Cyclophosphamide dose adjustment based on body weight and albuminemia in elderly patients treated with R-mini-CHOP.

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma in elderly patients, and R-CHOP chemotherapy is the standard treatment protocol for DLBCL. Elderly patients (often defined as 75 years of age) are treated with anticancer drugs with precaution; however, the pharmacokinetics and pharmacodynamics (PK and PD) of these agents have not been thoroughly investigated in this population. In this study, we investigated the PK of cyclophosphamide (CP) and doxorubicin (DOXO) in elderly patients in order to verify if there is an influence of age on the PK of these anticancer drugs. MATERIALS AND METHODS: This is a prospective multi-center clinical trial investigating the PK of CP and DOXO in elderly and very elderly patients with DLBCL treated by R-mini-CHOP regimen. Dose levels were 25 mg/m2, 0.7-1.4 mg/m2, 750 mg/m2, and 375 mg/m2 for DOXO, Vincristine (VCR), CP, and Rituximab, respectively. For PK analysis, 7 time point samples were collected over 48 h post-administration on cycle 3. CP and VCR plasma concentrations were measured using UPLC-MS/MS validated method. DOX plasma concentrations were measured using UPLC coupled with fluorescence detection-validated method. PK-POP modeling has been performed with a non-linear mixed-effect model program (Monolix). RESULTS: 31 patients (15 males and 16 females), 75 to 96 years old, were treated with R-miniCHOP protocol. Among them, 19 patients were treated with VCR. A one-compartment (1cpt) open model with linear elimination adequately described CP concentration-time courses. The population PK parameters for CP were: CL = 3.58 L/h, Vmale = 32.2 L, and Vfemale = 28.7 L. Body weight (BW), albuminemia, and gender demonstrated a significant impact on CP PK. A 2-compartment (2cpt) open model with linear elimination best described DOXO concentration-time courses. The population PK parameters for DOXO obtained for the structural model were: CL = 51.1 L/h, Q = 49.6 L/h, V1 = 29.4 L, V2 = 1,130 L (clearances: CL, Q, volumes of distribution: V1, V2). The main covariate effects on DOXO PK were related to gender, BW, and VCR administration. VCR increases DOXO V1 from 29.4 L to 57.5 L (p = 0.02). No hematologic and cardiac grade 3 or 4 toxicity were recorded. CONCLUSIONS: Usually, in the absence of specific data, the majority of the physicians empirically reduce anticancer drug dose in the elderly patients (Tourani in J Geriatr Oncol 3(1): 41-48, 2012), or even does not treat these very-old patients. A better knowledge of the pharmacokinetics in very-old patients should allow a better dose adjustment based on the most significant physiological factors that modify the pharmacokinetic parameters. In this study, no serious toxicity was observed in these very elderly patients (84.1 years). This indicates that dose adjustment of chemotherapies should not only be based on age and creatinine clearance, but also, based upon appropriate physiological and biological data. Our findings indicate that, CP dose adjustment should be done according to serum albumin levels and patients BW and gender.

Variations in schedules of ifosfamide administration: a better understanding of its implications on pharmacokinetics through a randomized cross-over study.

PURPOSE: The metabolism of ifosfamide is a delicate balance between a minor activation pathway (4-hydroxylation) and a mainly toxification pathway (N-dechloroethylation), and there remains uncertainty as to the optimal intravenous schedule. METHODS: This study assesses ifosfamide pharmacokinetics (PK) according to two standard schedules. Using a 1:1 randomized trial design, we prospectively evaluated ifosfamide PK on two consecutive cycles of 3 g/m2/day for 3 days (9 g/m2/cycle) given in one of two schedules either by continuous infusion (CI) or short (3 h) infusion. Highly sensitive analytical methods allowed determination of concentrations of ifosfamide and the key metabolites 4-hydroxy-ifosfamide, 2- and 3-dechloroethyl-ifosfamide. RESULTS: Extensive PK analysis was available in 12 patients and showed equivalence between both schedules (3 h versus CI) based on area under the curves (micromol/l x h) for ifosfamide, 4-hydroxy-ifosfamide, 2- and 3-dechloroethyl-ifosfamide (9,379 +/- 2,638 versus 8,307 +/- 1,995, 152 +/- 59 versus 161 +/- 77, 1,441 +/- 405 versus 1,388 +/- 393, and 2,808 +/- 508 versus 2,634 +/- 508, respectively, all P > 0.2). The classical auto-induction of metabolism over the 3 days of infusion was confirmed for both schedules. CONCLUSION: This study confirms similar PK for both active and toxic metabolites of ifosfamide in adult cancer patients when 9 g/m2 of ifosfamide is administered over 3 days by CI or daily 3-h infusions.

