Observed Trajectories of Cannabis Use and Concurrent Longitudinal Outcomes in Youth and Young Adults Receiving Coordinated Specialty Care for Early Psychosis.

Cannabis use is present and persistent in young adults with early psychosis receiving Coordinated Specialty Care (CSC) in the United States. While CSC programs are effective in improving quality of life, helping individuals reach goals, and promoting recovery, cannabis use may limit the extent of these improvements. This study extended upon previous findings to examine trajectories of cannabis use among individuals with early psychosis. The sample consisted of 1325 CSC participants enrolled for more than one year at OnTrackNY and followed up to two years, categorized into three groups: no use, reduced use, and persistent use. Baseline demographic and clinical differences were compared across groups and associations between clinical and psychosocial outcomes at 12 months and 24 months were examined across groups. Of the sample, 40 % remained persistent users over two years while 12.8 % reduced their use. At baseline, persistent users were younger (p = 0.011), more likely to be male (p < 0.001), had lower education levels (p = 0.019), and were more likely to have had past legal issues prior to admission (p < 0.001) than non-users. At 2 years, persistent users had significantly worse symptom scores than non-users (p = 0.0003) and reduced users (p = 0.0004). These findings highlight the presence of persistent cannabis use being common in this population and the need to improve substance use treatment offered to allow more CSC participants to achieve improved outcomes.

How Long Does Contouring Really Take? Results of the Royal College of Radiologists Contouring Surveys.

AIMS: The success and safety of modern radiotherapy relies on accurate contouring. Understanding the time taken to complete radiotherapy contours is critical to informing workforce planning and, in the context of a workforce shortfall, advocating for investment in technology and multi-professional skills mix. We aimed to quantify the time taken to delineate target volumes for radical radiotherapy. MATERIALS AND METHODS: The Royal College of Radiologists circulated two electronic surveys via email to all clinical oncology consultants in the UK. The individual case survey requested anonymous data regarding the next five patients contoured for radical radiotherapy. The second survey collected data on respondents' usual practice in radiotherapy contouring. RESULTS: The median time to contour one radiotherapy case was 85 minutes (IQR = 50-131 minutes). Marked variability between and within tumour sites was evident: paediatric cancers took the most time (median = 210 minutes, IQR = 87.5 minutes), followed by head and neck and gynaecological cancers (median = 120 minutes, IQR = 71 and 72.5 minutes respectively). Breast cancer contouring required the least time (median = 43 minutes, IQR = 60 minutes). Radiotherapy technique, inclusion of nodes and 4D CT planning were associated with longer contouring times. A non-medical professional was involved in contouring in 65% of cases, but clinical oncology consultants were involved in target volume delineation in 90% of cases, and OARs in 74%. Peer review took place in 46% of cases with 56% of consultants reporting no time for peer review in their job plan. CONCLUSION: Contouring for radical radiotherapy is complex and time-consuming, and despite increasing involvement of non-medical professionals, clinical oncology consultants remain the primary practitioners. Peer review practice is variable and time is often a limiting factor. Many factors influence the time required for contouring, and departments should take these factors and the need for peer-review into account when developing job plans.

Design of Smart Size-, Surface-, and Shape-Switching Nanoparticles to Improve Therapeutic Efficacy.

Multiple biological barriers must be considered in the design of nanomedicines, including prolonged blood circulation, efficient accumulation at the target site, effective penetration into the target tissue, selective uptake of the nanoparticles into target cells, and successful endosomal escape. However, different particle sizes, surface chemistries, and sometimes shapes are required to achieve the desired transport properties at each step of the delivery process. In response, this review highlights recent developments in the design of switchable nanoparticles whose size, surface chemistry, shape, or a combination thereof can be altered as a function of time, a disease-specific microenvironment, and/or via an externally applied stimulus to enable improved optimization of nanoparticle properties in each step of the delivery process. The practical use of such nanoparticles in chemotherapy, bioimaging, photothermal therapy, and other applications is also discussed.

Reversible Cerebral Vasoconstriction Syndrome: an important cause of thunderclap headache.

