Intergenerational accumulation of impairments in maternal behavior following postnatal social stress.

Early adversity such as depressed maternal care can have long-term physiological and behavioral effects on offspring and future generations. Exposure to chronic social stress (CSS), an ethologically model of postpartum depression and anxiety, during lactation impairs maternal care and exerts similar effects on the F1 dam offspring of the stressed F0 dams. These changes associate with increased corticosterone and neuroendocrine alterations. CSS F2 offspring further display decreased social behavior as juveniles and adults and decreased basal levels of corticosterone. This current study investigates the intergenerational inheritance of alterations in maternal behavior in F2 CSS dams together with neuroendocrine and immune markers to explore whether aspects of maternal behavior are intergenerationally inherited through immune and neuroendocrine mechanisms. We find that defects in maternal care behavior persist into the F2 generation with F2 dams exhibiting a pervasively depressed maternal care and increased restlessness throughout lactation. This occurs together with reduced basal cortisol (in contrast to an increase in F1 dams), a lack of changes in neuroendocrine gene expression, and reduced serum ICAM-1 (intercellular adhesion molecule-1) levels - a marker for inflammation and blood-brain barrier integrity. The data support the hypothesis that the effects of chronic social stress can accumulate across multiple generations to depress maternal care, increase restlessness and alter basal functioning of the immune system and hypothalamic pituitary adrenal axis.

Hemophilia A and hemophilia B: focus on arthropathy and variables affecting bleeding severity and prophylaxis.

Hemophilia A (HA) and hemophilia B (HB) are X-linked, recessive disorders. Although their clinical manifestations are essentially indistinguishable, it has been suggested that bleeding episodes in patients with HA are generally more severe and occur at higher frequency than in patients with HB. Nevertheless, considerable debate remains regarding the relative severity of HA and HB. Based on the relative risk of undergoing joint arthroplasty, it appears that patients with HA have more severe joint deterioration compared with patients with HB. Although it is difficult to speculate on the factors that might modify bleeding severity in patients with hemophilia, recent observations indicate that other coagulation proteins, such as tissue factor pathway inhibitor or polymorphisms in coagulation factor genes and genetic defects associated with hypercoagulability may account for the variability in clinical phenotype among patients with hemophilia. Numerous studies have provided evidence supporting the clinical and social benefits of administration of clotting factor in prophylaxis. However, it is still unclear why this approach is more commonly utilized in patients with HA than in those with HB.

Analysis of factors influencing aspiration risk following chemoradiation for oropharyngeal cancer.

Our aim was to identify risk factors for aspiration following concurrent chemoradiation for oropharyngeal cancer. 46 patients with locally advanced oropharyngeal carcinoma underwent concurrent chemoradiation at our institution. All patients underwent modified barium swallow to assess dysphagia severity and to determine the need for continued tube feedings after treatment. Dysphagia severity was graded as 1-7. There were 5 Grade 2, 11 Grade 3, 5 Grade 4, 5 Grade 5, 10 Grade 6 and 10 Grade 7 scores. 25 patients (54%) developed aspiration (5 trace, 20 severe). The aspiration rate for T1-T2 and T3-T4 tumours was 31% and 67%, respectively (p = 0.03). There was no statistical difference in the aspiration rate between the base of the tongue and tonsillar carcinoma (p = 0.23). Despite anatomical organ preservation, most patients with locally advanced oropharyngeal carcinoma had moderate to severe dysphagia after chemoradiation. Patients with large tumours had a significant risk of developing aspiration following treatment.

Analysis of the factors influencing dysphagia severity upon diagnosis of head and neck cancer.

Our aim was to assess the influence of age, co-morbidity factors and tumour characteristics on dysphagia severity in the diagnosis of head and neck cancer. Modified barium swallow (MBS) examinations were performed in patients at diagnosis of head and neck cancer. Dysphagia was graded on a scale of 1 to 7 of increasing severity. Between 2000 and 2006, 236 patients with dysphagia underwent MBS at diagnosis of their head and neck cancer. 82 patients were scored as Grade 1, 88 as Grade 2, 29 as Grade 3, 15 as Grade 4, 9 as Grade 5, 5 as Grade 6, and 8 as Grade 7. Grade 3-7 dysphagia occurred in 20% and 31% of patients with T1-T2 and T3-T4 tumours, respectively (p = 0.004). Corresponding values for N0-N1 and N2-N3 tumours were 20% and 39%, respectively (p = 0.002). The percentage of patients with Grade 3-7 dysphagia was 5%, 29%, 33% and 52% for oral cavity, laryngeal, oropharyngeal and hypopharyngeal tumours, respectively, (p = 0.002). Age and co-morbidity factors (e.g. diabetes, hypertension, coronary artery disease, peripheral vascular diseases and arthritis) did not appear to have an impact on swallowing in this limited retrospective study. Patients with locally advanced stages (T3-T4, N2-N3) are at risk of severe dysphagia. Patients with oral cavity tumours appear to be less at risk of dysphagia than those with tumours in different anatomic locations. The role of age and co-morbidity factors should be investigated in future prospective studies.