Anorectal malignant melanoma. A clinicopathologic study, including immunohistochemistry and DNA flow cytometry.

BACKGROUND: Anorectal malignant melanoma is a rare tumor with an extremely poor prognosis. DNA flow cytometric study as well as detailed immunohistochemical study have not been reported previously. METHODS: Eighteen cases of anorectal melanoma were studied, including immunohistology for melanoma markers and epithelial markers and DNA flow cytometric study of paraffin blocks. RESULTS: Most patients were Ashkenazi Jews, compared with Sephardi Jews and Arabs. Of the 17 patients followed, 14 died of disease at 4-39 months from presentation. Three patients were alive with disease at 12, 53, and 72 months of follow-up. Tumor thickness ranged from 3-35 mm (mean, 12.8 mm). The 2 long term survivors had tumor thickness < or = 7 mm. No correlation was found between the mode of primary surgical treatment (8 patients: abdominoperineal resection; 10 patients: local excision) and outcome. Vimentin, HMB-45, and S-100 protein stainings were positive in 18, 17, and 15 tumors, respectively. Polyclonal carcinoembryonic antigen (CEA), broad-spectrum cytokeratin, epithelial membrane antigen, monoclonal CEA, and TAG-72 (B72.3) stainings were positive in 13, 3 (only focal and rare staining), 2, 0, and 0 tumors, respectively. Thirteen tumors had adequate material for DNA analysis, and all were DNA aneuploid. S-phase fraction could be assessed in 11 tumors and ranged from 7.7-24% (mean, 14%). An S-phase fraction of < 10% was observed in the 2 long term survivors. CONCLUSIONS: Anorectal melanoma in this study carried a grave prognosis. The frequent staining for polyclonal CEA (with negative monoclonal CEA staining) was probably due to nonspecific cross-reacting antigens. The occasional staining for epithelial markers warrants a comprehensive immunohistochemical study to ensure a correct diagnosis, especially in small biopsies of amelanotic undifferentiated tumors that lack junctional changes. The aneuploidy of all tested tumors reflected their highly malignant behavior. A trend toward longer survival was observed in patients with thin tumors and an S-phase fraction of < 10%. However, due to the small number of survivors, the latter observation should be further tested in a larger scale series.

Ecstasy and dementia in a young subject.

We report a cerebrovascular accident after Ecstasy (MDMA) intake which induced a frontal dementia in a young man.

Phenobarbital administration does not affect high-dose ifosfamide pharmacokinetics in humans.

Ten patients (three males and seven females) were treated for sarcoma with high-dose ifosfamide (IFO) according to a 4 g/m2 1 h i.v. infusion schedule every day for 3 days. The courses were repeated every 4 weeks. Phenobarbital (PB) treatment was only started at the second course and was continued for the following courses at a p.o. dose of 60 mg/ day on the 3 days of IFO i.v. infusion. IFO pharmacokinetic studies were performed on the first and third day of each course. The results of the pharmacokinetic analysis showed a statistical difference of the IFO parameters between the first and third day of each course with or without PB co-administration. When we compared all the first days and all the third days, the statistical analysis showed no difference for all the pharmacokinetic parameters. The meaning of these results was that IFO kinetics was not stationary with an area under the curve decreasing from the first to the third day of each course and that concomitant PB administration, in our administration schedule, did not influence IFO pharmacokinetics.

Intraoperative frozen section examination of myometrial invasion depth in patients with endometrial carcinoma.

