Early phase trials in soft-tissue sarcomas: clinical benefit of inclusion in early lines of treatment, molecular screening, and histology-driven trials.

BACKGROUND: The prognosis of patients with advanced soft-tissue sarcomas (STS) remains dismal, and systemic therapeutic options are limited. Early phase trials are becoming increasingly safe and effective. This study aimed to identify the prognostic factors for progression-free survival (PFS). PATIENTS AND METHODS: This retrospective analysis included all STS patients participating in early phase trials at Gustave Roussy and Léon Bérard between 1 January 2012 and 31 December 2020. RESULTS: Overall, 199 patients accounted for 214 inclusions in advanced STS. The most frequent histotypes were well-differentiated/dedifferentiated liposarcomas (n = 55), leiomyosarcomas (n = 53), synovial sarcomas (n = 22), undifferentiated pleomorphic sarcomas (n = 15), angiosarcomas (n = 12), and myxoid liposarcomas (n = 10). The median PFS was 2.8 months (95% confidence interval 2.7-4.1 months). The median PFS in the first, second, and later lines was 8.3, 5.4, and 2.6 months, respectively (P = 0.00015). The median PFS was 2.8 months in case of molecular screening, 4.1 months in case of histology-driven screening, and 1.6 months (P = 0.00014) in the absence of either screening modalities. In univariate analysis, histotype (P = 0.026), complex genomics (P = 0.008), number of prior lines (P < 0.001), prior anthracyclines (P < 0.001), number of metastatic sites (P = 0.003), liver metastasis (P < 0.001), lung metastasis (P < 0.001), absence of molecular or histology-driven screening (P < 0.001), first-in-human trials (P < 0.001), dose-escalation cohorts (P = 0.011), and Royal Marsden Hospital (RMH) score >1 (P < 0.001) were significantly associated with shorter PFS. In multivariate analysis, independent prognostic factors for shorter PFS were myxoid liposarcoma (P = 0.031), ≥2 prior lines of treatment (P = 0.033), liver metastasis (P = 0.007), and RMH score >2 (P = 0.006). Factors associated with improved PFS were leiomyosarcomas (P = 0.010), molecular screening (P = 0.025), and histology-driven screening (P = 0.010). The median overall survival rates were 36.3, 12.6, and 9.2 months in the first, second, and later lines, respectively (P = 0.0067). The grade 3-4 toxicity rate was 36%. CONCLUSIONS: Early phase trials provide an active therapeutic option for STS, even in first-line settings. Molecular screening and histology-driven trials further improve the clinical benefit.

Can we cure patients with abdominal Desmoplastic Small Round Cell Tumor? Results of a retrospective multicentric study on 100 patients.

BACKGROUND: Despite being associated with a very poor prognosis, long-term survivors across all series of Desmoplastic Small Round Cell Tumor (DSRCT) have been reported. AIM OF THE STUDY: To analyze patients 'characteristics associated with a prolonged survival after DSRCT diagnosis. METHODS: All consecutive patients treated for DSRCT in nine French expert centers between 1991 and 2018 were retrospectively analyzed. Patients with a follow-up of less than 2 years were excluded and cure defined as being disease-free at least 5 years. RESULTS: 100 pts were identified (median age 25 years, 89% male). 27 had distant metastases at diagnosis and 80 pts underwent upfront chemotherapy (CT). 71 pts were operated, 20 pts without prior CT). Surgery was macroscopically complete (CC0/1) in 50 pts. Hyperthermic intraperitoneal Chemotherapy (HIPEC) was administered during surgery in 15 pts 54 pts had postoperative CT and 26 pts had postoperative whole abdomino-pelvic RT (WAP-RT). After a median follow-up of 103 months (range 23-311), the median overall survival (OS) was 25 months. The 1- year, 3-year and 5-year OS rates were 90%, 35% and 4% respectively. 5 patients were considered cured after a median disease-free interval of 100 months (range 22-139). Predictive factors of cure were female sex (HR = 0.49, p = 0.014), median PCI<12 (HR = 0.32, p = 0.0004), MD Anderson stage I (HR = 0.25, p < 0.0001), CC0/1 (HR = 0.34, p < 0.0001), and WAP-RT (HR = 0.36, p = 0.00013). HIPEC did not statistically improve survival. CONCLUSION: Cure in DSRCT is possible in 5% of patients and is best achieved combining systemic chemotherapy, complete cytoreductive surgery and WAP-RT. Despite aggressive treatment, recurrence is common and targeted therapies are urgently needed.

