Tobacco smoking and other substance use disorders associated with recurrent suicide attempts in bipolar disorder.

BACKGROUND: Suicide attempts (SA) are more frequent in bipolar disorder (BD) than in most other mental disorders. Prevention strategies would benefit from identifying the risk factors of SA recurrence in BD. Substance use disorders (SUD) (including tobacco-related) are strongly associated with both BD and SA, however, their specific role for the recurrence of SA in BD remains inadequately investigated. Thus, we tested if tobacco smoking - with or without other SUDs - was independently associated with recurrent SA in BD. METHODS: 916 patients from France and Norway with ascertained diagnoses of BD and reliable data about SA and SUD were classified as having no, single, or recurrent (≥2) SA. Five SUD groups were built according to the presence/absence/combination of tobacco, alcohol (AUD) and cannabis use disorders. Multinomial logistic regression was used to identify the correlates of SA recurrence. RESULTS: 338 (37%) individuals reported at least one SA, half of whom (173, 51%) reported recurrence. SUD comorbidity was: tobacco smoking only, 397 (43%), tobacco smoking with at least another SUD, 179 (20%). Regression analysis showed that tobacco smoking, both alone and comorbid with AUD, depressive polarity of BD onset and female gender were independently associated with recurrent SA. LIMITATIONS: Lack of data regarding the relative courses of SA and SUD and cross-national differences in main variables. CONCLUSION: Tobacco smoking with- or without additional SUD can be important risk factors of SA recurrence in BD, which is likely to inform both research and prevention strategies.

Persistent increase in TNF and IL-1 markers in severe mental disorders suggests trait-related inflammation: a one year follow-up study.

OBJECTIVE: We evaluated if plasma levels of inflammatory markers are persistently altered in severe mental disorders with psychotic symptoms or associated with state characteristics in a longitudinal study. METHODS: Soluble tumor necrosis factor receptor 1 (sTNF-R1), interleukin-1 receptor antagonist (IL-1Ra), von Willebrand factor (VWF), and osteoprotegerin (OPG) were measured in schizophrenia (n = 69) and affective (n = 55) spectrum patients at baseline and at one-year follow-up, and compared to healthy controls (HC) (n = 92) with analysis of covariance. Association between change in symptoms and inflammatory markers was analyzed with mixed-effects models. RESULTS: sTNF-R1 was higher in the schizophrenia (P < 0.0001) and affective disorders (P = 0.02) compared to HC, while IL-1Ra was higher in schizophrenia (P = 0.01) compared to HC at one year follow-up. There were no significant differences between schizophrenia and affective groups; however, levels in the affective group were in between schizophrenia and HC for sTNF-R1 and IL-1Ra. There were no significant associations between change in symptoms and inflammatory markers. CONCLUSION: Persistently increased sTNF-R1 and IL-1Ra after one year in patients with severe mental disorders primarily reflecting data from the schizophrenia group may suggest that inflammation is a trait phenomenon, and not only the result of stress-related mechanisms associated with acute episodes.

Cannabis use disorder is associated with greater illness severity in tobacco smoking patients with bipolar disorder.

OBJECTIVE: Cannabis use disorders (CUD) may influence the course of bipolar disorder (BD), but key confounding factors such as tobacco smoking have not been adequately addressed. This study examined whether CUD was associated with a more severe illness course in tobacco smoking BD patients. METHODS: A sample of French and Norwegian tobacco smoking patients with BD I and II (N=642) was investigated. DSM-IV diagnoses and other characteristics were obtained through personal interviews using structured questionnaires. The association between CUD and illness course was assessed in regression analyses. RESULTS: In bivariate analyses, CUD was associated with earlier BD onset, higher frequency of manic (in BD I) and depressive episodes and hospitalizations per illness year, and a higher occurrence of psychotic episodes. After controlling for potential confounders, the relationships with earlier BD onset (B=-5.60 95% CI=-7.65 to -3.64), and increased rates of manic episodes (OR=1.93, 95% CI: 1.15 to 3.23) and hospitalizations (OR=2.93, 95% CI: 1.85 to 4.64) remained statistically significant. LIMITATIONS: Despite the multivariate approach, differences between the two samples may lead to spurious findings related to hidden confounders. Substance use and mood episode information was collected retrospectively, and potential birth cohort effects could not be controlled for. CONCLUSION: Studies have found associations between tobacco smoking and poorer outcomes in BD. In this study on tobacco smoking BD patients we report an association between CUD and illness severity, suggesting that CUD exacerbates the disease evolution independently of tobacco smoking. Specific treatment and prevention programs addressing CUD in BD patients are warranted.

