Solution and solid state properties of a set of procaine and procainamide derivatives

A set of potential Class III antiarrhythmic agents of structure p-HOOC–R–CO–NH–C₆H₄–CO–X–C₂H₅–N(C₂H₅)₂ were isolated as crystalline solids of the amide and ester derivatives, I: succinylprocainamide (X=–NH–, R=–C₂H₄–); II: succinylprocaine (X=–O–, R=–C₂H₄–); III: maleylprocainamide (X=–NH–, R=–C₂H₂–) and IV: maleylprocaine (X=–O–, R=–C₂H₂–). Although compounds I–IV exhibit similar solution properties (i.e. acid–base speciation, with zwitterionic (+−) to neutral (00) form ratios higher than 10⁴), aqueous solubility of –NH– derivatives is significantly higher than that of –O– derivatives and also, solvent effects on solubility (i.e. the change of water by ethanol) is clearly different in both series. Solution and solid-state properties of I–IV were characterized to account for the observed differences. Results indicate that procainamide derivatives I and III crystallizes as (+−)_s but procaine derivatives II and IV as (00)_s. Besides, I is anhydrous but II–IV are hydrates. Aqueous solubility and solvent effect on solubility are controlled by the intrinsic solubility of the species (+−) in I and III and (00) in II and IV. The rise of hydrophilicity of species (00) due to the structural change from –O– to –NH– would determine the change in the structure of the precipitating crystals from (00)_s to (+−)_s. Solid structure (zwitterionic or neutral), as well as composition (anhydrous or hydrated) may be recognized as the main factors in determining the rank of aqueous solubility of the set: (+−)>(+−·H₂O)>(00·H₂O).     

Prognostic Score in Gastric Cancer: The Importance of a Conjoint Analysis of Clinical, Pathologic, and Therapeutic Factors

Background

This study was designed to establish a prognostic score for gastric cancer that takes into account factors related to the tumor, the patient, and the treatment.

Methods

Two hundred thirty patients with gastric adenocarcinoma admitted t o the Department of Abdominal Surgery at Hospital do Câncer A. C. Camargo (São Paulo) and treated by gastrectomy from January 1992 until December 1996 were included in this retrospective cohort. The prognostic score was created according to the variables identified in the multivariate analysis and by using the regression coefficients generated by the Cox regression.

Results

The 5-year overall survival rate was 44.5%. The final multivariate model identified six variables with a significant and independent effect on survival: sex, weight loss, lymphocyte count, tumor-node-metastasis staging, lymphadenectomy, and lymph node ratio. Patients were divided into four groups according to their scores, as follows: group 1, 0 to 3.0; group 2, 3.5 to 5.5; group 3, 6.0 to 8.5; and group 4, 9.0 to 14.0. The 5-year survival rates were 91.5%, 49.3%, 20.3%, and .0% for the score groups 1, 2, 3, and 4, respectively (P < .001). The score was superior in the assessment of prognosis when compared with tumor-node-metastasis staging alone.

Conclusions

It is possible to create a prognostic score that simultaneously includes factors related to the tumor, patient, and treatment, thus generating a more effective system in predicting the prognosis than the morphology-based staging systems.     

The addition of ifosfamide/etoposide to cisplatin/teniposide improves the survival of children with retinoblastoma and orbital involvement

This study aimed to determine the impact of the addition of ifosfamide/etoposide to a regimen containing cisplatin/teniposide on the survival of patients with retinoblastoma with orbital involvement. Thirty patients were treated at the A. C. Camargo Hospital, Brazil, from 1986 to 2002. From 1986 to April 1992 (period I, n=12), treatment consisted of 3 cycles of induction chemotherapy with cisplatin and teniposide, followed by maintenance with same drugs alternating with cyclophosphamide, vincristine, and doxorubicin every 21 days for 60 weeks. Since April 1992 (period II, n=18), the treatment consisted of 3 cycles of ifosfamide and etoposide followed by maintenance with same drugs, alternating with cisplatin and teniposide every 21 days for 36 weeks. In both periods, children were submitted to exenteration with eyelid preservation and orbital radiation therapy with 45 cGy, and also received intrathecal therapy with methotrexate plus dexamethasone and cytarabine. Kaplan-Meier method was used for survival analysis. The median age was 31 months. Most patients (86.7%) presented unilateral tumors. The 3-year overall survival was 34.4% and 72.2%, respectively, for patients treated during periods I and II (P=0.061). The addition of ifosfamide/etoposide to chemotherapy with cisplatin/teniposide improves survival in these patients, but further studies are still necessary.     

