CMT subtypes and disease burden in patients enrolled in the Inherited Neuropathies Consortium natural history study: a cross-sectional analysis.

BACKGROUND: The international Inherited Neuropathy Consortium (INC) was created with the goal of obtaining much needed natural history data for patients with Charcot-Marie-Tooth (CMT) disease. We analysed clinical and genetic data from patients in the INC to determine the distribution of CMT subtypes and the clinical impairment associated with them. METHODS: We analysed data from 1652 patients evaluated at 13 INC centres. The distribution of CMT subtypes and pathogenic genetic mutations were determined. The disease burden of all the mutations was assessed by the CMT Neuropathy Score (CMTNS) and CMT Examination Score (CMTES). RESULTS: 997 of the 1652 patients (60.4%) received a genetic diagnosis. The most common CMT subtypes were CMT1A/PMP22 duplication, CMT1X/GJB1 mutation, CMT2A/MFN2 mutation, CMT1B/MPZ mutation, and hereditary neuropathy with liability to pressure palsy/PMP22 deletion. These five subtypes of CMT accounted for 89.2% of all genetically confirmed mutations. Mean CMTNS for some but not all subtypes were similar to those previously reported. CONCLUSIONS: Our findings confirm that large numbers of patients with a representative variety of CMT subtypes have been enrolled and that the frequency of achieving a molecular diagnosis and distribution of the CMT subtypes reflects those previously reported. Measures of severity are similar, though not identical, to results from smaller series. This study confirms that it is possible to assess patients in a uniform way between international centres, which is critical for the planned natural history study and future clinical trials. These data will provide a representative baseline for longitudinal studies of CMT. CLINICAL TRIAL REGISTRATION: ID number NCT01193075.

[Sports injuries in children and adolescents]. / Sportverletzungen im Kindesalter.

CLINICAL/METHODOLOGICAL ISSUE: Due to active participation of children and adolescents in school sports as well as in club sports, sporting injuries in childhood are common. Because skeletal maturity is not yet complete, injury patterns in children differ from sporting injuries in adults. Knowledge of the pathophysiologic characteristics, as well as knowledge of typical injury sequelae, is of great relevance to radiologists. This review article therefore deals with common acute and chronic sporting injuries in children. STANDARD RADIOLOGICAL METHODS: Basic diagnostic imaging comprises conventional X­ray imaging in two planes. In addition, sonography, magnetic resonance imaging (MRI) and computed tomography (CT) are used. PRACTICAL RECOMMENDATIONS: Close consultation with clinical colleagues and knowledge of childhood-specific injuries help identify sports-associated trauma sequelae.

[Compatibility of family and profession. Survey of radiologists and medical technical personnel in clinics with different organizations]. / Vereinbarkeit von Familie und Beruf. Umfrage unter Radiologen und medizinisch-technischen Angestellten in Kliniken unterschiedlicher Ausrichtung.

PURPOSE: The compatibility of family and profession is especially difficult for employees in medical professions because of shift work and overtime. It seems that in the future women are going to represent the majority of medical professionals in Germany. Hence, with the forthcoming lack of physicians in Germany social aspects will also play a greater role in the choice of the place of employment. Therefore a statistical survey was made among employees on how they judge the compatibility of family and job and what they would like to improve. MATERIALS AND METHODS: From autumn 2009 until spring 2010 a total of 115 questionnaires were distributed to 8 different academic radiology departments. The anonymous questionnaire with partially open, partially graded questions and partially multiple answer questions was designed with the help of an expert for statistics and analytics and included questions about the employment and family situation, plans for the future, requested flexible working hours and childcare models, as well as ideas for improvement. Of the questionnaires 87 were analyzed with a specially designed access database using, for example descriptive statistics and histogram analyses. RESULTS: Of the interviewees 68% were female and 31% were male (1% not significant n.s.), 46% had children and 49% were childless (5% n.s.), 63% were medical doctors, 33% radiographers (3% other) and 82% worked full-time. Of the male respondents with children 42% indicated that their spouse was at home, 18% of female respondents with children indicated that their spouse was at home and only mothers worked part-time. Of the male respondents 73% would like to take parental leave, 44% of all respondents (70% of the male respondents and 34% of the female respondents) agreed that radiology is more compatible with family than other medical disciplines and 87% would like to have a childcare possibility in close proximity to the working place. DISCUSSION/CONCLUSIONS: In most of the families the classic role model prevails, although women are well-educated and men also set a high value on the compatibility of family and profession and would like to take parental leave and work flexible working hours. This is a chance especially for radiology.

