Efficacy of assisted reproductive technology after ovarian tissue transplantation in a cohort of 11 patients with or without associated infertility factors.

PURPOSE: IVF treatment in women with grafted frozen-thawed ovarian tissue is associated with poor reproductive outcomes. The aim of this study was to evaluate the efficacy of ovarian tissue transplantation (OTT) followed by assisted reproductive technology (ART) in women with or without associated infertility factors. METHODS: This is a prospective cohort study with retrospective data collection including eleven women, four of whom having an infertility factor (IF), who had undergone OTT in one university center between 2005 and 2017, followed by ART in six in vitro fertilization (IVF) centers. RESULTS: In total, 25 of the 85 cycles initiated (29%) were canceled, resulting in 60 oocyte retrievals. Ninety-five oocytes were retrieved: 36 were abnormal or immature, 29/39 fertilized (74%) after ICSI and 13/20 (65%) after IVF. Thirty-five embryos were transferred in seven patients (5/7 patients without IF and 2/4 patients with IF). After ART, one patient with IF experienced two pregnancies, one resulting in a live birth. For all patients, pregnancy rates and live birth rates were 7.4% and 3.7% per embryo transfer, respectively. Nine pregnancies and four live births occurred after spontaneous conception in five patients without IF, none in the infertility group. CONCLUSION: This study confirms that IVF treatment in women with grafted frozen-thawed ovarian tissue is associated with poor outcomes. However, the chances of natural conception are high in women without IF. Patients with IF, without the possibility of spontaneous pregnancy, should be informed of poor reproductive outcomes after OTT followed by ART. TRIAL REGISTRATION NUMBER: NCT02184806.

Impact of cancer chemotherapy before ovarian cortex cryopreservation on ovarian tissue transplantation.

STUDY QUESTION: How efficacious is transplantation of ovarian cortex previously exposed to chemotherapy? SUMMARY ANSWER: Prior exposure to chemotherapy did not disrupt the function of cryopreserved ovarian tissue after transplantation. WHAT IS KNOWN ALREADY: Ovarian tissue cryopreservation (OTC) followed by ovarian tissue transplantation (OTT) is an efficacious technique for restoration of female fertility. At least 130 children have been born following this procedure. To date, little is known about the efficacy of OTT in patients exposed to cancer chemotherapy prior to OTC. STUDY DESIGN, SIZE, DURATION: This study evaluates the recovery of ovarian function and fertility in 31 consecutive patients who had received OTT, between 2005 and 2015. PARTICIPANTS/MATERIALS, SETTING, METHODS: Thirty one patients, wanting children, were transplanted with autologous ovarian cortex, among which 22 patients (71%) had been exposed to chemotherapy before OTC. Recovery of ovarian function was considered total once menstruation occurred. Ovarian function recovery (OFR), ovarian graft survival, and incidence of pregnancy were related to previous chemotherapy exposure, type of chemotherapy and graft characteristics (number of grafted fragments and follicular density). MAIN RESULTS AND ROLE OF CHANCE: The amount of ovarian tissue collected was the only parameter to show any significant change between patients with versus without previous chemotherapy. At 1 year after OTT, the cumulative incidence of OFR was 83% (93% in patients exposed to chemotherapy and 67% in others (P = 0.14)). A low follicular density (<0.3 foll/mm2) in the transplant and a low number of grafted fragments (<16) were significantly associated with a delayed OFR. Graft survival at 2 years after OTT was 77%. It was significantly lower in patients exposed to bifunctional alkylating agents before ovarian cryopreservation and in patients with a low follicular density. The proportion of women who succeeded in having at least one live birth was 23% in the total population, 0% (0/9) in the group 'no previous chemotherapy', and 32% (7/22) in the group 'previous chemotherapy'. The cumulative incidence of pregnancy (Kaplan-Meier) at 3 years after OTT was 36% overall and 49% in case of previous chemotherapy, with no difference related to previous chemotherapy exposure. In total there were 13 pregnancies and 8 births in 7 patients. LIMITATIONS, REASONS FOR CAUTION: The pathology in the two groups of patients was not comparable. In the group of patients who had chemotherapy before OTC, there were 95% of hematological malignancies. In the group of patients who did not have chemotherapy before OTC only 1 out of 9 patients had a malignant hematological disease while 44% had some pathology affecting the ovaries. Few women are available for study and only large changes are likely to have statistical significance. WIDER IMPLICATIONS OF THE FINDINGS: These results suggest that prior cancer chemotherapy should no longer be considered a limitation to cryopreservation of ovarian tissue and current recommendations in this regard should be revised. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the Agence de la Biomédecine (France's biomedical office). There are no competing interests to report. TRIAL REGISTRATION NUMBER: NCT02184806.