Screening for BRCA1 and BRCA2 mutations among French-Canadian breast cancer cases attending an outpatient clinic in Montreal.

Study subjects were French-Canadian women with ductal carcinoma in situ (DCIS) or invasive breast cancer (incident or prevalent) who were treated and followed at a single breast cancer clinic affiliated with the Research Center of University of Montreal (CRCHUM), who were either aged less than 50 years at diagnosis or who were 50 years or older and with at least two affected first- or second-degree relatives. Subjects were tested for six founder mutations (three in BRCA1 and three in BRCA2); 1093 eligible cases were tested. Of these, 56 women (5.1%) were mutation carriers, including 43 BRCA2 carriers and 13 BRCA1 carriers. The prevalence of mutations was 5.3% for unselected women aged 50 and less and was 4.6% for familial cases over age 50. The prevalence of mutations was 3.3% for women with DCIS and was 5.3% for women with invasive cancer. It is rational to offer genetic testing to all French-Canadian women diagnosed recently or in the past with either DCIS or invasive breast cancer before age 50 or with familial breast cancer above age 50.

A randomized, placebo-controlled trial (NCIC CTG MAP.2) examining the effects of exemestane on mammographic breast density, bone density, markers of bone metabolism and serum lipid levels in postmenopausal women.

We hypothesized that exemestane (EXE) would reduce mammographic breast density and have unique effects on biomarkers of bone and lipid metabolism. Healthy postmenopausal women were randomized to EXE (25 mg daily) or placebo (PLAC) for 12 months and followed for a total of 24 months. The primary endpoint was change in percent breast density (PD) between the baseline and 12-month mammograms and secondary endpoints were changes in serum lipid levels, bone biomarkers, and bone mineral density (BMD). Ninety-eight women were randomized (49 to EXE; 49 to PLAC) and 65 had PD data at baseline and 12 months. Among women treated with EXE, PD was not significantly changed from baseline at 6, 12, or 24 months and was not different from PLAC. EXE was associated with significant percentage increase from baseline in N-telopeptide at 12 months compared with PLAC. No differences in percent change from baseline in BMD (lumbar spine and femoral neck) were observed between EXE and PLAC at either 12 or 24 months. Patients on EXE had a significantly larger percent decrease in total cholesterol than in the PLAC arm at 6 months and in HDL cholesterol at 3, 6, and 12 months. No significant differences in percent change in LDL or triglycerides were noted at any time point between the two treatment arms. EXE administered for 1 year to healthy postmenopausal women did not result in significant changes in mammographic density. A reversible increase in the bone resorption marker N-telopeptide without significant change in bone specific alkaline phosphatase or BMD during the 12 months treatment period and 1 year later was noted. Changes in lipid parameters on this trial were modest and reversible.

Validation study of the s classification for melanoma patients with positive sentinel nodes: the Montreal experience.

