Effect of duration of treatment on treatment outcome for patients with clear-cell sarcoma of the kidney: a report from the National Wilms' Tumor Study Group.

PURPOSE: To evaluate the effect of conventional and standard (ST) versus pulse-intensive (PI) chemotherapy and short-duration versus long-duration chemotherapy on relapse-free survival (RFS) and overall survival rates of patients with clear-cell sarcoma of the kidney (CCSK) entered onto the National Wilms' Tumor Study (NWTS)-4. PATIENTS AND METHODS: The 5-year and 8-year RFS rates were determined for patients with CCSK treated on the NWTS-4. After August 6, 1986, 40 previously untreated children younger than 16 years with CCSK were randomly assigned, after the completion of 6 months of chemotherapy, to discontinue (short) or continue 9 additional months (long) of treatment with chemotherapy regimens that included vincristine and either divided-dose (ST) courses (5 days) or single-dose (PI) treatment with dactinomycin and divided-dose (ST) courses (3 days) or single-dose (PI) treatment with doxorubicin. RESULTS: For patients with CCSK, the 5- and 8-year RFS rates were 65.2% and 60.6%, respectively, for patients randomly assigned to the short chemotherapy and 87.8% (both 5- and 8-year RFS) for patients randomly assigned to the long chemotherapy (P =.08). The overall survival rates for patients at 5 and 8 years were 95.5% and 85.9%, respectively, for the short chemotherapy and 87.5% (both 5- and 8-year overall survival) for the long chemotherapy (P =.99). In NWTS-4, the overall survival rates for patients with CCSK improved from NWTS-3 (83% v 66.9% at 8 years, respectively; P <.01). CONCLUSION: CCSK patients exhibit an improved RFS from a longer course of therapy when using vincristine, doxorubicin, and dactinomycin, but their long-term survival is unchanged compared with patients receiving 6 months of therapy. The overall survival rates for patients with CCSK have improved from NWTS-3.     

Synergistic cytotoxicity and pharmacogenetics of gemcitabine and pemetrexed combination in pancreatic cancer cell lines.

PURPOSE: Gemcitabine is an inhibitor of ribonucleotide reductase (RR) and DNA synthesis and is an effective agent in the treatment of pancreas cancer. The present study investigates whether the multitargeted antifolate pemetrexed would be synergistic with gemcitabine against MIA PaCa-2, PANC-1, and Capan-1 pancreatic cancer cell lines. EXPERIMENTAL DESIGN: Cells were treated with gemcitabine and pemetrexed, and the type of drug interaction was assessed using the combination index. Cytotoxicity of gemcitabine was examined with inhibitors of (a) deoxycytidine kinase (dCK), which activates gemcitabine by phosphorylation, and (b) 5'-nucleotidase (drug dephosphorylation) and cytidine deaminase (drug deamination), the main inactivating enzymes. The effects of gemcitabine and pemetrexed on cell cycle were analyzed by flow cytometry, and apoptosis was examined by fluorescence microscopy. Finally, quantitative, real-time PCR was used to study the pharmacogenetics of the drug combination. RESULTS: Synergistic cytotoxicity and enhancement of apoptosis was demonstrated, mostly with the sequence pemetrexed-->gemcitabine. Pemetrexed increased cells in S phase, the most sensitive to gemcitabine, and a positive correlation was found between the expression ratio of dCK:RR and gemcitabine sensitivity. Indeed, pemetrexed significantly enhanced dCK gene expression (+227.9, +86.0, and +135.5% in MIA PaCa-2, PANC-1, and Capan-1 cells, respectively), and the crucial role of this enzyme was confirmed by impairment of gemcitabine cytotoxicity after dCK saturation with 2'-deoxycytidine. CONCLUSIONS: These data demonstrate that the gemcitabine and pemetrexed combination displays schedule-dependent synergistic cytotoxic activity, favorably modulates cell cycle, induces apoptosis, and enhances dCK expression in pancreatic cancer cells.     

Plasma amino acid concentrations throughout normal pregnancy and early stages of intrauterine growth restricted pregnancy.

OBJECTIVES: Assessment of maternal plasma amino acids during normal gestation and in early stages of intrauterine growth restriction (IUGR). STUDY DESIGN: Plasma amino acid concentrations were measured in: (1) non-pregnant women (n=7); (2) normal pregnant women in the first (n=13), second (n=17) and third (n=12) trimester; and (3) pregnant women in the first trimester with later development of IUGR (n=8). Amino acid levels were quantified by electrochemical detection in a reversed-phase high-performance liquid chromatography (HPLC) system. RESULTS: The levels of most essential and non-essential amino acids changed markedly in the first trimester during normal pregnancy and thereafter remained almost constant. In the first trimester of IUGR, a number of both essential and non-essential amino acids were significantly different from those observed in normal pregnancies, with values more similar to those observed in non-pregnant women. CONCLUSIONS: Levels of most maternal amino acids decrease and some increase during early gestation reflecting a metabolic adaptation that occurs in normal pregnancies. Pregnancies that later develop IUGR show a lack of these adaptations for a significant number of both essential and non-essential amino acids, suggesting a lack of adaptation.     