[Compatibility of family and medical profession]. / Vereinbarkeit von Familie und ärztlichem Beruf.

The compatibility of family and profession is especially difficult for employees in medical professions because of shift work and overtime. It seems that in the future women are going to represent the majority of medical professionals. Hence, with the manifest lack of physicians social aspects will also play a bigger role in the choice of the place of employment. In most families the classic role model prevails although women are well educated and men also set a high value on the compatibility of family and profession and would like to take parental leave and work in flexible working hours. This represents a chance, especially for radiology.

Randomized trial of cyclophosphamide plus cisplatin with or without doxorubicin in ovarian carcinoma: a Gynecologic Oncology Group Study.

A randomized clinical trial was conducted in women with stage III ovarian carcinoma (less than or equal to 1 cm residual lesions), using cyclophosphamide plus cisplatin (CP) with or without doxorubicin. There were 349 evaluable patients, of whom 176 received CP while 173 patients received CP plus doxorubicin (CAP). Hematologic toxicity was almost identical. There was no significant difference in progression-free interval (PFI) (median, 22.7 months and 24.6 months), frequency of negative second-look laparotomy (30.2% and 32.8%), or survival (median, 31.2 months and 38.9 months) between CP and CAP, respectively. Thus, doxorubicin in the dose schedule employed does not improve combination chemotherapy of optimal stage III ovarian carcinoma. Several other findings, independent of treatment arm, were of interest. There was a significant difference in PFI and survival by residual disease category (yes v no) and by grade of differentiation (1 v 2 + 3). In multivariate analysis, age, residual disease at entry, cell type (clear cell carcinoma), and time from surgery to initiation of chemotherapy were significant predictors of survival. There was no difference in outcome comparing those who refused second-look with those who had a second-look.

Randomized comparison of fluorouracil plus cisplatin versus hydroxyurea as an adjunct to radiation therapy in stage IIB-IVA carcinoma of the cervix with negative para-aortic lymph nodes: a Gynecologic Oncology Group and Southwest Oncology Group study.

PURPOSE: In 1986, a protocol comparing primary radiation therapy (RT) plus hydroxyurea (HU) to irradiation plus fluorouracil (5-FU) and cisplatin (CF) was activated by the Gynecologic Oncology Group (GOG) for the treatment of patients with locally advanced cervical carcinoma. The goals were to determine the superior chemoradiation regimen and to quantitate the relative toxicities. METHODS: All patients had biopsy-proven invasive squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma of the uterine cervix. Patients underwent standard clinical staging studies and their tumors were found to be International Federation of Gynaecology and Obstetrics stages IIB, III, or IVA. Negative cytologic washings and para-aortic lymph nodes were required for entry. Patients were randomized to receive either standard whole pelvic RT with concurrent 5-FU infusion and bolus CF or the same RT plus oral HU. RESULTS: Of 388 randomized patients, 368 were eligible; 177 were randomized to CF and 191 to HU. Adverse effects were predominantly hematologic or gastrointestinal in both regimens. Severe or life-threatening leukopenia was more common in the HU group (24%) than in the CF group (4%). The difference in progression-free survival (PFS) was statistically significant in favor of the CF group (P = .033). The sites of progression in the two treatment groups were not substantially different. Survival was significantly better for the patients randomized to CF (P = .018). CONCLUSION: This study demonstrates that for patients with locally advanced carcinoma of the cervix, the combination of 5-FU and CF with RT offers patients better PFS and overall survival than HU, and with manageable toxicity.