Reversible cerebral vasoconstriction syndrome (rCVS) is an important cause of acute severe headache that is poorly understood and under-recognised. It typically presents with recurrent thunderclap headaches and is characterised by multifocal, segmental constriction and dilatation of the cerebral arteries, shown by a 'string of beads' appearance, on cerebral angiography. We describe a case of rCVS in a 39-year-old male presenting with post-coital thunderclap headaches following a whiplash-type injury.

Regional cerebral blood flow in children from 3 to 5 months of age.

BACKGROUND AND PURPOSE: Understanding the relationship between brain and behavior in early childhood requires a probe of functional brain development. We report the first large study of regional CBF by use of arterial spin-labeling in young children. MATERIALS AND METHODS: Cerebral blood flow by use of arterial spin-labeling was measured in 61 healthy children between the ages of 3 and 5 months. Blood flow maps were parcellated into 8 broadly defined anatomic regions of each cerebral hemisphere. RESULTS: There was no sex effect; however, group analysis demonstrated significantly greater CBF in the sensorimotor and occipital regions compared with dorsolateral prefrontal, subgenual, and orbitofrontal areas (P < .0001). A significant age effect was also identified, with the largest increase in blood flow between 3 and 5 months occurring in the following regions: orbitofrontal (P < .009), subgenual (P < .002), and inferior occipital lobe (P = .001). CONCLUSIONS: These results are consistent with prior histologic studies demonstrating regional variation in brain maturation and suggest that arterial spin-labeling is sensitive to regional as well as age-related differences in CBF in young children.

Results of mastectomy and postoperative irradiation in the management of locoregionally advanced carcinoma of the breast.

Between 1955 and 1984, 376 patients with locoregionally advanced breast carcinoma were treated at The University of Texas M. D. Anderson Cancer Center with mastectomy and irradiation and without adjuvant chemotherapy. Patients with inflammatory carcinoma or synchronous bilateral primary tumors were excluded. There were 202 patients with Stage IIIA disease and 174 patients with Stage IIIB disease (AJC Staging--1983). In 124 patients the surgical management was confined to the breast only--total mastectomy (BR) and in 252 dissection of the axilla was performed--extended total, modified radical, or classic radical mastectomy (BR + AX). All patients had postoperative irradiation. The follow-up period ranged between 8 and 34 years. At 10 years, the actuarial disease-specific, relapse-free survival (DSRFS) rate for the entire group was 40%, and the actuarial locoregional control rate was 82%. For patients with Stage IIIA disease the DSRFS was 48% and locoregional control rate was 88%. For those with Stage IIIB disease, the figures were 30% and 74%, respectively. Most of the failures occurred within 5 years of the mastectomy and essentially all occurred within 10 years. When analyzed by type of surgery, both the locoregional control and DSRFS rates were improved by the axillary dissection, the difference being largely caused by fewer axillary node recurrences after dissection of both the breast and axilla than after removal of the breast alone. In the 252 patients in whom the axilla was assessed, the number of positive nodes was a powerful predictor of both locoregional control and survival. The DSRFS rates at 10 years for patients with 0, 1-3, and greater than or equal to 4 positive nodes were 63%, 48%, and 30%, respectively. The actuarial locoregional control rates at 10 years exceeded 95% for patients with 0-3 positive nodes and 75% for those with greater than or equal to 4 nodes. These results show that locoregionally advanced breast cancer is not a uniformly fatal disease when treated without chemotherapy and provide a baseline upon which to assess the value of adjuvant systemic therapy for this stage of disease.

Decreased cardiac toxicity of doxorubicin administered by continuous intravenous infusion in combination chemotherapy for metastatic breast carcinoma.

