Cetuximab-based treatment of metastatic anal cancer: correlation of response with KRAS mutational status.

BACKGROUND: No standard chemotherapy regimen can be defined for patients with metastatic squamous cell carcinoma of the anus due to the low incidence of this disease and the high cure rate of localized tumors. Anal cancers universally express the epidermal growth factor receptor (EGFR) and KRAS mutations have not been reported in anal cancer thus far. METHODS: We report on 7 patients with metastatic anal cancer treated with cetuximab - a chimeric antibody against EGFR - on a compassionate use basis along with the results of KRAS mutational analysis. RESULTS: Marked tumor shrinkage was noted in several patients using cetuximab monotherapy or cetuximab/irinotecan combination as first or subsequent treatment line (usually after failure of cisplatin-based regimens). Two out of seven patients harbored KRAS mutations. Both patients had progressive disease receiving cetuximab, while the remaining 5 patients had either a partial remission (n = 3), a minor remission (n = 1) or no change lasting > or =6 months after previous rapid tumor progression. CONCLUSION: Cetuximab-based treatment appears to be a valuable treatment option for patients with metastatic KRAS wild-type anal cancer after failure of or as an alternative to cisplatin/5-fluorouracil-based therapy.

Distribution of mucins and antimicrobial substances lysozyme and lactoferrin in the laryngeal subglottic region.

The subglottic region of the larynx is of high clinical relevance with regard to infections and malignancies. Little is known about the distribution of mucins and antimicrobial substances in this area. In this study, we have investigated the mucin distribution in the normal subglottis of the larynx. Moreover, we analysed the expression of lysozyme and lactoferrin in this area. Therefore, the subglottic region of 34 larynges was investigated immunohistochemically with different antibodies to mucins and antimicrobial substances. The epithelium reacted positive with antibodies to mucins MUC1 (34/34), 5AC (26/34), 5B (10/34), 7 (8/34), 8 (10/34) and 16 (19/34); submucosal glands were positive to mucins MUC1 (34/34), 5B (10/34), 7 (8/34), and 16 (19/34); high columnar epithelial cells and serous parts of subepithelial seromucous glands were also positive for lysozyme (34/34) and lactoferrin (34/34). The results show that human subglottic epithelium and subepithelial submucosal glands produce a broad spectrum of mucins that is almost comparable with that in other areas of the respiratory tract. We hypothesize that the mucin diversity of the subglottis has an impact on positive functional consequences during vocal production and antimicrobial defence. This antimicrobial defence is supported by synthesis and secretion of antimicrobial substances such as lysozyme and lactoferrin. Moreover, knowledge of the observed distribution pattern of mucins in the subglottis can be a useful tool for a classification of subglottic laryngeal carcinomas.

Leukocytoclastic vasculitis and acute renal failure after influenza vaccination in an elderly patient with myelodysplastic syndrome.

BACKGROUND: Influenza vaccination is recommended for individuals over 65 years of age and for all patients with chronic diseases who are at risk. Side effects which are seen in 1-10% of the vaccinated individuals are usually mild and consist of local reactions and constitutional symptoms. Since 1974, about 30 cases of vasculitis following influenza vaccination have been reported. CASE REPORT: We here describe a 70-year-old male patient with a 5-year history of myelodysplastic syndrome, who had received continuous steroid treatment since 2004 and presented with leukocytoclastic vasculitis and acute renal failure requiring hemodialysis therapy 1 week after influenza vaccination. High-dose steroid treatment was promptly initiated, but hemodialysis was needed for 9 days. Maintained steroid treatment for 2 weeks was associated with complete recovery of renal function and skin lesions. CONCLUSION: As influenza vaccination is increasingly used, physicians should be aware of the potential serious side effect of leukocytoclastic vasculitis, particularly in patients who are immunocompromised either due to an underlying disorder or as a treatment-related side effect.

Pegylated liposomal doxorubicin and mitomycin C in combination with infusional 5-fluorouracil and sodium folinic acid in the treatment of advanced gastric cancer: results of a phase II trial.