Production of recycled manure solids for bedding in Canadian dairy farms: I. Solid-liquid separation.

Canadian dairy producers have an increasing interest in recycled manure solids (RMS) as bedding material because of reduced availability of traditional bedding resources. Information regarding methods to obtain RMS and composition of RMS is very limited. Hence, a 2-part investigation was developed to compare the performances of 3 mechanical solid-liquid manure separators (part I) and 4 composting methods (part II; companion paper in this issue) for the production of high quality RMS. In this first study, a roller press, a screw press, and a decanter centrifuge were tested for the separation of slurry manure from a commercial dairy farm. During the experiment, the quantity of slurry manure processed and the volume and mass of the liquid and solid fractions were measured. The energy consumption of each separator was recorded, and samples of the slurry, liquid, and solid effluents were collected for analysis. The type of separator did not significantly influence the chemical and bacteriological composition of RMS produced. The choice of a separator for Canadian dairy producers should thus be based on the equipment cost and its capacity, targeted solids dry matter (DM) content and structure, and fertilizing quality of the separated liquid. The decanter centrifuge produced the solid phase with the highest DM and best separation efficiencies for DM, N, and P. However, its low production capacity (1.5 m3/h vs. 9.1-20.3 m3/h) combined with its high acquisition cost (Can$145,000 vs. Can$75,000) and energy consumption (4.99 kWh/m3 vs. 0.10-0.35 kWh/m3) reduce its technical and profitability values. Besides, the centrifuge produced fine structured RMS and a low-quality liquid fraction, not suitable as dairy cow bedding and fertilizer, respectively. Both presses reached acceptable production capacity at a minimal operation cost. However, the poor performance in terms of DM (25%) of the model of screw press used in this study produced RMS unsuitable for immediate use without further processing. The model of roller press used in this study had the advantages of almost reaching the recommended DM content in RMS (>34%), being flexible in terms of inputs, and producing fluffy RMS. Nevertheless, its compression process seemed to allow greater passage of solids into the liquid fraction compared with the screw press. Part II of this work explores different composting methods to reduce the health risks associated with screw-pressed RMS before their use as bedding.

Production of recycled manure solids for use as bedding in Canadian dairy farms: II. Composting methods.

Recent technological advances in the dairy industry have enabled Canadian farms with liquid manure systems to use mechanical solid-liquid separation paired with composting of the separated solids for on-farm production of low-cost bedding material. However, because several approaches are available, it is difficult for farmers to select the appropriate one to achieve high quality recycled manure solids (RMS). Whereas 3 solid-liquid manure separators were compared in part I of the series (companion paper in this issue), the present study (part II) aims to assess the performance of 4 composting methods (static or turned windrow and drum composter for 24 or 72 h) under laboratory conditions. Parameters evaluated included temperature, physico-chemical characteristics, and bacterial composition of RMS, as well as airborne microorganisms, dust, and gases associated with composting RMS. Because each treatment attained the desired composting temperature range of 40 to 65°C (either in heaps or in the drum composter), reductions in bacteria were a better indicator of the sanitation efficiency. The treatment of fresh RMS in a drum composter for 24 h showed decreased bacterial counts, especially for Escherichia coli (from 1.0 × 105 to 2.0 × 101 cfu/g of dry matter) and Klebsiella spp. (from 3.2 × 104 to 4.0 × 102 cfu/g of dry matter). Increasing the time spent in the rotating vessel to 72 h did not result in further decreases of these pathogens. Composting in a static or turned windrow achieved similar E. coli and Klebsiella spp. reductions as the 24-h drum composting but in 5 or 10 d, and generally showed the lowest occupational exposure risk for dairy farmers regarding concentrations of airborne mesophilic bacteria, mesophilic and thermotolerant fungi, and total dust. Drum-composted RMS stored in piles exhibited intermediate to high risk. Composting approaches did not have a major influence on the physico-chemical characteristics of RMS and gas emissions. Drum composting for 24 h was the best compromise in terms of product quality, temperature reached, decreased bacterial numbers, and emitted airborne contaminants. However, because levels of pathogenic agents rapidly increase once composted RMS are spread in stalls, bacteriological characteristics of RMS along with milk quality and animal health and welfare features should be monitored in Canadian dairy barns applying recommended separation (part I) and composting (part II) systems to evaluate health risk and optimize management practices.