Two hundred and seventy-four consecutive patients with measurable metastatic breast cancer, without prior exposure to cytotoxic agents were treated with tamoxifen, 5-fluorouracil, doxorubicin, and cyclophosphamide (FAC). The initial 133 patients received doxorubicin by bolus IV administration and for the next group of 141 patients doxorubicin was administered via a central venous catheter over a 48-hour (79 patients) or 96-hour (62 patients) continuous infusion schedule. Patients treated with bolus doxorubicin had this agent discontinued usually when 450 mg/m2 were reached; for patients in the infusion group treatment was continued until evidence of progressive disease or clinical or subclinical cardiac dysfunction developed. The complete remission rate was 21% the partial remission rate, 59%. There were no differences in response rate, response duration, or survival duration between groups of patients treated with doxorubicin by bolus, 48-hour or 96-hour infusion FAC. The incidence of moderate and severe nausea and vomiting was lower in the group of patients treated with infusion FAC as compared to bolus FAC (P less than 0.001); however, the incidence of mucositis was higher in the infusion group than in the bolus group (P less than 0.001). Doxorubicin administered by continuous infusion schedules was less cardiotoxic than when administered by bolus, as shown by a greater than 75% decrease in the frequency of clinical congestive heart failure at cumulative dosages greater than or equal to 450 mg/m2 (P = 0.004). Doxorubicin administered as a 48-hour or 96-hour continuous IV infusion is safer, and better tolerated than doxorubicin administered by bolus.

Prognostic implications of age in breast cancer patients treated with tumorectomy and irradiation or with mastectomy.

Conservation breast treatment is of particular interest to young women, but whether saving the breast carries a penalty in shorter survival or local-regional recurrent disease has not been well-established. At The University of Texas M.D. Anderson Hospital and Tumor Institute at Houston, 1161 patients treated prior to 1983 with Stage I or II breast cancer were reviewed. Of these patients, 378 were treated with tumorectomy plus irradiation, and 783 were treated with radical or modified radical mastectomy. The two patient groups were compared relative to local-regional disease recurrence and overall and disease-free survivals. Local recurrences in the breast appear to be more frequent in patients less than or equal to 35 years of age treated with tumorectomy and irradiation than in patients older than 35 years, but in patients aged less than or equal to 50 or greater than 50 or less than or equal to 35 or greater than 35 years, there was no significant statistical difference between tumorectomy and irradiation or mastectomy nor was there a difference in disease-free survival. Overall survival rates favored patients treated by tumorectomy and irradiation.

Combined antiestrogen and cytotoxic therapy with pseudomonas vaccine immunotherapy for metastatic breast cancer. A prospective, randomized trial.

One hundred thirty-three consecutive, previously untreated patients who had metastatic breast cancer were treated with a combination of 5-fluorouracil, doxorubicin (Adriamycin), and cyclophosphamide (FAC). They were randomly assigned to receive nonspecific immunotherapy with a heptavalent pseudomonas vaccine. Sixty-five patients were treated with pseudomonas vaccine, whereas 68 did not receive immunotherapy. In addition, all patients with estrogen receptor-positive tumors or tumors with an estrogen receptor status were also treated with tamoxifen. To allow clinical assessment of hormone sensitivity in vivo, tamoxifen was started 6 weeks before chemotherapy except in patients who had life-threatening disease. After the initial 6 weeks of tamoxifen, 3% of patients had achieved a complete remission, 9% a partial remission, while 16% achieved a minor response. The maximum response after tamoxifen and chemotherapy included complete remissions in 20% of patients and partial remissions in 61% of patients for an overall remission rate of 81%. The median response duration was 15 months, and the median survival time, 27 months. There were no differences in remission rate, remission duration, or survival time between the groups treated with or without pseudomonas vaccine. Eleven patients with limited metastatic disease received radiotherapy consolidation to initially involved sites. In these patients the median time from radiotherapy to progression of disease was 33 months, and the median survival time was 46 months. We conclude that nonspecific immunotherapy with pseudomonas vaccine failed to increase remission rate or survival time. Furthermore, the addition of tamoxifen to FAC chemotherapy did not improve the remission rate or duration compared to a recent, historical control group of patients treated with only FAC chemotherapy.

Comparison of different trials of adjuvant chemotherapy in stage II breast cancer using a natural history data base.