The risk of venous thromboembolic disease in patients with monoclonal gammopathy of undetermined significance.

BACKGROUND: Recent evidence indicates that patients with multiple myeloma receiving combination chemotherapy containing thalidomide are at a significantly high risk for venous thromboembolic disease (VTD). However, information on the occurrence of VTD in a related disorder, benign monoclonal gammopathy of undetermined significance (MGUS), is limited. PATIENTS AND METHODS: We prospectively investigated patients with MGUS for the occurrence of VTD. The diagnosis of MGUS was based on well known criteria for the disorder. The variables examined were sex, age, race, presence of underlying conditions, level and type of immunoglobulin [serum monoclonal (M)-protein] platelet counts and level of fibrinogen. RESULTS: Of a total of 310 patients with MGUS, 19 (6.1%) developed VTD after a median follow-up of 44 months (range 12-67 months). In a univariate analysis, age >/=65 years (P=0.01), M-protein >/=16 g/l (P=0.001) and progression to plasma cell or lymphoproliferative disorders (28 of 310 patients; P=0.001) were significant risk factors for VTD. In multivariate analysis, M-spike >/=16 g/l [risk ratio (RR)=6.3; 95% confidence interval (CI) 2.25-17.6; P=0.001] and future development of plasma cell or lymphoproliferative disorder (RR = 4.2; 95% CI 1.64-10.7; P=0.003) were variables strongly associated with the occurrence of VTD. A total of 46 patients (14.8%) died during the follow-up period of the study. CONCLUSION: This study demonstrates that patients with MGUS are at increased risk for VTD. Although a clear reason for the pre-thrombotic state in these patients is not currently evident, few risk factors were identified in the group of patients examined.

Dysphagia following chemoradiation for locally advanced head and neck cancer.

BACKGROUND: To assess the prevalence, severity and morbidity of dysphagia following concurrent chemoradiation for head and neck cancer. PATIENTS AND METHODS: Patients who underwent chemotherapy and radiation for head and neck malignancies were evaluated for their ability to resume oral feeding following treatment. Modified barium swallow (MBS) studies were performed if the patients complained of dysphagia or if there was clinical suspicion of aspiration. The severity of dysphagia was graded on a scale of 1-7. If significant abnormalities were found, swallowing studies were repeated until resolution of dysphagia. RESULTS: Between March 1999 and May 2002, 55 patients with locally advanced head and neck cancer underwent concurrent chemotherapy and radiation. Aspiration pneumonia was observed in eight patients, three during treatment and five following treatment. Five patients died from pneumonia. Two patients developed respiratory failure requiring intubation as a complication of pneumonia. At a median follow-up of 17 months (range 6-48 months), 25 patients (45%) developed severe dysphagia requiring prolonged tube feedings for more than 3 months (22 patients) or repeated dilatations (three patients). Among 33 patients who underwent MBS following treatment, 12 patients (36%) had silent aspiration (grade 6-7 dysphagia). Thirteen patients (39%) developed grade 4-5 dysphagia which required prolonged enteral nutritional support to supplement their oral intake. Most patients had severe weight loss (0-21 kg) during treatment, likely due in part to mucositis in the orodigestive tube. CONCLUSIONS: Dysphagia is a common, debilitating and potentially life-threatening sequela of concurrent chemoradiation for head and neck malignancy. Physicians should be aware that the clinical manifestations of aspiration may be unreliable and insidious, because of the depressed cough reflex. Modified and traditional barium swallows should be performed following treatment to assess the safety of oral feeding and the structural integrity of the pharynx and esophagus. Patients with severe dysphagia may benefit from rehabilitation. Tube feeding should be continued for those with aspiration.

Treatment of acquired haemophilia with factor eight inhibitor bypassing activity.