Phase III trial of standard-dose intravenous cisplatin plus paclitaxel versus moderately high-dose carboplatin followed by intravenous paclitaxel and intraperitoneal cisplatin in small-volume stage III ovarian carcinoma: an intergroup study of the Gynecologic Oncology Group, Southwestern Oncology Group, and Eastern Cooperative Oncology Group.

PURPOSE: To compare the progression-free and overall survival in small-volume residual ovarian cancer after treatment with intravenous (IV) cisplatin and paclitaxel or an experimental regimen of IV carboplatin followed by IV paclitaxel and intraperitoneal cisplatin. PATIENTS AND METHODS: Patients were randomized to receive either IV paclitaxel 135 mg/m(2) over 24 hours followed by IV cisplatin 75 mg/m(2) every 3 weeks for six courses or IV carboplatin (area under curve 9) every 28 days for two courses, then IV paclitaxel 135 mg/m(2) over 24 hours followed by intraperitoneal (IP) cisplatin 100 mg/m(2) every 3 weeks for six courses. RESULTS: Of the 523 patients who entered this trial, 462 were determined to be assessable, with prognostic factors well balanced between the treatments. Neutropenia, thrombocytopenia, and gastrointestinal and metabolic toxicities were greater in the experimental arm. As a result, 18% of the patients received < or = two courses of IP therapy. Progression-free survival was superior for patients randomized to the experimental treatment arm (median, 28 v 22 months; relative risk, 0.78; log-rank P =.01, one-tail). There was a borderline improvement in overall survival associated with this regimen (median, 63 v 52 months; relative risk, 0.81; P =.05, one-tail). CONCLUSION: An experimental regimen including moderately high-dose IV carboplatin followed by IP paclitaxel and IV cisplatin yielded a significant improvement in progression-free survival when compared with a standard regimen of IV cisplatin and paclitaxel. Because the improvement in overall survival was of borderline statistical significance and toxicity was greater, the experimental arm is not recommended for routine use. However, the results provide direction for further clinical investigation in small-volume ovarian cancer.

Hydroxyurea versus misonidazole with radiation in cervical carcinoma: long-term follow-up of a Gynecologic Oncology Group trial.

PURPOSE: Long-term follow-up data of a randomized trial that compared hydroxyurea and the hypoxic-cell radiosensitizer to misonidazole as adjuncts to standard radiation therapy in locally advanced carcinoma of the cervix are reported. PATIENTS AND METHODS: Three hundred eight women were entered, and all 294 eligible patients are assessable as randomized. Eighty-one percent of patients have been monitored for 5 years or to death. RESULTS: There was an advantage for hydroxyurea in progression-free interval and survival (P = .05 and P = .066, respectively). There was no significant difference in the distribution of sites of failure between the regimens. For the 39% of patients with stages III to IVA disease, the advantage in progression-free interval for hydroxyurea was significant (47.8% v 33.6%). More leukopenia occurred on the hydroxyurea regimen than on the misonidazole regimen. CONCLUSION: In summary, these data provide stronger evidence than our previous analysis that hydroxyurea is superior to misonidazole as an adjunct to radiation therapy. For patients with locally advanced carcinoma of the cervix, hydroxyurea continues to be the adjunct of choice with radiation.

Groin dissection versus groin radiation in carcinoma of the vulva: a Gynecologic Oncology Group study.

PURPOSE: The objective of this study was to determine if groin radiation was superior to and less morbid than groin dissection. METHODS AND MATERIALS: Members of the Gynecologic Oncology Group randomized 58 patients with squamous carcinoma of the vulva and nonsuspicious (N0-1) inguinal nodes to receive either groin dissection or groin radiation, each in conjunction with radical vulvectomy. Radiation therapy consisted of a dose of 50 Gray given in daily 200 centiGray fractions to a depth of 3 cm below the anterior skin surface. RESULTS: The study was closed prematurely when interim monitoring revealed an excessive number of groin relapses on the groin radiation regimen. Metastatic involvement of the groin nodes was projected to occur in 24% of patients based on this Group's previous experience. On the groin dissection regimen, there were 5/25 (20.0%) patients with positive groin nodes. These patients received post-operative radiation. There were five groin relapses among the 27 (18.5%) patients on the groin radiation regimen and none on the groin dissection regimen. The groin dissection regimen had significantly better progression-free interval (p = 0.03) and survival (p = 0.04). CONCLUSION: Radiation of the intact groins as given in this study is significantly inferior to groin dissection in patients with squamous carcinoma of the vulva and N0-1 nodes.