[Surgery and sentinel node examination in early vulvar cancer]. / Kirurgi og undersøkelse av vaktpostlymfeknute ved tidlig vulvacancer.

BACKGROUND: Less than radical vulvectomy for primary vulvar cancer has been controversial. Less mutilating surgery without sacrificing benefits in prognosis is warranted. MATERIAL AND METHODS: Based on relevant literature and our own experience, we give a review of surgery and sentinel node examination in early vulvar cancer. RESULTS: Regional lymph node metastasis rarely occurs when tumour thickness is less than 1 mm. Smaller lesions (< 2 cm in diameter) should therefore be treated by wide excision only and without lymph node dissection. Other T1 lesions with deeper invasion should be radically excised with at least 2 cm margins and extend deep to the inferior fascia of the urogenital diaphragm. Complete inguinal-femoral lymphadenectomy should be performed in patients without groin metastases to avoid a small, but definite risk of recurrence, although the incidence of lymph node metastases for all clinical stage I patients is less than 10%. Lymphatic mapping with 99mTechnetium and patent blue technique is a potentially valuable intraoperative tool for assuring removal of the sentinel node most likely to have metastasis, defining the extent of the superficial inguinal lymphadenectomy and identifying uncommon anatomic variations. INTERPRETATION: Until reliable data on the benefits of selective lymphadenectomy using intraoperative lymphoscintigraphy are available, the procedure should only be performed in an approved research setting.

[Lymphedema and lymphangioscintigraphy]. / Lymfødem og lymfangioscintigrafi.

INTRODUCTION: The diagnoses of lymphoedema is generally based on clinical examination. Sometimes supplementary laboratory techniques are required. MATERIAL AND METHODS: A practical lymphangioscintigraphic method is described based on a survey of the literature and trial and error in a series of about 40 patients. The method gives an excellent picture of lymphatic pathology and the lymph stasis present in most lymphoedema patients. RESULTS: The use of the method in 48 patients is reported. An abnormal scintigraphic pattern was seen in 25 patients. In 20 cases with a well established clinical diagnose, the lymphangioscintigram was positive in 15 cases. INTERPRETATION: Lymphangioscintigraphy is a non-invasive method recommendable as first choice in supplementary examination of lymphoedema.

Internal radionuclide therapy of primary osteosarcoma in dogs, using 153Sm-ethylene-diamino-tetramethylene-phosphonate (EDTMP).

Fifteen dogs were referred because of a spontaneous bone tumor, lameness, and local pain. The osteosarcoma diagnosis was established by clinical examination, X-ray, bone scintigraphy, and histological examination of biopsy material. The tumors were located in the extremities (n = 12), scapula (n = 1), maxilla (n = 1), and the frontal bone (n = 1). The dogs were given one to four i.v. injections of 153Sm-labeled ethylene-diamino-tetramethylene-phosphonate (153Sm-EDTMP; 36-57 MBq/kg body weight). Three dogs had surgery in addition to the radionuclide treatment. Platelet and WBC counts showed a moderate and transient decrease. No other toxicity was observed. Average tumor doses after a single injection were approximately 20 Gy, considerably higher in some areas because of inhomogeneous uptake. Macroscopically distant metastases were detected in seven dogs at autopsy. One dog died from an intercurrent disease, free of cancer, 5 months after the radionuclide treatment. None of the dogs was cured. The median and mean survival times from the first treatment to death or euthanasia were 150 and 252 days, respectively. Nine of the dogs had obvious pain relief, and five of them seemed pain-free: one for 20 months and one for 48 months. It is concluded that high tumor doses may be deposited in dog osteosarcomas by 153Sm-EDTMP, and the ratio between tumor dose and the dose to surrounding tissues is favorable. The treatment gives pain relief and in some cases tumor growth delay. In combination with surgery, 153Sm-EDTMP may prolong life significantly and possibly cure the disease because the development of metastases are seemingly postponed. No serious side effects were observed.

[Measurement of glomerular filtration rate in connection with 99Tc-DTPA renography]. / Måling av glomerulaer filtrasjonshastighet i tilknytning til renografi med 99mTc-DTPA.