Morbidity, mortality and long-term sequelae of West Nile virus disease in Québec.

We aimed to describe the clinical characteristics of West Nile patients reported in Québec in 2012 and 2013 and to document physical, mental and functional status 24 months after symptom onset according to illness severity. The cases were recruited by a public health professional. Data were collected from public health files, medical records and two standardised phone questionnaires: the Short Form-36 and the Instrumental Activities of Daily Living. In all, 92 persons participated in the study (25 had West Nile fever (WNF), 18 had meningitis and 49 had encephalitis). Encephalitis participants were older, had more underlying medical conditions, more neurological symptoms, worse hospital course and higher lethality than meningitis or WNF participants. Nearly half of the surviving hospitalised encephalitis patients required extra support upon discharge. At 24-month follow-up, encephalitis and meningitis patients had a lower score in two domains of the mental component: mental health and social functioning (P = 0.0025 and 0.0297, respectively) compared with the norms based on age- and sex-matched Canadians. Physical status was not affected by West Nile virus (WNV) infection. In addition, 5/36 (15%) of encephalitis, 1/17 (6%) of meningitis and 1/23 (5%) of WNF participants had new functional limitations 24 months after symptom onset. In summary, mental and functional sequelae in encephalitis patients are likely to represent a source of long-term morbidity. Preventive measures should target patients at higher risk of severe illness after WNV infection.

Risk factors associated with seropositivity to California serogroup viruses in humans and pet dogs, Quebec, Canada.

Jamestown Canyon and snowshoe hare viruses are two emerging human pathogens associated with cases of neuroinvasive disease in North America. This study aimed to identify environmental and individual risk factors for seropositivity to these arboviruses in humans and pet dogs from Québec, Canada, 2012-2014. In humans, areas with moderate densities of white-tailed deer (Odocoileus virginianus) were associated with higher odds of seropositivity compared with areas with low densities of white-tailed deer (OR 2.50, P = 0.009) and odds of seropositivity were higher in males than in females (OR 2.03, P = 0.016). Among humans reporting more than 10 mosquito bites weekly, the odds of being seropositive were 4.44 times higher (P = 0.004) for people living in hardwood forested areas. Exposure to areas with coniferous forests was identified as the main environmental risk factor for seroconversion in dogs (OR 2.39, P = 0.04). These findings may help target further public health research, diagnostic and surveillance efforts in Canada.

Comparison of a Mediterranean to a low-fat diet intervention in adults with type 1 diabetes and metabolic syndrome: A 6-month randomized trial.

BACKGROUND AND AIMS: The metabolic syndrome (MS) is an emerging complication in patients with type 1 diabetes (T1D), with no preventive or therapeutic treatment reported yet. We wanted to compare the impact of two 6-month nutritional interventions, based on a Mediterranean (MED) or a low-fat diet, on waist circumference, anthropometric and metabolic outcomes in patients with both T1D and the MS. METHODS AND RESULTS: Participants were randomized into 2 intervention groups: 1) MED-diet or 2) low-fat diet. The 6-month study included 9 teaching sessions with a registered dietitian. Anthropometric (primary outcome: waist circumference), metabolic and nutritional assessments were performed at inclusion, 3 and 6-month. We used mixed effects models to assess the effects of both interventions. 28 participants were included (50.9 ± 10.3 years old) with a mean BMI of 30.7 ± 3.3 kg/m2 and a waist circumference of 105.5 ± 8.9 cm at inclusion. A trend towards a greater reduction of dietary fat intakes in the low-fat diet group was observed (P-interaction = 0.09). Waist circumference was reduced at 6-month in both groups (-3.5 cm low-fat; -1.5 cm MED-diet) with no significant difference between groups (P-interaction = 0.43). Body mass index also significantly decreased in both groups (-0.7 kg/m2 low-fat; -1.1 kg/m2 MED-diet; P-interaction = 0.56). No significant differences between groups were observed for other metabolic parameters. CONCLUSIONS: This study suggests that a 6-month non-restrictive dietary intervention in patients with T1D and MS could contribute to weight management, without significant differences between interventions for anthropometric and metabolic parameters. Further studies should investigate the long-term benefits of these diets. CLINICAL TRIAL REGISTRY: NCT02821585 (https://clinicaltrials.gov/).