BACKGROUND: Standard of care is to perform a complete lymph node dissection (CLND) in melanoma patients with positive sentinel lymph nodes (SLNs). However, less than 20% will have metastases in non-SLNs. The S classification was described to predict the non-SLN status, hoping to identify a subset of patients who can be spared the CLND. We tried to validate the feasibility and usefulness of this classification. MATERIALS AND METHODS: We performed a retrospective chart review. All melanoma cases between 1996 and 2006 were included, and 359 patients with SLN biopsies were identified. All pathology slides were reviewed with an emphasis on the S classification. RESULTS: There were 365 SLN biopsies performed. A total of 82 patients (22.8%) had positive SLNs, while 277 patients (77.2%) had negative SLNs. There were 22 patients classified as SI, 18 as SII, 37 as SIII, and 5 were unclassified. On CLND, only 10 patients (12.2%) had positive non-SLNs. None of these were classified as SI while 2 patients (11%) were classified as SII and 8 (22%) as SIII. The S category was found to be a predictor of non-SLN status, and this reached statistical significance (P = 0.044). On univariate analysis, only an increasing Breslow depth and ulceration were predictive of a non-SI status. CONCLUSION: Our results suggest that the S classification is easily feasible and predicts the status of non-SLNs. No patient with SI status was found to have additional non-SLN positive nodes. A larger-scale, prospective trial should be done to confirm these results and possibly spare patients the morbidity of CLND with a positive SLN.

The contribution of founder mutations to early-onset breast cancer in French-Canadian women.

In an ethnically-homogeneous population, it is valuable to identify founder mutations in cancer-predisposing genes. Founder mutations have been found in four breast-cancer-predisposing genes in French-Canadian breast cancer families. The frequencies of the mutant alleles have been measured neither in a large series of unselected breast cancer patients from Quebec, nor in healthy controls. These estimates are necessary to measure their contribution to the hereditary burden of breast cancer in Quebec and to help develop genetic screening policies which are appropriate for the province. We studied 564 French-Canadian women with early-onset invasive breast cancer who were treated at a single Montreal hospital. Patients had been diagnosed at age 50 or less, and were ascertained between 2004 and 2008. We screened all 564 patients for nine founder mutations: four in BRCA1, three in BRCA2 and one each in PALB2 and CHEK2. We also studied 6433 DNA samples from newborn infants from the Quebec City area to estimate the frequency of the nine variant alleles in the French-Canadian population. We identified a mutation in 36 of the 564 breast cancer cases (6.4%) and in 35 of 6443 controls (0.5%). In the breast cancer patients, the majority of mutations were in BRCA2 (54%). However, in the general population (newborn infants), the majority of mutations were in CHEK2 (54%). The odds ratio for breast cancer to age 50, given a BRCA1 mutation, was 10.1 (95% CI: 3.7-28) and given a BRCA2 mutation was 29.5 (95% CI: 12.9-67). The odds ratio for breast cancer to age 50, given a CHEK2 mutation, was 3.6 (95% CI: 1.4-9.1). One-half of the women with a mutation had a first- or second-degree relative diagnosed with breast or ovarian cancer. Thus, it can be concluded that a predisposing mutation in BRCA1, BRCA2, CHEK2 or PALB2 is present in approximately 6% of French-Canadian women with early-onset breast cancer. It is reasonable to offer screening for founder mutations to all French-Canadian women with breast cancer before age 50. The frequency of these mutations in the general population (0.5%) is too low to advocate population-based screening.

Algorithm for autologous breast reconstruction for partial mastectomy defects.

BACKGROUND: The use of lateral thoracic skin and fat for breast reconstruction is advantageous because it does not require the use of muscle transfer, and the donor-site incision is well hidden under the arm. In patients with redundant skin at the thoracic flank, use of this tissue has the added benefit of removal of an unsightly roll. The lateral thoracic skin and fat flap can be harvested using microsurgical technique based on three different pedicles: the thoracodorsal artery perforators; a direct cutaneous branch of the thoracodorsal, axillary, or lateral thoracic arteries; and the lateral thoracic intercostal perforating vessel. METHODS: The authors describe the techniques for harvest of lateral thoracic tissue based on each of the pedicle options. A case is then presented to illustrate each option, and an algorithm is suggested for deciding which pedicle to use. RESULTS: The authors have used lateral thoracic tissue for partial breast reconstruction for a variety of defects. In this report, the authors review the results of three illustrative cases. CONCLUSIONS: Partial breast reconstruction may be required for patients after breast-conserving therapy or after breast reconstruction by other methods. Lateral thoracic tissue can be safely transferred to correct defects in treated or reconstructed breast, or to obtain symmetry. Knowledge of the vascular anatomy to this region is helpful in understanding the pedicle options when harvesting this tissue. The authors present an algorithm for determining which pedicle is most appropriate for the transfer of lateral thoracic tissue for partial breast reconstruction.