Glomerular filtration rate (GFR) was measured in two groups of cancer patients. In 20 patients, glomerular filtration rate was measured simultaneously with 51Cr-EDTA, 99mTc-DTPA and the X-ray contrast agent iohexol as markers, and with a complete set of eight blood samples during 24 hours. In a second group of 120 patients, we used 99mTc-DTPA only and tested various simplified methods, based on one or two blood samples. Glomerular filtration rate was also calculated from serum creatinine. There was excellent agreement between the values measured with the three markers, and, in the same group of patients, very good agreement with the results of simplified methods. The larger study carried out with 99mTc-DTPA on the second group of patients, confirmed a very good agreement between methods based on the slope of the plasma curve and a method based on one blood sample only. The correlation was worse between the values obtained by any of the radionuclide methods and those calculated from serum creatinine. The latter method should therefore not be used for determination of renal function.

Objective responses after fractionated infusional brachytherapy of unresectable pancreatic adenocarcinomas.

BACKGROUND: The prognosis of unresectable pancreatic adenocarcinoma is poor. Therefore, the treatment potential of an intratumoral infusional brachytherapy using macroaggregated human albumin in combination with radioactive chromic phosphate [32P] was investigated in this group of patients. METHODS: Seventeen patients with unresectable tumors received intratumoral infusional brachytherapy. Treatment and assessment of response was performed with the aid of ultrasonography. RESULTS: Four patients had complete response with a duration ranging from 2-57 weeks and 5 patients had partial response with a duration ranging from 4-21 weeks, corresponding to an objective response of 53% (9 of 17 patients). Six of these patients were alive 33-57 weeks after treatment. Radiation necrosis was observed in 1 patient after a 19,000-gray cumulative radiation dose and a slight decrease in blood counts was observed in 2 patients. CONCLUSIONS: Intratumoral infusional brachytherapy using radioactive colloidal chromic phosphate has the potential to reduce inoperable pancreatic tumors with few side effects.

Maxillectomy and targeted radionuclide therapy with 153Sm-EDTMP in a recurrent canine osteosarcoma.

An eight-year-old dog with a local relapse of an osteosarcoma was treated with partial maxillectomy and systemic radionuclide therapy that involved two injections, 43 and 45 megabecquerels per kg bodyweight of the bone-seeking agent samarium-153-ethylenediaminetetramethylene phosphonic acid (153Sm-EDTMP), 15 weeks apart. A transient drop in white blood cell count and platelet count was observed following each 153Sm-EDTMP treatment. Follow-up 21 months after surgery revealed no evidence of local recurrence or metastases. The dog was in excellent condition, suffering only minor sequelae from the surgical procedure. Compared with historical controls treated with surgery alone, the combination of surgery and systemic radionuclide therapy seems a promising strategy for the treatment of canine osteosarcoma.

Targeted radiotherapy of osteosarcoma using 153 Sm-EDTMP. A new promising approach.

We report a case where targeted radionuclide therapy using 153Sm-EDTMP gave substantial palliative effect. A 35-year-old male with a primary osteosarcoma located in the first lumbar vertebra relapsed with progressive back pain after conventional treatment modalities had failed. He became bedridden, and developed paraparesis and impaired bladder function. On a diagnostic bone-scan intense radioactivity was localized in the tumor. He therefore was given 153Sm-EDTMP treatment twice, 8 weeks apart, 35 and 32 MBq/kg body weight respectively. After a few days the pain was significantly relieved and by the second radionuclide treatment the pareses subsided. For six months he was able to be up and about without any neurological signs or detectable metastases. Eventually, however, he experienced increasing local pain, developed paraparesis, was re-operated but died 4 months later. The dramatic transient improvement observed in this case warrants further exploration using 153Sm-EDTMP as a boost technique, supplementary to conventional external radiotherapy.

Alpha-particle radiotherapy with 211At-labeled monodisperse polymer particles, 211At-labeled IgG proteins, and free 211At in a murine intraperitoneal tumor model.

Four different chemical forms of the alpha-particle emitting radionuclide 211At were injected intraperitoneally in mice inoculated intraperitoneally 30 hr in advance with 10(6) cells of the K13 murine hybridoma cell line. The different 211At forms were (a) free 211At, (b) 211At-labeled TP-3 nonspecific monoclonal antibody (211At-TP-3), (c) 211At-labeled human IgG kappa (211At-hIgG kappa), and (d) 211At-labeled monodisperse polymer particles (211At-MDPP). A significantly prolonged survival (P < 0.05) was observed with injected doses down to 7 kBq for the 211At-MDPP, and down to 25 kBq for 211At-hIgG kappa. There were no significant differences in survival between 211At-MDPP, 211At-hIgG kappa, and 211At-TP-3 at the dose level of 200 kBq. The group receiving 250 kBq free 211At per animal had a shorter survival than the three other forms at 200 kBq. The groups treated with 500, 200, and 65 kBq 211At-MDPP had a similar survival. The group given the highest dose of 211At-hIgG kappa (275 kBq) had the highest fraction (50%) of long-term survivors of all groups. Biodistribution measurements and total body scintigrams in mice without tumor revealed that the free 211At was distributed all over the body within 10 min after injection while at 2 hr a high fraction of the 211At-TP-3 and 211At-hIgG kappa was still present intraperitoneally. In conclusion this study indicates that 211At-labeled MDPP and 211At-labeled IgG's may be efficient tools for treatment of intraperitoneal superficial tumor cells and malignant ascites.