The objective of this study was to evaluate the accuracy of frozen sections (FS) as a method for estimation of the depth of myometrial invasion in patients with stage I endometrial carcinoma. During a 3-year period (1989-1992), 46 consecutive patients with FIGO stage I endometrial carcinoma were included in this study. The depth of myometrial invasion was estimated by FS examination performed during surgery. The final histologic findings of the surgical specimen were compared to the FS evaluation. The results of this study demonstrate that deep or superficial myometrial invasions were correctly diagnosed by FS in 42 out of 46 cases (91.3%). Three cases (6.6%) with deep myometrial invasion were falsely diagnosed as superficially invasive. One case with superficial invasion (2.1%) was falsely diagnosed as deeply invasive. In conclusion, intraoperative FS examination of depth of myometrial invasion by endometrial carcinoma is a simple and accurate method, providing a good correlation with the final histologic report of the surgical specimen.

The reproductive system of male rats exposed to very low doses of ionizing radiation, 1: Hormonal profile of animals exposed after sexual maturity.

Adult male rats were treated with a single, whole body exposure to a dose of 0.001, 0.01 or 0.1 Gy (1 Gy = 100 rad). The animals were sacrificed 1, 7, 30, 100 or 180 days following exposure. Serum testosterone, serum and hypophyseal LH, FSH and prolactin as well as hypothalamic LHRH were measured. In the 0.1 Gy irradiated rats, serum LH and FSH were 100% higher and serum prolactin was 30% lower as compared to controls, 30 days after irradiation. The concentrations of these hormones remained significantly different from control values even after 180 days after exposure. On the other hand, the hypophyseal content of LH, FSH and prolactin decreased in the 0.1 Gy treated rats, 100 days after irradiation. In the group of the 0.01 Gy irradiated rats, serum FSH increased by 70% and hypophyseal FSH decreased. No changes were observed in serum testosterone and hypothalamic LHRH in any of the irradiated groups and no changes were observed in the group exposed to 0.001 Gy. It may be concluded that a long term damage to the reproductive system of the male rat was induced by a single, whole body exposure to 0.1 Gy of gamma radiation.

Ciliary ultrastructure of respiratory and fallopian tube epithelium in a sterile woman with Kartagener's syndrome. A quantitative estimation.

Ciliary ultrastructure was studied and quantitatively estimated in a 27-year-old sterile woman suffering from complete KS. Ciliated epithelium was obtained from both nasal mucosa and a fallopian tube. Cilia from both locations were devoid of DA. Various MT abnormalities were found in 16 percent of respiratory epithelial and 21 percent of fallopian tube ciliary cross-sections. The abnormality related to radial spoke defect was frequently seen. The findings in the fallopian tubes were compared to three normal control cases. In these, DA were visible, and MT defects were mainly of excess or missing microtubules. The relevance of these findings to fertility is not clear.

Stage III-IV epithelial carcinoma of the ovary: is the second-look operation of any value for the patient?

A second-look operation (SLO) was performed in 18 of 24 patients operated for Stage III-IV epithelial carcinoma of the ovary in order to assess the effect of chemotherapy and to decide if further treatment, such as radiation therapy, was indicated. All patients had postoperative combination chemotherapy: either with PA [Platinol (Bristol, UK) and adriamycin] or with CHAD (cyclophosphamide, hexamethylmelamine, adriamycin and cis-diamminedichloroplatinum). In 7 of 18 (39%) patients who had SLO following chemotherapy, macroscopic tumor was present; in 7 (39%) patients, microscopic residual or recurrent disease was found, as proven by histological examination of the biopsies taken during the operation. Only in four patients (29.7%) was the SLO negative. Of these patients, three had recurrent disease after 3,6 and 7 months postoperatively. These findings indicate that the SLO was noncontributory to the management of the patients. The role of the SLO commonly used in most current treatment protocols of patients with Stage III-IV epithelial carcinoma of the ovary is questionable and requires further evaluation.

The pattern of epithelial mucin secretion in normal, hyperplastic, and adenocarcinomatous endometrium.