Characterizing environmental risk factors for West Nile virus in Quebec, Canada, using clinical data in humans and serology in pet dogs.

The identification of specific environments sustaining emerging arbovirus amplification and transmission to humans is a key component of public health intervention planning. This study aimed at identifying environmental factors associated with West Nile virus (WNV) infections in southern Quebec, Canada, by modelling and jointly interpreting aggregated clinical data in humans and serological data in pet dogs. Environmental risk factors were estimated in humans by negative binomial regression based on a dataset of 191 human WNV clinical cases reported in the study area between 2011 and 2014. Risk factors for infection in dogs were evaluated by logistic and negative binomial models based on a dataset including WNV serological results from 1442 dogs sampled from the same geographical area in 2013. Forested lands were identified as low-risk environments in humans. Agricultural lands represented higher risk environments for dogs. Environments identified as impacting risk in the current study were somewhat different from those identified in other studies conducted in north-eastern USA, which reported higher risk in suburban environments. In the context of the current study, combining human and animal data allowed a more comprehensive and possibly a more accurate view of environmental WNV risk factors to be obtained than by studying aggregated human data alone.

Emerging arboviruses in Quebec, Canada: assessing public health risk by serology in humans, horses and pet dogs.

Periodic outbreaks of West Nile virus (WNV), Eastern equine encephalitis virus (EEEV) and to a lesser extent, California serogroup viruses (CSGV), have been reported in parts of Canada in the last decade. This study was designed to provide a broad assessment of arboviral activity in Quebec, Canada, by conducting serological surveys for these arboviruses in 196 horses, 1442 dogs and 485 humans. Sera were screened by a competitive enzyme linked immunosorbent assay and positive samples confirmed by plaque reduction neutralisation tests. The percentage of seropositive samples was 83·7%, 16·5%, 7·1% in horses, 18·8%, 0·6%, 0% in humans, 11·7%, 3·1%, 0% in adult dogs and 2·9%, 0·3%, 0% in juvenile dogs for CSGV, WNV and EEEV, respectively. Serological results in horses and dogs appeared to provide a meaningful assessment of risk to public health posed by multiple arboviruses.

Efficacy of domestic cooking inactivation of human hepatitis A virus in experimentally infected manila clams (Ruditapes philippinarum).

AIM: The aim of this work was to evaluate the efficacy of domestic cooking in inactivating Manila clams experimentally infected with human hepatitis A virus (HAV). METHODS AND RESULTS: Electronic temperature probes were positioned to measure the internal temperature of Manila clams during domestic cooking. Two batches were infected with 10(7) and 10(5) TCID50  ml(-1) of HAV. The infected whole-in-shell clams were divided into three replicates and cooked on a conventional stove both singularly and in group and removed from the pan at fixed intervals. Pools of three digestive glands were examined by virus isolation for three blind passages and cell culture supernatant tested with real-time PCR. CONCLUSION: Results showed that 2-min cooking by a traditional domestic method at a temperature close to 100°C, after the opening up of the valves of all the clams, can completely devitalize the HAV in high viral load-infected clams. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first study on inactivation of HAV in experimentally infected Manila clams subjected to domestic cooking. At present, labelling all lagoon products as 'requiring cooking before consumption' is highly recommended, but no specifications are given on how long and at what temperature they should be cooked. Considering the high commercial value of Manila clams, our results can provide both the producers and the consumer with useful indications on how to cook clams to prevent the risk of HAV foodborne illness.

A rapid assessment of the National Regulatory Systems for medical products in the Southern African Development Community.