Magnetic resonance imaging and 67gallium scan in mediastinal malignant lymphoma: a prospective pilot study.

BACKGROUND: A residual mediastinal mass is common after treatment for bulky mediastinal lymphoma and represents a difficult diagnostic problem. PATIENTS AND METHODS: 19 patients with bulky mediastinal masses due to malignant lymphoma had computed tomography (CT), magnetic resonance imaging (MRI) and 67Gallium scan (67Ga) before treatment, after four cycles of chemotherapy, and two, six and twelve months after end of treatment. RESULTS: MRI and 67Ga showed active tumor in all patients before treatment. Twelve months after treatment full consistency was found between the results of the two techniques. During treatment and the first six months after treatment, the two techniques were not in accord in some patients, partly due to later normalization of MRI compared with 67Ga. CONCLUSION: Both MRI and 67Ga are useful in assessing tumor activity in lymphoma mediastinal masses.

Immunoscintigraphy of bone sarcomas--results in 5 patients.

The feasibility of using the murine monoclonal antibody, TP-1, for clinical immunoscintigraphy was examined in a pilot study involving 5 patients with bone sarcomas. 131I-labelled F(ab')2 antibody fragments were injected in doses of 0.8-1.0 mg (90-130 MBq), and the accumulation of radioactivity was examined by scintigraphy, and assessed by direct measurements on biopsied tumour and normal tissue. One osteosarcoma patient had a primary tumour in the femur, whereas the other 4 had single lung metastases detected by other diagnostic methods. Immunoscintigraphy of the femoral primary was optimally visualised after 22 h. In 2 patients, the method failed to detect lung metastasis, in 1 of the cases possibly related to less than optimal methodological conditions. In 2 other patients, increased accumulation of radioactivity indicated one and three lung tumours, in addition to the single metastasis observed by X-ray and CT scanning, tumours that were later confirmed and removed surgically. The concentration of radioactivity in tumour and normal tissues 44-72 h after antibody injection could be measured in 4 patients. The tumour to blood ratios were in the range of 1.2-4.2, compared to 0.1-0.8 for various normal tissues. The results indicate that immunoscintigraphy with TP-1 antibody fragments have a potential for early detection of lung metastases in patients with bone sarcoma.

Animal models for radiolabeled monoclonal antibodies in cancer research.

A review of the different animal tumor model systems used for radiolabeled monoclonal antibody research is given. Problems within the field of radioimmunotargeting are presented, and the tumor models are discussed in relation to the types of problems which can be investigated, and the ability of the models to answer different questions.

Follow-up of breast cancer patients stage I-II: a baseline strategy.

In 430 stage I-II breast cancer patients the cost-benefit of investigations during follow-up have been studied. Median follow-up time was 8 years and 128 patients had relapsed, 91 with metastatic disease. High costs of routine chest X-ray, limited skeletal X-ray and bone scan examinations were associated with low incidence of diagnosed relapses not suspected otherwise. In the eight blood analyses examined, increases of more than 10 mm/h in erythrocyte sedimentation rate (ESR), 20 U/l in gamma-glutamyltransferase (GT) or 60 U/l in alkaline phosphatase (ALP) resulted in a combined sensitivity of 55% and specificity of 91% for relapses with distant metastases. Elevation of at least two blood tests gave a combined sensitivity of 31% and a specificity of 98%. The importance of using individual reference values in screening for recurrences is emphasised. Symptomatic relapse or relapse detected at interval visits were not independent prognostic factors. The blood tests ALP, ESR and GT were strong predictors of survival measured from relapse which increase their legitimacy in follow-up. A more frequent follow-up for patients with 4+ involved nodes is proposed: three visits annually the first 5 years vs. two visits annually for the others. We conclude that history, clinical examination, ALP, ESR and GT are sufficient as a baseline screening for relapse in breast cancer patients.

Distribution of intraperitoneally injected microspheres labeled with the alpha-emitter astatine (211At) compared with phosphorus (32P) and yttrium (90Y) colloids in mice.