Mitomycin C (MMC) in combination with infusional 5-fluorouracil (5-FU) is a well-tolerated active combination therapy for advanced gastric cancer. Pegylated liposomal doxorubicin (Caelyx) has been combined with this regimen in a phase I study exhibiting promising activity in patients with upper gastrointestinal tumors. In the present study, we investigated activity and tolerability of this three-drug regimen in patients with gastric cancer. Patients with advanced or metastatic gastric cancer were recruited to receive weekly infusional 5-FU (2000 mg/m2) mixed with sodium folinic acid (FA; 500 mg/m2) in one pump (days 1, 8, 15, 22, 29, 36). On days 1 and 29, Caelyx (20 mg/m2) was given as a 1-h, and MMC (7 mg/m2) was applied as bolus injection on days 8 and 36. Treatment courses were repeated on day 57. Twenty-seven patients with a median age of 66 years were recruited in a single center; 56% had histologically proven peritoneal carcinomatosis and 26 patients are evaluable for toxicity. Common Toxicity Criteria of the National Cancer Institute grade 3 toxicity was recorded in 34% of the patients (anemia 12%, leukocytopenia 8%, febrile neutropenia 4%, thrombocytopenia 12%, nausea 15%, diarrhea 8% and mucositis 4%). One patient developed hemolytic-uremic syndrome. One complete (5%) and eight partial responses (42%) were observed in 19 patients evaluable for response according to WHO criteria. Seven patients had no change (37%) and three (16%) progressive disease. Six patients with peritoneal carcinomatosis not amenable to WHO response assessment had progression-free intervals between 8 and 21 months. Median survival for all patients was 14.7 months and median time to progression was 8.4 months. We conclude that this new three-drug combination regimen yields a promising overall response rate (47%) in patients with gastric cancer despite the inclusion of a majority of elderly patients at moderate or high risk of death in this trial. Its safety and good tolerability as established in the phase I trial was confirmed.

Genomic anatomy of the specific reciprocal translocation t(15;17) in acute promyelocytic leukemia.

The genomic breakpoints in the t(15;17)(q22;q21), associated with acute promyelocytic leukemia (APL), are known to occur within three different PML breakpoint cluster regions (bcr) on chromosome 15 and within RARA intron 2 on chromosome 17; however, the precise mechanism by which this translocation arises is unclear. To clarify this mechanism, we (i). assembled the sequence of RARA intron 2, (ii). amplified and sequenced the genomic PML-RARA junction sequences from 37 APL patients, and (iii). amplified and sequenced the reverse RARA-PML genomic fusion in 29 of these cases. Three significant breakpoint microclusters within RARA intron 2 were identified, suggesting that sequence-associated or structural factors play a role in the formation of the t(15;17). There was no evidence that the location of a breakpoint in PML had any relationship to the location of the corresponding breakpoint in RARA. Although some sequence motifs previously implicated in illegitimate recombinations were found in the microcluster regions, these associations were not significant. Comparison of forward and reverse genomic junctions revealed microhomologies, deletions, and/or duplications of either gene in all but one case, in which a complex rearrangement with inversion of the PML-derived sequence was found. These findings are consistent with the hypothesis that the t(15;17) occurs by nonhomologous recombination of DNA after processing of the double-strand breaks by a dysfunctional DNA damage-repair mechanism.

Specific aneusomies in Chinese hamster cells at different stages of neoplastic transformation, initiated by nitrosomethylurea.

Aneuploidy is ubiquitous in cancer, and its phenotypes are inevitably dominant and abnormal. In view of these facts we recently proposed that aneuploidy is sufficient for carcinogenesis generating cancer-specific aneusomies via a chain reaction of autocatalytic aneuploidizations. According to this hypothesis a carcinogen initiates carcinogenesis via a random aneuploidy. Aneuploidy then generates transformation stage-specific aneusomies and further random aneusomies autocatalytically, because it renders chromosome segregation and repair mechanisms error-prone. The hypothesis predicts that several specific aneusomies can cause the same cancers, because several chromosomes also cooperate in normal differentiation. Here we describe experiments on the Chinese hamster (CH) that confirm this hypothesis. (i) Random aneuploidy was detected before transformation in up to 90% of CH embryo cells treated with the carcinogen nitrosomethylurea (NMU). (ii) Several specific aneusomies were found in 70-100% of the aneuploid cells from colonies transformed with NMU in vitro and from tumors generated by NMU-transformed cells in syngeneic animals. Among the aneuploid in vitro transformed cells, 79% were trisomic for chromosome 3, and 59% were monosomic for chromosome 10, compared with 8% expected for random distribution of any aneusomy among the 12 CH chromosomes. Moreover, 52% shared both trisomy 3 and monosomy 10 compared with 0.6% expected for random distribution of any two aneusomies. Among the tumor cells, 65% were trisomic for chromosome 3, 51% were trisomic for chromosome 5, and 30% shared both trisomies. Aneuploid cells without these specific aneusomies may contain minor transformation-specific aneusomies or may be untransformed. (iii) Random aneusomies and structurally altered chromosomes increased with the generations of transformed cells to the point where their origins became unidentifiable in tumors. We conclude that specific aneusomies are necessary for carcinogenesis.