Retinoblastoma in children older than 5 years of age

BACKGROUND: Retinoblastoma is a malignant tumor of the embryonic neural retina. About 80% of cases are diagnosed before age 4, with a median age at diagnosis of 2 years. OBJECTIVE: To determine characteristics and prognosis of retinoblastoma in children older than 5 years. PROCEDURES: From 1986 to 2002, medical records of 16 patients out of 453 cases referred to Hospital do Cancer AC Camargo, S?o Paulo, Brazil. RESULTS: Median age at diagnosis was 73.7 months (range 65-144) and there was an equal gender distribution. Fifteen patients presented with unilateral disease. The mean time between first symptoms and diagnosis was 9.6 months (range 0-48). Most cases were diagnosed in advanced stages and 15 eyes were enucleated. Eleven patients presented with intraocular tumor (1 Reese II and 10 Reese V) and five presented with extraocular disease (one CCG II and four CCG III). Twelve patients are still alive with a median follow-up of 92 months (range 65-199). CONCLUSIONS: Because of its low incidence at this age, diagnosis of retinoblastoma is usually delayed due to low level of suspicion. Therefore, it is important that physicians are aware of this disease in order to perform an earlier diagnosis, and decrease treatment-related morbidity.     

Trends in eye cancer mortality among children in Brazil, 1980-2002

BACKGROUND: In the last few decades mortality from childhood cancers has shown substantial declines in industrialized countries, with smaller favorable trends in South America. OBJECTIVE: This study describes mortality trends in childhood eye cancer in Brazil from 1980 to 2002. PROCEDURE: Age-specific eye cancer death rates (0-4, 5-9, and 10-14 years) were calculated according to gender. Age-standardized mortality rates for children under 15 years were obtained through the direct method, using the 1960 world population as the standard. Trends in mortality were modeled using linear regression methods, with the age-standardized mortality coefficient (3-year centered moving average) as the dependent variable and the calendar year as the independent variable. RESULTS: The age-standardized mortality rates among the boys decreased from 0.14/100,000 habitants in 1981 and 1985 to 0.06 in 1994, whereas the observed corresponding decline among girls was from 0.17/100,000 habitants in 1982 and 1983 to 0.07 in 2001. Statistically significant declining trends in eye cancer mortality rates were observed for boys (r(2) adjusted = 0.54, P < 0.001) and also for girls (r(2) adjusted = 0.53, P < 0.001). When only subsite retina was analyzed a statistically significant decrease in mortality coefficients was also noted for males (r(2) adjusted = 0.55, P < 0.001) and females (r(2) adjusted = 0.32, P = 0.005). CONCLUSIONS: A consistent decrease in eye cancer mortality rates was noted in Brazil. In the absence of changes in incidence rates, this decline could be attributed to the improvement in treatment protocols and survival.     

Trilateral retinoblastoma

Background

Trilateral retinoblastoma (TRB) is a syndrome consisting of unilateral or bilateral hereditary retinoblastoma (Rb) associated with an intracranial neuroblastic tumor. Although its incidence is low, the prognosis is very poor. This article reports four cases of TRB and discusses the role of neuroimaging screening for early detection.

Procedure

From January 1986 to December 2003, 470 children with Rb were admitted to the Pediatrics and Ophthalmology Departments, A C Camargo Hospital, São Paulo, Brazil.

Results

There were four patients with pineoblastoma, two of whom had a positive familial history. The age at diagnosis of Rb was 4, 6, 10, and 24 months while the age of diagnosis of TRB was 10, 25, 57, and 72 months. One patient presented TRB at initial diagnosis of Rb. Three patients had bilateral disease and all of them had one eye enucleated, followed by chemotherapy and/or external beam radiation therapy (EBRT). One child with unilateral disease was only submitted to enucleation. In spite of intensive treatment, all patients died with progressive disease within 7, 8, 12, and 12 months after diagnosis of TRB.

Conclusions

Early diagnosis as well as new therapeutic approaches are needed to achieve better results. Pediatr Blood Cancer 2007;48:306–310. © 2006 Wiley‐Liss, Inc.     

Enterococcal infection in children

From relative obscurity, enterococci have become a leading cause of nosocomial infection. This has been attributed, in part, to the growth in susceptible host populations, increased use of intravascular devices, prolonged hospital stay, and widespread antibiotics use. Furthermore, the facility with which enterococci acquire resistance characteristics coupled with their capacity to survive in the environment renders them uniquely suited as nosocomial opportunists and have resulted in global dissemination of resistant strains. Debate continues as to whether most serious infections arise from a person's indigenous flora or dissemination of virulent clones. Enterococci are normal inhabitants of the human gastrointestinal tract. Classically associated with endocarditis and wound and urinary tract infections, increasingly they are a cause of nosocomial bacteremia. The rise in incidence of serious enterococcal infection has been particularly evident in neonatal, paediatric intensive care, and haematology/oncology units. Spread of resistant phenotypes has posed a difficult therapeutic challenge. We have been rescued, albeit perhaps only temporarily, by the addition of newer agents, such as linezolid, to the therapeutic armamentarium. However, there is no room for complacency. Linezolid resistance already has been reported. Efforts must continue to focus on prevention of the emergence and dissemination of resistance through policies of rational antibiotic use, infection control and education.