The alpha-emitter 211At was bound to polymer microspheres with a diameter of 1.8 microns. The distributions in mice of intraperitoneally injected 211At microspheres, 90Y silicate colloid, and 32P chromic phosphate colloid were compared. The microspheres with 211At spread rapidly in the peritoneal cavity and remained mainly on the intraperitoneal surfaces. Intraperitoneal injection of 90Y colloid resulted in high levels in intraperitoneal fat and the diaphragm, but 1 day after injection 8.5% of the injected dose per gram was found in blood and after 6 days 2.5% was observed in bone. The highest accumulation of 32P was found in liver and spleen. The injection of additional nonradioactive chromic phosphate colloid resulted in an even higher accumulation of 32P in spleen and liver. The same phenomenon was not observed with 211At microspheres. It is suggested that it is not only the particle size which is important in the distribution of intraperitoneally injected colloid, but the amount of colloid, the type of colloid, the addition or presence of other substances such as ascites, and the animal species might also influence the distribution. In conclusion, the intraperitoneal distribution of 211At-labeled microspheres in mice was favorable compared with 90Y and 32P colloid. These data must be viewed cautiously since the distribution might be different in other animal species or humans.

89Strontium in bone metastases from hormone resistant prostate cancer: palliation effect and biochemical changes.

Hematological and biochemical parameters were evaluated in 31 patients receiving 150 MBq 89Strontium (89Sr) intravenously due to painful skeletal metastases from hormone resistant prostate cancer. Two and 3 months after the injection prostate specific antigen (PSA) had increased by a median of 36% and 100%, respectively, as compared to the pretreatment value whereas alkaline phosphatase (APHOS) had decreased by about 20% (median). The leucocyte and platelet counts were reduced by about 20-35%, without reaching grade greater than or equal to 2 toxicity. Pain relief was reported in 14 of 29 evaluable patients at 2 months and in 11 of 23 patients at 3 months. It is concluded that 89Sr represents a worthwhile therapeutic modality in the palliation treatment of patients with hormone resistant prostate cancer, though the biological significance of frequently increasing PSA and decreasing APHOS is not yet completely understood.

Randomized trial comparing cisplatin with radioactive phosphorus or whole-abdomen irradiation as adjuvant treatment of ovarian cancer.

In this study, 347 patients with epithelial ovarian cancer without residual tumor after primary laparotomy, were assigned randomly to receive either intraperitoneal instillation of radioactive phosphorus (32P) or six courses of cisplatin (50 mg/m2). Patients randomized to receive 32P with extensive intraperitoneal adhesions were treated with whole-abdomen irradiation instead of 32P (n = 28). The median follow-up was 62 months. Crude and disease-free survival were similar in all groups. Late bowel complications occurred more often in patients treated with 32P compared with the cisplatin group. The estimated 5-year crude survival rate was as high as 95% in patients with borderline or well-differentiated tumors in Stage I. It is suggested that these patients can be treated adequately by operation alone. Patients with moderately or poorly differentiated cancers in Stage I disease had a 5-year crude survival rate of 75%. In these patients, the relapse risk was high enough to warrant postoperative treatment. The efficacy of adjuvant treatment in this subgroup of patients can only be established in a prospective randomized study comparing postoperative adjuvant treatment with a no-treatment arm. Because of the high number of late bowel complications after 32P treatment, it was recommended that cisplatin be used as standard adjuvant treatment for subsequent controlled studies.

Long-term biodistribution in tumored mice of murine and chimeric B72.3-IgG antibody radiolabeled with 114mIn via both DTPA and a macrocyclic chelator.

To assess the possibilities of using 114mIn as a therapeutic agent, the long-term biodistribution of 114mIn was studied, in tumor-bearing nude mice, after injection of labeled monoclonal antibody (MoAb) B72.3 IgG, either DTPA-coupled murine, DTPA-coupled chimeric, or macrocycle-coupled chimeric antibody. Although the biodistributions in all cases were similar, there were important differences. The use of DTPA-coupled chimeric antibody led to higher concentrations of radioactivity in tumor, and to lower concentrations in liver and bone, as compared to DTPA-coupled murine antibody. The use of macrocycle-coupled chimeric antibody led to higher concentrations of radioactivity in the liver and in bone as compared to the DTPA-coupled chimeric antibody. However, in this case there were no significant differences in tumor uptake or clearance. Radiation doses were calculated based on the organ retention and by neglecting source-to-target contributions. Radiation dose distribution was marginally favorable for therapy in the group injected with DTPA-coupled chimeric antibody.