Stains for mucosubstances were performed on endometrial curetting material of normal and pathological endometrium. The study included normal proliferative and secretory endometrium, cystic and adenomatous hyperplasia, and endometrial adenocarcinoma. It was attempted to characterize the epithelial mucin in each of these conditions and to differentiate between them. The stains used were Alcian blue at pH 0.5 and 2.5; PAS with and without diastase digestion; and Toluidine blue. It was concluded that the Alcian blue stain at pH 2.5 was preferable for differentiating two groups: group one included benign conditions--normal endometrium, cystic hyperplasia, and adenomatous hyperplasia without atypia--in which the cytoplasm did not show any staining reaction. Group two included premalignant and malignant conditions, namely adenomatous hyperplasia with severe atypia and endometrial adenocarcinoma. In these conditions, definite staining of the cytoplasm was visible with Alcian blue at pH 2.5. The difference was statistically significant. In addition, strongly positive staining of the apical border was noted in both groups. Alcian blue at pH 0.5, PAS stain, and Toluidine blue were of no aid in differentiating the two groups. PAS stain resulted in positive apical and cytoplasmic staining in a large percentage of cases of all the different conditions. Toluidine blue did not show consistent staining of the cells. It was deduced that the cytoplasm of the premalignant and malignant group contained sulphated and nonsulphated acid mucopolysaccharides, as opposed to the benign conditions, in which the cytoplasm contained neutral mucopolysaccharides and glycogen. In each of the conditions acid and neutral mucopolysaccharides were present at the apical border. The finding of stainable cytoplasmic mucosubstances in endometrial adenocarcinoma is in contrast to what has been generally reported that such mucosubstances were characteristic of adenocarcinoma of endocervical origin only. Our study enabled us to differentiate endometrial adenomatous hyperplasia with severe atypia and adenocarcinoma from the more benign conditions by staining of cytoplasmic mucin with Alcian blue at pH 2.5.

Outpatient diagnostic endometrial aspiration curettage with a new aspiration curette.

During a period of 2 years (1981-1982), 226 outpatient endometrial aspiration curettages (EACs) were performed with a new aspiration curette that had been developed by the authors. All patients had risk for general anesthesia. From 17 of them, endometrial polyps were removed by the EAC. Endometrial carcinoma was diagnosed in eight others, adenomatous hyperplasia in four, and cystic hyperplasia in two women. The main advantage of the new curette is the ability to aspirate endometrial polyps through its modified opening.

Giant chorioangioma of the placenta.

We report a case of giant chorioangioma of the placenta which was complicated by breech presentation, placenta praevia, hydramnios, toxemia and premature separation of the placenta. These complications are described separately in the literature as being associated with chorioangioma of the placenta, but rarely appear together in a single case.

Leydig-cell tumor of the ovary: visualization using 131I-19-iodocholesterol scintigraphy.

A Leydig (Hilus)-cell tumor of the ovary was diagnosed in a 54-year-old woman with severe hirsutism and virilization. This case is unique in that it was diagnosed in a postmenopausal female 24 years after ovarian irradiation for sterilization, and the tumor was successfully localized preoperatively using 131I-19-iodocholesterol scintigraphy. This nuclear scanning technique may be of use in documenting the biologic activity of ovarian masses and in localizing functioning ovarian tumors which are too small to palpate or to localize by other means.

[Multiple primary malignant melanomas. A report of five cases (author's transl)]. / Mélanomes malins primitifs multiples. A propos de cinq observations.

The authors present 5 cases of primary malignant melanomas occurring simuatlneously or successively, diagnosed at Institut Gustave Roussy over a period of 10 years. This work emphasizes the need for searching possible changes of nevi in melanoma patients.

[Indications for hysterectomy in placental tumors]. / Les indications de l'hystérectomie dans les tumeurs placentaires.

Indications for hysterectomy in placental tumours are now most often to carry out hysterectomy as a second attack designed to deal with residual lesions of choriocarcinoma that prove resistant to chemotherapy. Of 80 patients treated, 24 were first seen for chemotherapy after hysterectomy and this is too great a number. On the remaining 56 patients we carried out hysterectomy in 8 cases of whom 7 were secondary to chemotherapy. Seven times we found a residual lesion. These patients are now apparently cured.