BACKGROUND: Access to quality-assured, safe and efficacious medical products is fundamental for Universal Health Coverage and attaining Sustainable Development Goal 3: Ensure Healthy Lives and Well-being for All. To guarantee this right, there is a need for robust and efficiently performing national regulatory systems for the regulation of medical products. Well-functioning regulatory systems apply globally accepted standards which ensure that the level of control is proportionate to the level of public health risk. OBJECTIVE OF THE STUDY: The study aimed at analysing the regulatory systems for medical products in the 16 Member States of the Southern African Development Community (SADC). It provides an overview of the national regulatory systems for medical products in the region in 2017 and outlines the institutional frameworks, which enable the implementation of regulatory functions. METHODOLOGY: A survey was conducted in March-December 2017 in English, French and Portuguese. National Regulatory Authorities for medical products (NMRAs) of the 16 Member States within SADC responded to the questions asked and sent in their answers. The survey was constructed around five themes instrumental for implementation of the Universal Health Coverage actions framework. Three of the themes are discussed in this article. RESULTS: The outcome of the survey demonstrates that within SADC, NMRAs vary in terms of organisational set-up and modalities of medical product regulation. The majority are within the Ministries of Health, and a few are either semi-autonomous or autonomous. Legal frameworks for medical products are in place for some of the SADC NMRAs, although they vary in the scope of products subject to regulation. Traditional medicines, biologicals and medical devices are regulated, however not uniformly across the region. CONCLUSION: Despite major progress over the years, the survey demonstrates variable levels of governance and regulatory framework among NMRAs in SADC. The survey supports the need for shifting from the broad strengthening of the regulatory systems which exist and are underpinned by the mandates, to more product-type focused approaches. This shift will ensure that medical products are quality-assured, safe and effective for a performant Health Systems attainment of the Universal Health Coverage and Sustainable Development Goals.

APAF1 is a key transcriptional target for p53 in the regulation of neuronal cell death.

p53 is a transcriptional activator which has been implicated as a key regulator of neuronal cell death after acute injury. We have shown previously that p53-mediated neuronal cell death involves a Bax-dependent activation of caspase 3; however, the transcriptional targets involved in the regulation of this process have not been identified. In the present study, we demonstrate that p53 directly upregulates Apaf1 transcription as a critical step in the induction of neuronal cell death. Using DNA microarray analysis of total RNA isolated from neurons undergoing p53-induced apoptosis a 5-6-fold upregulation of Apaf1 mRNA was detected. Induction of neuronal cell death by camptothecin, a DNA-damaging agent that functions through a p53-dependent mechanism, resulted in increased Apaf1 mRNA in p53-positive, but not p53-deficient neurons. In both in vitro and in vivo neuronal cell death processes of p53-induced cell death, Apaf1 protein levels were increased. We addressed whether p53 directly regulates Apaf1 transcription via the two p53 consensus binding sites in the Apaf1 promoter. Electrophoretic mobility shift assays demonstrated p53-DNA binding activity at both p53 consensus binding sequences in extracts obtained from neurons undergoing p53-induced cell death, but not in healthy control cultures or when p53 or the p53 binding sites were inactivated by mutation. In transient transfections in a neuronal cell line with p53 and Apaf1 promoter-luciferase constructs, p53 directly activated the Apaf1 promoter via both p53 sites. The importance of Apaf1 as a p53 target gene in neuronal cell death was evaluated by examining p53-induced apoptotic pathways in primary cultures of Apaf1-deficient neurons. Neurons treated with camptothecin were significantly protected in the absence of Apaf1 relative to those derived from wild-type littermates. Together, these results demonstrate that Apaf1 is a key transcriptional target for p53 that plays a pivotal role in the regulation of apoptosis after neuronal injury.

[Surgical and functional results of rectosigmoidal resection for severe endometriosis]. / Résection rectosigmoïdienne pour endométriose profonde : résultats chirurgicaux et fonctionnels.

OBJECTIVES: Indications of colorectal resection for endometriosis are controversial because of the risk of major complications. This study aims to evaluate the value of different diagnostic tests in decision-making, and to evaluate the surgical results and complications, as well as long-term functional results after surgery. PATIENTS AND METHODS: In the set of a retrospective case series, 50 patients who have been admitted for a colorectal resection because of deep endometriosis were included. Most of them have had an MRI and an endorectal ultrasonography. Specific questionnaires have been proposed in order to evaluate symptoms, sexuality (BISF-W) and quality of life (EHP-30). RESULTS: For the diagnosis of rectal involvement, the sensitivity of MRI and endorectal ultrasonography were 55 and 100%, respectively. Forty-one colorectal amputations and nine partial colorectal resections have been done by 24 laparotomies, two laparoscopies and 24 laparoconversions. Major complications included six (12.5%) digestive fistulas, three (6%) anastomotic strictures, one ureterovaginal fistula and one ureteral stricture. Risk factors associated with digestive fistulas were the association of a vaginal opening (p=0.002) and an additional ileocaecal resection (p=0.007). The mean follow-up period was of 42 months. A significant improvement of dysmenorrhea (p<10(-4)), dyschesia (p<10(-4)), chronic pelvic pain (p<10(-4)), and of some digestive symptoms such as catamenial epreintes (p=0.002) and catamenial diarrheas (p=0.006), was noted. We noted postoperative 14 dysurias, six constipations and 12 rectal polykynesias. Four patients have had deep recurrent lesions. Twenty patients had a desire of pregnancy after the operation, 17 pregnancies were obtained (eight spontaneous and nine by ART) giving birth to 14 living children. Sexuality evaluation was below normal range. The quality of life was improved for most of the items. The global satisfaction was good (91%). DISCUSSION AND CONCLUSION: Colorectal resection for deep endometriosis improve significantly most of the pain symptoms, but the women should have detailed counselling about the risks of major complications and recurrence.