International prospective evaluation of scintimammography with technetium-99m sestamibi: interim results.

OBJECTIVE: The purpose of this study is to evaluate the validity and reliability of scintimammography with technetium-99m (99mTc)-labeled sestamibi as an adjunct radiodiagnostic agent in the diagnosis of breast cancer. METHODS: This is a multicenter prospective cohort clinical trial that was initiated in June 1999 and will terminate May 2001. All patients with a physical or mammographic finding visiting any of the participating clinics are enrolled in the study. Patients who are younger than 18 years, pregnant, not willing to sign the consent form, or who have undergone an invasive procedure on the breast 30 days or less before scintimammography are excluded. At the time of the first interim report, 633 patients had been recruited from six Canadian centers. To date complete data have been collected for 530 patients. RESULTS: The mean (SD) age of the patients is 56 (12) years with a range between 24 and 85. There were 122 (23%) of the women in the sample who were postmenopausal and 36 (7%) who were perimenopausal. Breast density was graded as dense for 127 (24%), normal for 260 (50%), and fatty for 138 (26%). Of the 530 women in the study 156 (29%) had a palpable mass at physical examination. The mammographic results were classified as 76 (14%) breast imaging reporting and data system (BIRADS) 5, 60 (11%) BIRADS 4, 70 (13%) BIRADS 3 and the remaining BIRADS 2 or 1. The scintimammography results were positive for 118 (23%) of the patients and negative for 412 (78%). The histopathology showed malignant breast disease for 66 (12.5%) of the patients in the sample. Sensitivity and specificity of scintimammography for the detection of breast cancer was estimated 90.9% and 87.5%, respectively. A positive predictive value (PPV) of 50.8% with a negative predictive value of 98.5% and an accuracy of 87.5% were calculated. The PPV is interpreted as the posttest probability of disease given a positive test result. In this sample the pretest probability of disease would be best estimated by the prevalence of disease, which is equal to 12.5%. A positive scintimammography result would change the estimated probability to 51%, which is equivalent to a 400% change from the pretest value. Therefore a positive scintimammography result significantly increases our ability to predict the presence of malignant disease in this population. CONCLUSION: The interim results of the present study suggest that scintimammography with 99mTc-sestamibi is accurate and potentially useful as an adjunct to mammography for the detection of breast cancer.

[Pilot study of interferon alpha-2b tolerance in patients with stage III melanoma]. / Etude pilote sur la tolérance à l'interféron alpha-2b chez des patients atteints d'un mélanome stade III.

GOAL: Evaluation of interferon alpha-2b adjuvant treatment (INF alpha-2b) toxicity by monitoring biologic parameters in patients with stage III melanoma. METHOD: Between January 7th till October 29th 1998, we administered 674 injections of INF alpha-2b to eight patients who previously had undergone surgery for stage III melanoma. Patients received 20 MU/m2/d IV for a month and 10 MU/m2/d sub-cutaneously three time a week for 48 weeks. All these patients were followed with at least one complete blood count and hepatic profile every week. Interferon alpha-2b doses were changed accordingly. RESULTS: Patients received on average 51.5% of the total dose. Doses were decreased in patients with neutropenia or hepatic profiles anomalies. Only one patient could received 100% of the total regimen. In four patients treatment was discontinued. In three out of four patients this was due to disease progression, and in one out of four patients this was due to hepatic toxicity. CONCLUSION: INF alpha-2b is less well tolerated than initially thought. Dosage was frequently decreased due to hematologic and hepatic toxicities. This could compromise the treatments efficacity. The minimal dose required to obtain an optimal response will thus have to be defined.