Prognostic factors and treatment were analyzed for 2,578 patients to assess the impact of various forms of adjuvant chemotherapy on the natural history of operable stage II (node-positive) breast cancer. The outcome after surgery alone (or with radiotherapy) was determined in 1,014 patients in the natural history data base (NHDB). Adjuvant chemotherapy consisted of L-phenylalanine mustard (L-PAM; 130 patients); cyclophosphamide, methotrexate, and 5-fluorouracil (CMF; 645 patients); doxorubicin and cyclophosphamide (AC; 241 patients); CMF plus vincristine and prednisone (CMFVP; 263 patients); and 5-fluorouracil plus AC (FAC; 285 patients). L-PAM had minimal effect on relapse-free survival (RFS) compared to the NHDB, but all combination chemotherapy programs significantly improved RFS and survival compared to the NHDB. In women with 1-3 positive nodes, all combination chemotherapy programs produced similar results. In women with 4-9 positive nodes, the FAC regimen appeared to be associated with superior RFS compared to other programs, but all were superior to the NHDB. In women with 10 or more positive nodes, FAC was the only regimen associated with improved RFS. The use of a NHDB and known pretreatment characteristics, such as nodal status and tumor size, permits comparison of patients at similar risk of recurrence of breast cancer who have received adjuvant chemotherapy and provides leads for evaluation in future prospective clinical trials.

Development and use of a natural history data base of breast cancer studies.

Pretreatment information, type of treatment, and longitudinal follow-up on 1,971 patients with operable breast cancer were used to establish a breast cancer natural history data base (NHDB). Data were available for 957 patients with stage I (node-negative) breast cancer and 1,014 stage II (node-positive) patients. In women with negative nodes, information was available on 759 patients treated at the Milan National Cancer Institute and 188 patients treated at the Royal Marsden Hospital. After adjustment for differences in the distribution of patient prognostic factors, relapse-free survival and overall survival were not significantly different. Of the 1,014 node-positive patients, 540 were treated at the Milan National Cancer Institute, 258 at the Royal Marsden, and 216 at the M. D. Anderson Hospital. Relapse-free survival and overall survival did not significantly differ between Milan patients and those treated at the Royal Marsden Hospital. However, M. D. Anderson Hospital patients did have significantly better relapse-free and overall survival. In each institution, outcome was consistently most dependent on the number of involved axillary lymph nodes and tumor size. Also, similar patterns of survival were observed for each of the institutions. The development of an NHDB can be of value in the identification and evaluation of consistency of prognostic factors, permitting improved comparisons between clinical trials. The development of such a natural history data base (NHDB) provides a reference for assessing the impact of different adjuvant chemotherapy programs, and aids in the design of new protocols.

Lack of concordance of growth rates of primary and recurrent breast cancer.

The degree of concordance of growth rates of primary tumors with corresponding recurrences was investigated by using data from 184 patients with breast cancer with measurable recurrences. For conduction of this examination, the detection processes of both the primary tumor and the recurrence were explored. The probability of detection of a recurrence per unit time was found to be nearly proportional to the tumor's diameter. Approximately 60,000 cells initiated the recurrence, and the distribution of doubling times of the recurrences was exponential, with a mean of 2.1 months. The probability of detection of the primary tumor per unit time was approximately proportional to its volume. The distribution of doubling times of primary tumors was nearly exponential; from other evidence, we inferred that the mean doubling time was also close to 2.1 months. Several techniques to measure growth rate agreement between the primary and recurrent tumors within individuals were developed, and all of them yielded the result that the growth rates are nearly unrelated.

Management of locoregional recurrent breast cancer.

The influence of radiation and/or chemotherapy on locoregional tumor control and survival in patients treated for recurrent breast cancer after radical or modified radical mastectomy is retrospectively evaluated in 164 patients treated between 1972 and 1983 at the University of Texas M. D. Anderson Hospital. Treatment consisted of radiation alone in 57 patients, chemotherapy alone in 50 patients, and a combination of radiation and chemotherapy in 57 patients. Important differences in the composition of these three groups include a preponderance of postmenopausal women (44% vs. 32%) and more patients with four or more positive axillary nodes at the time of initial mastectomy (32% vs. 18%) in the radiotherapy group. Locoregional control of recurrent cancer was achieved in 65% of patients with radiotherapy compared to 46% of patients with chemotherapy (P = 0.049) and 67% with chemotherapy and radiotherapy. The addition of chemotherapy produced a trend toward improved disease-free survival rates. The two prognostic factors affecting tumor control and survival in this study are the tumor burden of the recurrence and the histologic axillary node status at the time of the initial mastectomy.