Haemorrhagic manifestations in patients with acquired haemophilia can be fatal if not recognized and treated appropriately. A retrospective analysis of the efficacy of factor eight inhibitor bypassing activity (FEIBA) in patients with acquired haemophilia treated in three medical centres in the past 10 years was conducted. The median inhibitor titre at treatment was 128 Bethesda Units (BU) in patients with severe and 34 BU in patients with moderate bleeding; P = 0.001. The majority of patients received FEIBA at a dose of 75 u kg-1 every 8-12 h. The number of FEIBA doses administered was higher in patients with severe compared with moderate haemorrhage, 10 vs. 6 doses per bleeding episode; P = 0.001. Complete response (CR) was achieved in 76% of severe and 100% of moderate bleeding episodes with a total CR of 86%. When compared with patients with human inhibitor titre <50 BU, those with titre >51 BU at treatment had lower median porcine titre, 1 vs. 9.5 BU; P < 0.05, fewer doses of FEIBA, 6 vs. 8.5 doses; P < 0.05, and shorter time to CR, 29 vs. 42 h; P < 0.05. Patients exposed to factor VIII concentrates prior to FEIBA had significantly higher maximum recorded human inhibitor titre compared with patients without such exposure, 273 vs. 38 BU; P = 0.0001. Treatment with FEIBA was very well tolerated and with very few side effects. This study provides evidence that FEIBA is an effective agent in acquired haemophilia and suitable for all types of patients regardless of severity of haemorrhage, underlying disease or inhibitor titre.

Concurrent interferon-alpha and radiation for head and neck melanoma.

Melanoma cells are resistant to radiation in part due to their capacity to repair sublethal damage. A large fraction dose is therefore often utilized. However, if the tumour is located close to critical structures with modest tolerance, high fraction doses increase the risk for late complications compared with standard fractionation, but using the latter alone risks the desired outcome. Concurrent systemic biotherapy with standard radiation fractions may therefore represent an acceptable compromise. The outcome of concurrent systemic interferon-alpha (IFNalpha) and radiation in three patients with head and neck melanoma was evaluated. Standard radiation fractions were used because of the radiosensitizing properties of IFNalpha. Acute toxicity was significant and required treatment interruptions. However, all side effects subsided following treatment. All three patients achieved local control at follow-up periods of 24, 18 and 19 months, respectively. One patient developed widespread distant metastases. The combination of IFNalpha with radiation is considered feasible in terms of outcome and should be investigated with a larger cohort of patients. Toxicity is significant, and the addition of radioprotectors could be desirable.

Analysis of factors related to the occurrence of chronic disseminated candidiasis in patients with acute leukemia in a non-bone marrow transplant setting: a follow-up study.

BACKGROUND: Chronic disseminated candidiasis (CDC) is a serious complication of treatment in patients with acute leukemia. Although some general risk factors are known to predispose to systemic fungal infections, few studies have addressed the relevance of certain clinical and laboratory features in patients with CDC. PATIENTS AND METHODS: To define a subset of patients at high risk for CDC, the authors evaluated the demographics and clinical and laboratory characteristics of 423 patients with acute leukemia. Patients who had bone marrow transplant before the diagnosis of CDC were excluded from the analysis. The diagnosis of CDC was based on blood cultures, liver biopsy, and imaging studies. The authors conducted 2 separate regression analyses on 3 subsets of patients: patients without documented candidiasis (n = 374), patients with CDC (n = 23), and patients with candidemia (n = 26). RESULTS: According to multivariate analysis, younger age (P = 0.009; odds ratio [OR], 1.96; 95% confidence interval [CI], 1.72-2.99), duration of neutropenia of 15 days or longer (P = 0.0003; OR, 11.7; 95% CI, 3.04-45.1), and use of prophylactic quinolone antibiotics (P = 0.039; OR, 3.85; 95% CI, 1.11-13.4) emerged as independent factors related to the development of CDC in patients with acute leukemia. The presence of severe mucositis, colonization with Candida, and administration of high-dose ara-C were statistically significant parameters in univariate analysis only (P = 0.0001, P = 0.003, and P = 0.058, respectively). CONCLUSIONS: On the basis of the results of this investigation, it is possible to define a subset of patients with acute leukemia at very high risk for CDC. Because of the morbidity and mortality of this infection, a targeted prophylactic approach may be more effective and less costly than the random administration of antifungal agents.

Disseminated intravascular coagulation in solid tumors: clinical and pathologic study.

Disseminated intravascular coagulation (DIC) is a well known hemostatic complication of solid tumors. We evaluated the occurrence of DIC in 1117 patients with solid tumors. Of these patients, 76 (6.8%) were diagnosed with DIC. There were a total of 145 bleeding and clotting episodes reported in the 76 patients. Thrombocytopenia, hypofibrinogemia, elevated D-dimer and fibrinogen degradation products were the most common coagulation abnormalities encountered in patients with DIC. In multivariate analysis, older age (p = .0001), male gender (p = .009), advanced malignancies (p = .027), breast cancer (p = .038) and the presence of necrosis in the tumor specimen (p = .004), emerged as independent factors significantly related to the occurrence of DIC in patients with solid tumors. Of the 76 patients, 25 (33%) achieved response to treatment of DIC as defined in the study. Patients with early stage and advanced malignancies who developed DIC had inferior survival when compared with their counterparts without DIC (p = .039 and p = .005, respectively). Taken together, this study indicates that certain clinical and laboratory features are more common in patients with solid tumors who developed DIC. The occurrence of DIC appears to have an independent effect on survival of patients with cancer. Cooperative studies are encouraged to better address the usefulness and optimal prophylactic heparin regimen in patients at risk for DIC.