Cervical carcinoma metastatic to para-aortic nodes: extended field radiation therapy with concomitant 5-fluorouracil and cisplatin chemotherapy: a Gynecologic Oncology Group study.

PURPOSE: A multicenter trial of chemoradiation therapy to evaluate the feasibility of extended field radiation therapy (ERT) with 5-fluorouracil (5-FU) and cisplatin, and to determine the progression-free interval (PFI), overall survival (OS), and recurrence sites in patients with biopsy-confirmed para-aortic node metastases (PAN) from cervical carcinoma. METHODS AND MATERIALS: Ninety-five patients with cervical carcinoma and PAN metastases were entered and 86 were evaluable: Stage I--14, Stage II--40, Stage III--27, Stage IVA--5. Seventy-nine percent of the patients were followed for 5 or more years or died. ERT doses were 4500 cGy (PAN), 3960 cGy to the pelvis (Stages IB/IIB), and 4860 cGy to the pelvis (Stages IIIB/IVA). Point A intracavitary (IC) doses were 4000 cGy (Stages IB/IIB), and 3000 cGy (Stages IIIB/IVA). Point B doses were raised to 6000 cGy (ERT + IC) with parametrial boost. Concomitant chemotherapy consisted of 5-FU 1000 mg/m2/day for 96 hours and cisplatin 50 mg/m2 in weeks 1 and 5. RESULTS: Eighty-five of 86 patients completed radiation therapy and 90% of patients completed both courses of chemotherapy. Gynecologic Oncology Group (GOG) grade 3-4 acute toxicity were gastrointestinal (18.6%) and hematologic (15.1%). Late morbidity actuarial risk of 14% at 4 years primarily involved the rectum. Initial sites of recurrence were pelvis alone, 20.9%; distant metastases only, 31.4%; and pelvic plus distant metastases, 10.5%. The 3-year OS and PFI rate were 39% and 34%, respectively, for the entire group. OS was Stage I--50%, Stage II--39%, and Stage III/IVA--38%. CONCLUSIONS: Extended field radiation therapy with 5-FU and cisplatin chemotherapy was feasible in a multicenter clinical trial. PFI of 33% at 3 years suggests that a proportion of patients achieve control of advanced pelvic disease and that not all patients with PAN metastases have systemic disease. This points to the importance of assessment and treatment of PAN metastases.

Radiation therapy versus pelvic node resection for carcinoma of the vulva with positive groin nodes.

From 1977 to 1984, 114 eligible patients with invasive squamous cell carcinoma of the vulva and positive groin nodes after radical vulvectomy and bilateral groin lymphadenectomy were randomized to receive either radiation therapy or pelvic node resection. Fifty-three of the 59 patients randomized to radiation therapy received a 4500- to 5000-rad tumor dose in five to 6.5 weeks bilaterally to the groins and to the midplane of the pelvis even if only unilateral positive groin nodes had been detected; no radiation was given to the central vulvar area. Fifty-three of the 55 patients randomized to further surgery had pelvic node resection performed on the side containing positive groin nodes either unilaterally or bilaterally. Acute and chronic morbidity was similar for both regimens. The two major poor prognostic factors were clinically suspicious or fixed ulcerated groin nodes and two or more positive groin nodes. The difference in survival for the 114 evaluable patients was significant, favoring the adjunctive radiation therapy group (P = .03). The estimated two-year survival rates were 68% for the radiation therapy group and 54% for pelvic node resection group. The most dramatic survival advantage for radiation therapy was in patients who had either of the two major poor prognostic factors present; at this time, the benefit of radiation therapy for the remaining patients is uncertain. In this randomized prospective study, the addition of adjunctive groin and pelvic irradiation therapy after radical vulvectomy and inguinal lymphadenectomy proved superior to pelvic node resection.

