la lumière de deux patients de notre collectif, nous observons une corrélation entre reflux non acide et symptômes ORL dans le premier cas et une suppression acide insuffisante dans le deuxième cas. Ces résultats nous orientent vers un traitement spécifique complémentaire aux inhibiteurs de la pompe à protons. La pH-impédancemétrie détecte les reflux aussi bien acides que non acides, et analyse la concordance entre les symptômes et les épisodes de reflux. Elle permet ainsi une meilleure compréhension des manifestations ORL du reflux gastro-œsophagien et une prise en charge thérapeutique mieux adaptée. ENT symptoms of gastro-esophageal reflux are frequent. pH-impedance can detect acid and non-acid reflux and measure their proximal extension. The technique identifies the refluxate by changes in impedance. We discuss 2 clinical situations where correlation of symptoms could be explained by a non-acid reflux in the first case, and a lack of acid suppression in the second case, respectively. These results lead to a specific additional treatment to proton pump inhibitors (PPI). This technology provides a better understanding of the pathogenesis of reflux laryngitis, and affords the prescription of PPI on a proven diagnosis. Detection of non-acid reflux leads to an optimized medical treatment.

Long-term follow-up of colorectal carcinoma patients by repeated CEA radioimmunoassay.

One of the major practical applications of carcinoembryonic antigen (CEA) assay is the monitoring of colorectal carcinoma patients after complete tumor resection. During the last 5 years, we have followed by repeated CEA assays 66 patients with histologically confirmed colon or rectum adenocarcinoma. Among 19 patients who developed a tumor recurrence, 17 had increased CEA levels preceding the clinical diagnosis by 2 to 26 months. Among the 47 patients who did not show any clinical evidence of tumor recurrence, 35 had CEA values remaining below the limit of 5 ng/ml, whereas 12 had moderate elevations of CEA level fluctuating around this limit. The majority of patients in this last group were heavy smokers or had liver enlargement, but in a few of them we did not find a satisfactory explanation for their moderately increased CEA levels. While our results confirm that repeated CEA assays can predict tumor recurrence with a lead time of several months over clinical diagnosis, they also give a word of warning concerning the interpretation of moderate elevations of CEA level. A moderate increase of CEA level can be the result of early distant metastases, local recurrence or exacerbation of an inflammatory disease. We feel that the decision of second look operations based on CEA results should be made only if increasing CEA values have been observed on three different blood samples taken within a period of 3 months and if no nonmalignant diseases known to increase CEA level are present. Ultimately only randomized clinical studies will determine if second look operations motivated by elevated CEA levels can improve the quality and length of survival of patients with colorectal carcinoma.

Mesenteric venous thrombosis: MDCT features according to the underlying etiology [C-463]

Purpose: To work out certain, well‑defined aetiologies frequently associated with mesenteric venous thrombosis (MVT) in order to predict a typical population at risk, since MVT is nowadays often incidentally detected on cross‑sectional imaging. To demonstrate the MDCT features, frequency and extent of associated bowel ischemia according to the underlying pathology. Methods and Materials: Our electronic database revealed 71 patients (25 women, mean age 55) with thrombosis of the superior and/or inferior mesenteric vein detected by MDCT between 2000 and 2008. Two radiologists jointly reviewed the corresponding MDCT features including intraluminal extension, underlying aetiology and associated bowel ischemia, if present. Results: MVT was associated with carcinoma in 31 (43.7%) patients (pancreas 21.1%, liver 9.9%, others 12.7%). Concomitant inflammation was seen in 15 (21.1%) patients (pancreatitis 11.3%, diverticulitis 4.2%, others 5.6%), whereas coagulation/hematologic disorders were found in 7 (9.9%) patients, liver cirrhosis in 6 (8.5%), mixed/miscellaneous causes in 5 (7%) and still unknown aetiologies in 5 patients (7%). MVT resulted from recent operations in 2 (2.8%) patients. MDCT features of venous bowel ischemia were present in 15 patients (21.1%). 46.5% of MVT were (sub)acute, while 53.5% chronic. The luminal extension was complete in 52.1%, subtotal (50% of lumen) in 22.5% and partial (50% of lumen) in 25.4% of patients, consisting either of blood clots (76.1%) or tumoral tissue (23.9%), the latter mainly due to pancreas adenocarcinoma (76.4%). Conclusion: MDCT features of MVT are seen with a wide range of underlying diseases. Signs of intestinal ischemia are infrequently associated, mostly occurring with coagulation/hematologic disorders (40%).