Predictors of cardiovascular risk among patients with type 1 diabetes: A critical analysis of the metabolic syndrome and its components.

Patients with type 1 diabetes (T1D) are at increased risk for cardiovascular diseases. The metabolic syndrome (MetS), a complex disorder defined by a cluster of interconnected factors including abdominal obesity, hypertension, dyslipidaemia and insulin resistance, has been proposed to identify patients with T1D at high cardiovascular risk. The MetS has been identified in 8-45% of patients with T1D, depending on the definition and cohort studied. However, clinicians and researchers face several issues with the criteria for MetS in patients with T1D, therefore questioning its value in routine care. For example, three criteria can lead to overestimation of MetS prevalence; the impaired fasting glucose criterion is irrelevant as it is automatically fulfilled; and the widespread use of antihypertensive and lipid-lowering medications for cardiac and renal preventative purposes can contribute to overestimations of the prevalence of raised blood pressure and elevated triglycerides. In cross-sectional studies, the MetS has been associated mostly with an increased risk of microvascular complications whereas, in prospective cohorts, the predictive value of MetS for micro- and macrovascular outcomes has been inconsistent. While identifying diabetes patients at increased risk for cardiovascular complications and early mortality is crucial from a prevention standpoint, for patients with T1D, the current definition of MetS may not be the most suitable tool. The aims of the present report are to review the applicability and limitations of the MetS in patients with T1D, and to discuss alternative avenues to identify high-risk patients.

[Reflection on one case of acute peritonitis due to adjustable gastric banding during pregnancy]. / Réflexion sur un cas de péritonite aiguë sur anneau gastrique modulable pendant la grossesse.

Improving the information delivered to pregnant women with adjustable gastric banding is desirable. Indeed, we report a case of peritonitis on gastric banding due to Klebsiella pneumoniae complicated with fetal death. Then, we discuss the specific risks of infection on the gastric band during pregnancy. Although, according to the literature, prophylactic fluid removal from the band in early pregnancy is not recommended, data about complications in pregnancy due to gastric banding are limited.

Respiratory-swallowing coordination in normal subjects: Lung volume at swallowing initiation.

This study was designed to investigate the significance of bolus types and volumes, delivery methods and swallowing instructions on lung volume at swallowing initiation in normal subjects in a single experiment using a multifactorial approach. Our broad range goal was to determine optimal lung volume range associated with swallowing initiation to provide training targets for dysphagic patients with disordered respiratory-swallow coordination. Our hypothesis was that swallows would be initiated within a limited range of quiet breathing lung volumes regardless of bolus volume, consistency or task. Results confirmed this hypothesis and revealed that swallows were initiated at mean lung volume=244ml. Cued swallows were initiated at lower quiet breathing volumes than un-cued swallows (cued=201ml; un-cued=367ml). Water boluses were initiated at slightly higher quiet breathing volumes than solids. Data suggest that swallows occur within a restricted range of lung volumes with variation due to instructions, bolus type and other experimental variables.

Local failure is responsible for the decrease in survival for patients with breast cancer treated with conservative surgery and postoperative radiotherapy.