Early stage I carcinoma of the vulva treated with ipsilateral superficial inguinal lymphadenectomy and modified radical hemivulvectomy: a prospective study of the Gynecologic Oncology Group.

Although cure rates are high, the morbidity of radical operation for carcinoma of the vulva is substantial. Between 1983-1989, member institutions of the Gynecologic Oncology Group entered 155 patients in a prospective evaluation of modified radical hemivulvectomy and ipsilateral inguinal lymphadenecctomy for clinical stage I vulvar cancer. Only patients with neoplastic thickness of 5 mm or less, without vascular space invasion, and negative inguinal lymph nodes were eligible for this study. There have been 19 recurrences and seven deaths from disease among the 121 eligible and evaluable patients. Patients whose disease recurred on the vulva were frequently (eight of ten patients) salvaged by further operation. Five of the seven deaths due to cancer occurred among patients whose first recurrence was in the groin. Acute and long-term morbidity as well as hospital stay were each less than in the Group's previous experience in a comparable patient population treated with radical vulvectomy and bilateral inguinal-femoral lymphadenectomy. There was a significantly increased risk of recurrence but not death when compared with these same historic controls. Modified radical hemivulvectomy and ipsilateral inguinal lymphadenectomy is an alternative to traditional radical operation for these selected patients with stage I carcinoma of the vulva. The number of patients who experienced recurrence in the operated groin is of concern and may be attributable to the decision to leave the femoral nodes intact.

Teniposide (VM-26) in patients with advanced endometrial carcinoma. A phase II trial of the Gynecologic Oncology Group.

Twenty-two evaluable patients with advanced endometrial cancer were treated with teniposide 100 mg/m2/week administered as a 30-60-minute infusion. Escalations of 20 mg/m2/week to a maximum dose of 160 mg/m2 were performed in patients without toxicity. Seventeen of the 22 patients had prior chemotherapy. Two patients had a partial response (95% upper confidence bound for response: 25.9%). Toxicity was minimal. Four patients had white blood cell counts of less than 2,000/mm3 but only two with less than 1,000/mm3. Only one patient had a platelet count between 25,000 and 50,000, and no bleeding or septic episodes were noted. Four patients had mild nausea, and eight mild nausea and vomiting. Teniposide displays no major activity in patients with advanced endometrial cancer who have had prior chemotherapy.

Mitoxantrone in the treatment of advanced uterine sarcoma. A phase II trial of the Gynecologic Oncology Group.

Twenty-nine evaluable patients with metastatic or recurrent leiomyosarcoma or malignant mixed mesodermal tumors of the uterus were treated with mitoxantrone 12 mg/m2 every 3 weeks. All patients had good performance status and measurable disease. Nineteen had prior chemotherapy but only five had prior doxorubicin. No complete or partial responses were seen in 12 patients with leiomyosarcoma (95% confidence interval for a response of 0-22%) or 17 patients with mixed mesodermal tumors (95% confidence interval for a response of 0-16%). The median progression-free interval for patients with leiomyosarcoma was 1.4 months and the median survival 4.1 months. The median progression-free interval for patients with mixed mesodermal was 1.4 months and median survival 4.0 months. Mitoxantrone does not appear to be very active against leiomyosarcoma or mixed mesodermal tumors as second-line therapy.

Mitoxantrone (NSC 301739) in patients with advanced cervical carcinoma. A phase II study of the Gynecologic Oncology Group.

Twenty-six evaluable patients with advanced or recurrent squamous cell carcinoma of the uterine cervix were treated with mitoxantrone at a dosage of 12 mg/m2 every 3 weeks. Twenty-five of 26 patients had had prior irradiation and 24 prior chemotherapy. There were two partial responses, one in a patient with pelvic recurrence and another in a patient with a right upper quadrant mass. Progression-free intervals for these two patients were 5.1 and 4.6 months, respectively. Toxicity was moderate and consisted mainly of leukopenia. No septic or bleeding complications were observed. Mitoxantrone is minimally active in patients with advanced cervical cancer who have been previously treated.