Bronchogenic cyst of the right hemidiaphragm.

A rare case of bronchogenic cyst of the right hemidiaphragm is reported. The literature is reviewed briefly. Clinical presentation, diagnosis, and treatment of this entity are discussed further.

Does asthma or treatment with theophylline limit children's academic performance?

BACKGROUND: Asthma is a major cause of morbidity in childhood, restricting activity and causing absences from school. Theophylline, although effective in managing chronic asthma, has been reported to cause deficits in cognitive functioning and school performance. We therefore examined the effect of asthma and its treatment on academic achievement in a large, representative population of school-age children; matched sibling controls were used for comparison. METHODS: We identified 255 consecutive children with asthma (mean age, 12.0 years) who had taken nationally standardized scholastic achievement tests administered routinely by the schools. One hundred one of these children had siblings without asthma with whom comparisons could be made in reading, mathematics, and a composite measure of achievement. RESULTS: Academic achievement among the children with asthma was similar to normative standards in Iowa and higher than national standards, as reflected in a mean composite T-score of 57.1 (expected mean [+/- SD], 50 +/- 10). For the 101 children with sibling controls, composite T-scores were 58.3 for the children with asthma and 57.5 for the siblings. Eighty-five of these 101 children with asthma were receiving daily maintenance medication for chronic asthma; 72 of these were receiving theophylline. The mean composite T-scores were 58.5 for the theophylline-treated patients and 58.4 for their siblings without asthma. None of the differences between the children with asthma and the sibling controls were statistically significant. CONCLUSIONS: Academic achievement among children with asthma, at least those whose status is closely monitored in a structured treatment program, generally appears to be unaffected by asthma or by its treatment with appropriate doses of theophylline.

Extrapulmonary effects of maintenance corticosteroid therapy with alternate-day prednisone and inhaled beclomethasone in children with chronic asthma.

Extrapulmonary effects of alternate-day prednisone and inhaled beclomethasone dipropionate therapy were examined in 24 and 32 children with asthma, respectively. Early morning serum cortisol values were significantly lower among patients receiving alternate-day prednisone than among patients receiving inhaled beclomethasone dipropionate and control subjects at 24 hours but not at 48 hours after an alternate-day prednisone dose. Urinary-free cortisol output during the second 24 hours of the alternate-day prednisone regimen were similar to values among patients receiving inhaled beclomethasone and were significantly lower than among control subjects for both groups. Mean heights among patients before being placed on maintenance corticosteroids were at the thirty-fifth percentile and were similar for both regimens. This was significantly lower than initial measurements for control subjects who, on average, were near the fiftieth percentile for both children with asthma not requiring maintenance corticosteroids and normal healthy Iowa children. Mean heights for both corticosteroid-treated groups remained at the thirty-fifth percentile after more than a 2-year average duration of follow-up. Heights of children with chronic asthma not requiring maintenance corticosteroids were initially significantly higher (fifty-first percentile) than the patients who subsequently required maintenance corticosteroids and increased significantly to the sixty-first percentile during a mean 2.7-year follow-up. Heights of healthy Iowa children remained near the fiftieth percentile during a mean 7-year follow-up. Disproportionate weight gain, although it was not consistently present, was significantly more likely with the alternate-day prednisone. Other extrapulmonary effects of the corticosteroid regimens appeared not to be of clinical importance during the time period of the study.

Allergy and pulmonary impairment in Iowa veterinarians.

If small animal practice exposure, including the laboratory animal situations encountered in academic and other research pursuits, is more detrimental to veterinarians than large animal practice exposure for induction of allergic respiratory disease, then preventive measures such as increased ventilation, use of high efficiency particulate filters, and wearing of masks should be encouraged to reduce allergen exposures. Migration from large animal practice, likewise, should be discouraged. Failure to migrate to low occupational allergy risk situations early enough in a veterinary career can have severe and even fatal results. If the observed respiratory disease in veterinarians is in fact due to exposure, then unfortunately, it may in some cases be progressive and not just chronic. Data which could provide criteria for predicting occupational allergy and possible related respiratory disease outcome is scant at this time and career counselling is difficult. If the veterinary occupational animal allergy data should be proven correct such results can be used to help others.