Prognosis for papillary serous carcinoma of the endometrium after surgical staging.

BACKGROUND: To investigate the pattern of failure and the prognosis following pathological staging for uterine papillary serous carcinoma (UPSC). PATIENTS AND METHODS: A retrospective review was conducted of 22 patients with UPSC, treated between 1989 and 1998 at a single institution. All patients were surgically staged. Two patients with advanced disease received chemotherapy only. Two patients with early-stage disease were followed without further treatment. Eighteen patients received postoperative irradiation; eight patients received whole abdominal irradiation (WART), and the remaining 10 patients, pelvic irradiation (PRT). In addition, seven of these patients received vaginal cuff irradiation with low-dose-rate or high-dose-rate brachytherapy. Toxicity, pattern of failure, and survival were evaluated and compared to the literature. RESULTS: Seven patients (32%) developed distant metastases, three out of seven (42%) after WART. Four out of seven patients who had distant metastases died from disease progression during subsequent chemotherapy. All patients with distant metastases had locally advanced-stage disease at presentation (six stage III, one stage IV). Four patients with pelvic recurrences developed concurrent (2) and subsequent (2) distant metastases. Three patients had isolated distant metastases. No patient with early stage-disease (stage I and II) died from disease progression. CONCLUSION: Pathological staging should be performed for all patients with UPSC to determine the prognosis as well as to tailor the treatment. The role of abdominal irradiation in the treatment of UPSC is yet to be determined; however, such an approach may not be necessary for the control of disease for patients with early-stage (I and II) disease. Patients with locally advanced-stage (stage III) disease are at risk of local regional failures and distant metastases despite WART. Therefore, the benefit of WART for advanced-stage disease is also questionable. Paclitaxel-based chemotherapy is currently being investigated in this setting.

Interferon-alpha combined with radiotherapy in the treatment of unresectable melanoma.

A case of recurrent and twice resected sinonasal melanoma is presented. The large recurrent tumor was found to regress by a concurrent combination of 6660 cGy photon radiation and subcutaneous interferon-alpha injections given for a period of 8 weeks. Possible mechanisms of potentiation between interferon and radiation are discussed. The unexpected result in this case report raises interesting questions about this treatment combination.

Treatment of refractory T-cell malignancies using gemcitabine.

We have treated 10 patients with relapsed or refractory T-cell malignancies using gemcitabine. The drug was administered intravenously over 30 min at a dose of 1200 mg/m2 on d 1, 8 and 15 of each 28-d cycle. The mean age of the patients was 62 years and the mean number of administered cycles was three. Of the 10 patients, two achieved a complete response and four a partial response, for an overall response rate of 60% (95% confidence interval 20--35%). The toxicity of chemotherapy was mild and manageable in all patients. These encouraging results warrant further investigation of gemcitabine either as a single agent or in combination regimens as early salvage treatment for patients with refractory T-cell haematological neoplasms.

Future development of lymphoproliferative disorders in patients with autoimmune hemolytic anemia.

The association between autoimmune hemolytic anemia (AIHA) and subsequent appearance of lymphoproliferative disorders (LPDs) has not been properly addressed in large-scale studies. We evaluated 107 patients with idiopathic (67 patients) or underlying (40 patients) immune disorders diagnosed with AIHA between 1992 and 1999. The following variables were examined in univariate and multivariate analysis: age; sex; type of AIHA (warm- or cold-active antibodies); presence of underlying immune disorders; and serum monoclonal protein. Of the 107 patients, 19 (18%) developed malignant LPDS: The median time to develop malignancy was 26.5 months (range, 9-76 months). At multivariate analysis, advanced age (P = 0.005), underlying autoimmune diseases (P = 0.002), and the presence of serum gammopathy (P = 0.045) were risk factors for future development of LPDs in these patients. Also, serum monoclonal IgM protein was a significant predictor (P = 0.0001) for the appearance of LPDs in patients with AIHA. The present study provides evidence that AIHA in some patients should be considered as a precursor of malignant LPDS: Knowledge of certain characteristics may help identify patients at risk for this transformation; periodic clinical and laboratory assessment of these patients is warranted.