Dual-Port 2D and 3D Endoscopy: Expanding the Limits of the Endonasal Approaches to Midline Skull Base Lesions with Lateral Extension

Objective To investigate a novel dual-port endonasal and subtemporal endoscopic approach targeting midline lesions with lateral extension beyond the intracavernous carotid artery anteriorly and the Dorello canal posteriorly. Methods Ten dual-port approaches were performed on five cadaveric heads. All specimens underwent an endoscopic endonasal approach from the sella to middle clivus. The endonasal port was combined with an anterior or posterior endoscopic extradural subtemporal approach. The anterior subtemporal port was placed directly above the middle third of the zygomatic arch, and the posterior port was placed at its posterior root. The extradural space was explored using two-dimensional and three-dimensional endoscopes. Results The anterior subtemporal port complemented the endonasal port with direct access to the Meckel cave, lateral sphenoid sinus, superior orbital fissure, and lateral and posterosuperior compartments of the cavernous sinus; the posterior subtemporal port enhanced access to the petrous apex. Endoscopic dissection and instrument maneuverability were feasible and performed without difficulty in both the anterior and posterior subtemporal ports. Conclusion The anterior and posterior subtemporal ports enhanced exposure and control of the region lateral to the carotid artery and Dorello canal. Dual-port neuroendoscopy is still minimally invasive yet dramatically increases surgical maneuverability while enhancing visualization and control of anatomical structures.     

Association between trauma and cancer of the testis: the importance of self-palpation of the testis for the early detection: two case reports

introduction: Cancer of the testis is not always early detected and recognised, both by the physician and by the patient: sometimes physicians do not make an accurate genitals exam while patients often underestimate this problem. Case reports: Case I: 42-year-old man accepted from another hospital's Emergency, because of pain and edema of the right testis after a recent trauma on the gonad. At US, evidence of increased volume of the right testis with a large intraparenchymal hematoma. The markers were higher than normal. We performed a right orchiecthomy. The pathologist noted the presence of a mixed cancer of the testis (95% embryonal, 5% seminoma). Case II: 49-year-old man with hematuria, accepted from Emergency. The abdominal US revealed the presence of a voluminous neoformation (diameter of 12 cm) of the right kidney with neoplastic thrombosis of the right kidney vein. At the general physical exam, we detected the presence of an increased right testis, that at the US appared to be suspicious for cancer. Tumor markers were normal with the exception of αFP. We performed right nephro-adrenalectomy, right orchiectomy and removal of local nodes. The definitive histological examination demonstrated the presence of a seminoma of the testis and papillary carcinoma of the kidney with node metastasis. Discussion: Current studies showed an association between trauma and cancer of the testis, even if some authors did not find this association because they consider that patients with trauma undergo US and in that occasion cancer is incidentally detected. Conclusions: The association between trauma and cancer of the testis is controversial in current studies. Furthermore screening for the cancer of the testis does not seem to be useful, even if the self- and the physician's palpation of the testis seem to be very important because in these two cases they should allow the early detection of the condition, with a resulting better prognosis.     

Co-expression of cancer testis antigens and topoisomerase 2-alpha in triple negative breast carcinomas

Triple negative breast cancers (TNBC) are characterized by aggressive tumor biology, lack of targeted treatments and poor prognosis. Anthracyclins were shown to induce immunogenic death in target cells, potentially leading to “endogenous” vaccination. We comparatively assessed expression of cancer testis antigens (CTA) and topoisomerase 2-alpha (TOPO2A), a well defined molecular target of anthracyclins, in TNBC fully characterized for basal-like (BL) immunophenotype, BL morphology and conventional clinicopathological factors. The study included 83 patients undergoing surgery between January 2003 and December 2009. Tissue sections were stained with CK5/6, CK14, EGFR, Ki-67, TOPO2A, MAGE-A1, MAGE-A10, NY-ESO and multi-MAGE-A specific reagents. Of the 83 TNBC, >66.3% had BL immunophenotype and 48.2% had BL morphology. MAGE-A1 specific staining was most frequently detectable (69.2%), followed by multi-MAGE-A (58%), NY-ESO (27.1%) and MAGE-A10 (16%) specific staining. MAGE-A10 expression significantly correlated with tumor size (p = 0.026). Furthermore, MAGE-A1, MAGE-A10 and multi-MAGE-A specific stainings significantly correlated with advanced clinical stage (p = 0.024, p = 0.041, p = 0.031, respectively). We found no significant association between CTA expression and disease free (DFS) or overall survival (OS). Most interestingly, a significant correlation was observed between expression of MAGE-A10 and NY-ESO and expression of TOPO2A (p = 0.005, p = 0.013). Expression of defined CTA and TOPO2A are significantly correlated in TNBC. Considering the limited therapeutic options for TNBC, these findings might suggest novel forms of combination therapies that should be further explored.