Early intervention with short courses of prednisone to prevent progression of asthma in ambulatory patients incompletely responsive to bronchodilators.

The effect of high orally administered doses of prednisone for 1 week early in the course of an acute exacerbation of asthma incompletely responsive to bronchodilators was examined in 41 patients randomly assigned to receive either prednisone or an identical appearing placebo. All 22 of the patients who received prednisone improved during the week of treatment, although one had a subsequent exacerbation 5 days after discontinuing the study medication. Of the 19 who received placebo, eight required rescue intervention (P = less than 0.004) in association with continued symptoms, increased frequency of metered-dose inhaler use, and decreased pulmonary function; the other 11 improved at about the same rate as those who received prednisone. Although the mean initial FEV1 was suggestively lower among those who did not improve and required intervention, there was considerable overlap with those who improved spontaneously, and no reliable distinguishing characteristics were found at entry into the study that could serve as predictors of those who would or would not improve spontaneously. There were no clinically important adverse effects from the prednisone. Because continued symptoms of asthma often result in emergency care or hospitalization, these data support early intervention with orally administered prednisone for acute exacerbations that do not respond fully to bronchodilators, at least in those patients with a prior history of a protracted course or emergency care.

Etoposide and cisplatin salvage chemotherapy for small cell lung cancer.

Thirty patients with previously treated small cell lung cancer received salvage combination chemotherapy with etoposide and cisplatin. Two complete and six partial responses were observed, for a major response rate of 27%. Responses occurred promptly and sustained palliation was achieved among responders. Myelosuppression was the major dose-limiting toxic effect. A schedule of etoposide (115 mg/m2 iv on Days 1-3) and cisplatin (25 mg/m2 iv on Days 1-3 every 28 days) is recommended for further clinical trials.

Central nervous system pharmacokinetics of high-dose cytosine arabinoside.

The cerebrospinal fluid (CSF) pharmacokinetics of cytosine arabinoside (Ara-C) was determined in 8 patients with metastatic cancer in the central nervous system. High dose (3 gm/M2) one-hour intravenous infusions of Ara-C were given with serial CSF sampling obtained from indwelling Ommaya reservoirs. CSF was analyzed by high pressure liquid chromatography. Mean Ara-C elimination half life of 140 minutes in CSF was eight times longer than that in plasma. The peak mean CSF concentration of Ara-C (2.1 micrograms /ml) was about 7% of the plasma concentration (30 micrograms/ml). A total of 28 treatment courses were administered with minimal hematopoietic, gastrointestinal and neurological toxicities. A schedule of administration of 2 high-dose treatments 12 hours apart repeated every two weeks should maintain cytotoxic CSF concentrations which could prove useful in the management of CNS leukemia and lymphoma.

Desenvolvimento do radioimunoensaio para determinacao do estriol no fluido salivar. / Development of a radioimmunoassay for estriol determination in salivary fluid

O objetivo deste trabalho foi o de desenvolver um sistema de deteccao sensivel e especifico, necessitando assim, pequenas quantidades de saliva, e pouca ou nenhuma purificacao das amostras, alem de ser o ensaio rapido o suficiente para ser efetuado varias vezes num so dia, e realizavel na maioria dos laboratorios do nosso meio. Utilizaram-se 60 amostras de saliva de gestantes escolhidos ao acaso, em diferentes idades gestacionais colhidas 5 minutos apos estimulo com goma de mascar (Trident). Foram comparados 2 metodos: metodo com extracao e metodo direto. E apresentado um protocolo final de teste com analise dos parametros de sensibilidade, exatidao e precisao. O metodo desenvolvido apresenta caracteristicas que permite o seu uso para a determinacao do estriol no fluido salivar