Mitoxantrone in the treatment of advanced vulvar and vaginal carcinoma. A gynecologic oncology group study.

Nineteen evaluable patients with advanced carcinoma of the vulva or vagina were treated with mitoxantrone, 12 mg/m2, every 3 weeks. All patients had good performance status and measurable disease and only nine had received prior chemotherapy. No complete or partial responses were noted. The major toxicity was myelosuppression; other toxicity was mild, and no cardiac toxicity or drug deaths occurred. The median progression-free interval was 1.3 months for patients with vulvar cancer and 1.6 months for patients with vaginal cancer. Median survival was 3.2 months for patients with vulvar cancer and 2.7 months for patients with vaginal cancer. Mitoxantrone displays no activity in patients with advanced carcinoma of the vulva or vagina.

A phase II trial of medroxyprogesterone acetate in epithelial ovarian cancers. A Gynecologic Oncology Group study.

Twenty-four evaluable patients with advanced or recurrent epithelial ovarian carcinoma who progressed on platinum-containing combination chemotherapy were treated with medroxyprogesterone acetate (C.T. Provera) 50 mg orally three times a day until progression of disease. One patient had a partial response (4.2%), 9 patients had stable disease (37.5%), and 14 (58.3%) had increasing disease. The 95% upper confidence limit for response is less than or equal to 18.3%. There was no toxicity associated with its use. C.T. Provera has limited activity in patients with epithelial ovarian cancer who have failed combination chemotherapy.

Chemotherapy of advanced squamous carcinoma of the cervix: a phase I-II study of high-dose cisplatin and cyclophosphamide. A pilot study of the Gynecologic Oncology Group.

Sixteen patients with recurrent squamous cell carcinoma of the cervix were treated with a combination of cyclophosphamide and cisplatin to determine a tolerable dose schedule, major adverse effects, and a general estimate of response rate and duration. Toxicity was substantial with a dose of cyclophosphamide 1000 mg/m2 and cisplatin 100 mg/m2 given intravenously every 3 weeks. Renal, hematologic, and gastrointestinal toxicities were severe. Of the 12 patients with measurable disease, there were two complete responses and three partial responses for a response rate of 42%. The median duration of response was 24 weeks. Six patients remained stable during therapy and one patient had progression of disease. Use of cyclophosphamide and cisplatin in combination chemotherapy for recurrent carcinoma of the cervix was tolerable but associated with substantial toxicity. The responses seen in this study are encouraging and warrant further comparative trials with this combination of drugs.

A phase II study of PALA (NSC 224131) in patients with advanced ovarian carcinoma. A Gynecologic Oncology Group study.

Pala, 5G /M2 i.v. every 3 weeks was given to 32 evaluable patients with ovarian carcinoma (31 previously treated). No complete or partial responses were noted. Ten patients had stable disease for a median progression-free interval of 4.7+ months, while the remainder had progression of disease from the start of therapy. The major toxicity was dermatologic, and five patients had severe skin rash with desquamation or ulceration. There was no substantial hematologic or gastrointestinal toxicity. PALA displays no useful activity in previously-treated patients with ovarian cancer.

PALA (NSC-224131) in advanced carcinoma of the cervix. A phase II study of the Gynecologic Oncology Group.

Thirty-six patients with advanced carcinoma of the cervix received PALA at a dosage of 5 gm/m2 every three weeks. Thirty-three patients had received prior irradiation therapy and chemotherapy. No complete or partial responses were seen. The major toxicity was dermatologic and occurred in 16/36 (44%) of patients. Three patients experienced dose limiting disorientation or confusion. PALA was not associated with any antitumor activity in patients with advanced carcinoma of the cervix who had received prior chemotherapy. The results of this study indicate that PALA has no substantial activity in patients with advanced squamous carcinoma of the cervix who have previously received chemotherapy.