PURPOSE: The aim of the present study was to evaluate the role of local failure (LF) in the survival of patients treated with lumpectomy and postoperative radiotherapy and to investigate whether LF is not only a marker for distant metastasis (DM) but also a cause. METHODS: Charts of patients treated with breast conservative surgery between 1969 and 1991 were reviewed retrospectively. There were 2,030 patients available for analysis. The median duration of follow-up was 6 years. A Cox regression multivariate analysis was performed using LF as a time-dependent covariate. RESULTS: Local control (LC) was 87% at 10 years. Local failure led to poorer survival at 10 years than local control (55% v 75%, P < .00). In a Cox model, local failure was a powerful predictor of mortality. The relative risk associated with LF was 3.6 for mortality and 5.1 for DM (P < .00). In patients with LF, the rate of DM peaked at 5 to 6 years, whereas it peaked at 2 years for patients with LC. The mean time between surgery and DM was 1,050 days for patients without LF and 1,650 days for patients with LF (P < .00). CONCLUSION: Our results show that local failure is associated with an increase in mortality. The difference in the time distribution of distant metastasis for LF and LC could imply distinct mechanisms of dissemination. Local failure should be considered not only as a marker of occult circulating distant metastases but also as a source for new distant metastases and subsequent mortality.

Does histologic grade have a role in the management of head and neck cancers?

PURPOSE: High histologic grade is usually associated with a greater propensity to distant metastases (DM). Its role to predict DM in head and neck cancer is not yet defined. The aim of this study is to evaluate the role of histologic grade as an independent predictor of DM and to determine a subgroup of patients who may benefit from systemic chemotherapy. PATIENTS AND METHODS: This is a retrospective study of 1,266 consecutive patients treated by definitive or postoperative radiotherapy between 1989 and 1997. All patients received at least 50 Gy. All stages and subsites of head/neck were included. DM rates were evaluated by the Kaplan-Meier method with a subsequent Cox analysis. RESULTS: There is a strong correlation of grade with N stage (P <.000001). The metastases-free survival (MFS) was 98%, 90%, and 72% for grades 1, 2, and 3, respectively (P <.000001). In patients with N0 stage, MFS is always greater than 90%, whatever the grade. In the 222 N1 patients, MFS was more than 90% in grade 1 and 2 but dropped to 75% for grade 3 (P =.001). In patients with N2 and N3, MFS was 91%, 79%, and 59% for grades 1, 2, and 3, respectively (P =.008). The same conclusion is applicable when only patients with neck control are analyzed. In a Cox model, grade was an independent predictor of DM (P =.000001) as well as T stage (P =.003), N stage (P =.000001), and neck failure (P =.0003). Higher grade was also an independent predictor of survival (P =.02). CONCLUSION: Patients with histologic grade 1 and grade 2 (except N3) are at low risk of DM. Patients with grade 2 and N3 or patients with grade 3 and N1 to N3 have a higher risk of distant metastases and should be considered for systemic treatment.

Markers of radioresistance in squamous cell carcinomas of the head and neck: a clinicopathologic and immunohistochemical study.

PURPOSE: The lack of accurate criteria to predict the response to radiotherapy for individual patients with squamous cell carcinoma of the head and neck (HN-SCC) remains a major problem. The purpose of this study was to investigate the role of several biologic tumor markers to complement clinical prognostic factors in the assessment of response to radiotherapy in SCCs. PATIENTS AND METHODS: p53, ki-67, c-erb B-2, heat-shock protein-27 (HSP-27), and glutathione S transferase (GSTpi) were evaluated by immunohistochemistry on biopsies from 101 patients treated for head and neck cancer by radical radiotherapy. Expression of each marker was correlated with local control and survival using Kaplan-Meier curves. A Cox regression multivariate analysis was also performed that included all clinical and immunohistochemical variables. RESULTS: Expression of p53 and low cell proliferation allowed identification of patients whose tumors did not respond to radiation. Patients with p53-expressing tumors displayed a relative risk (RR) of 3.78 for not being controlled by radiotherapy compared with patients with p53-negative tumors. For tumors with a high growth fraction (ki-67 > 20%) the RR was 0.25 compared with tumors with a low growth fraction (ki-67 < 20%). When p53 expression and cell proliferation were considered simultaneously in a Cox model, the association with resistance to radiation was significant (P = .000004). The RR for resistance with one (p53 staining or ki-67 < 20%) or two (p53 staining and ki-67 < 20%) unfavorable markers was, respectively, 3.8 and 14.87. CONCLUSION: Patients whose tumor expressed p53 with low growth fraction (ki-67 < 20%) had a strong probability not to respond to radiation therapy. Similarly, absence of p53 expression with a high cell proliferation predicted an excellent outcome after radiotherapy even for patients with advanced disease. Prediction of the outcome of radiotherapy would eventually facilitate the early choice of an adequate treatment.