Tumor volume, nodal status, and metastasis in breast cancer in women.

The relationship between primary tumor volume at detection, number of positive nodes, and probability of and time until first distant metastasis was examined for a group of 2,663 women with breast cancer. Time until metastasis was shown to decrease and probability of metastasis to increase as tumor volume and number of nodes increased. Either factor remained significant after correction for the other. Simple proportional hazards models were shown to be inadequate to describe the data. Graphic techniques were used to obtain nonparametric estimates of the forms of the relationships between tumor volume, nodal status, and the time course of the occurrence of metastasis. A simple calculation demonstrated that the average contribution per cell to the probability of metastasis decreased with increasing volume.

Radiation therapy and breast cancer. Past, present, and future.

After radical mastectomy, postoperative irradiation unquestionably diminishes the incidence of local-regional failures, and there are series in which the survival rates are improved for a subset of patients. The comparative survival rates shown in Table 6 suggest that adjuvant postoperative irradiation produces survival benefits. For more advanced tumors, simple mastectomy and axillary dissection with chemotherapy and irradiation is effective, with the optimal sequence still to be determined. In selected patients, tumorectomy and irradiation produce survival rates equivalent to radical mastectomy with very satisfactory cosmetic results. In all situations, gross masses in the breast and axilla should be removed leaving for irradiation only subclinical disease that is controlled with doses that do not produce significant sequelae.

Results of irradiation in the treatment of locoregional breast cancer recurrence.

A retrospective review is presented of 255 patients with chest wall and/or regional nodal recurrent breast cancer treated between January 1956 through December 1981 at the University of Texas M. D. Anderson Hospital; 61 patients had such massive or diffuse disease that only palliative irradiation was given, and 194 patients were treated with curative intent and form the basis of this report. All patients treated with radical irradiation received greater than or equal to 4500 rad, and 65% of the patients received boost therapy through reduced fields. Thirty-two percent of patients were treated only to a single recurrent site, 11% of two sites, and 57% to the chest wall and regional nodes. Failure to control recurrent disease within or on the border of the irradiated field occurred in 27% of patients. Of 62 patients treated to the local recurrence site, 27% had further recurrences in adjacent unirradiated sites. The patients with the greatest success for tumor control (78%) and survival at 5 years (48% disease-free) are those patients with histologically negative nodes at time of mastectomy and a single chest wall recurrence. Possible prognostic factors are discussed: initial clinical stage, age of the patient, axillary histology at the time of mastectomy, disease-free interval between mastectomy and recurrence, number and size of recurrences, and prior chest wall recurrence.

Local regional effectiveness of surgery and radiation therapy in the treatment of breast cancer.

Although gross tumor can be controlled with high doses of radiation therapy, control is achieved at the expense of severe radiation sequelae. In order to improve tumor control with minimum complications, the field of treatment should contain only subclinical disease. This article reviews the successful combination of surgery for the removal of gross cancer and radiation of moderate dose for the treatment of subclinical disease in patients with breast cancer. In patients with clinically favorable and operable disease, the combination of a radical or modified radical mastectomy and postoperative radiation therapy of 5000 rad to the peripheral lymphatics and chest wall can secure 90% of the treated areas. For patients with locally and regionally advanced breast cancer, the combination of a simple mastectomy and dissection of the lateral axilla followed by postoperative irradiation of 5000 rad in 5 weeks to the chest wall, axilla, and peripheral lymphatic areas will control more than 85% of the patients treated as compared with approximately 70% control when surgery or radiotherapy alone is used, even with chemotherapy. Yet another clinical application of the subclinical disease concept is the successful combination of conservation surgery (whether segmental mastectomy, quadrantectomy, or wide excision) for gross tumor in the breast and axilla and irradiation for residual microscopic and multiple foci of tumor, yielding more than 90% control of locoregional disease with survival rates equal to those patients treated with radical or modified radical mastectomy. Results of multiple clinical trials and reported series are reviewed.