Osimertinib benefit in EGFR-mutant NSCLC patients with T790M-mutation detected by circulating tumour DNA.

Background: Approximately 50% of epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC) patients treated with EGFR tyrosine kinase inhibitors (TKIs) will acquire resistance by the T790M mutation. Osimertinib is the standard of care in this situation. The present study assesses the efficacy of osimertinib when T790M status is determined in circulating cell-free tumour DNA (ctDNA) from blood samples in progressing advanced EGFR-mutant NSCLC patients. Material and methods: ctDNA T790M mutational status was assessed by Inivata InVision™ (eTAm-Seq™) assay in 48 EGFR-mutant advanced NSCLC patients with acquired resistance to EGFR TKIs without a tissue biopsy between April 2015 and April 2016. Progressing T790M-positive NSCLC patients received osimertinib (80 mg daily). The objectives were to assess the response rate to osimertinib according to Response Evaluation Criteria in Solid Tumours (RECIST) 1.1, the progression-free survival (PFS) on osimertinib, and the percentage of T790M positive in ctDNA. Results: The ctDNA T790M mutation was detected in 50% of NSCLC patients. Among assessable patients, osimertinib gave a partial response rate of 62.5% and a stable disease rate of 37.5%. All responses were confirmed responses. After median follow up of 8 months, median PFS by RECIST criteria was not achieved (95% CI: 4-NA), with 6- and 12-months PFS of 66.7% and 52%, respectively. Conclusion(s): ctDNA from liquid biopsy can be used as a surrogate marker for T790M in tumour tissue.

Exploring human biology with N-of-1 clinical trials.

Studies on humans that exploit contemporary data-intensive, high-throughput 'omic' assay technologies, such as genomics, transcriptomics, proteomics and metabolomics, have unequivocally revealed that humans differ greatly at the molecular level. These differences, which are compounded by each individual's distinct behavioral and environmental exposures, impact individual responses to health interventions such as diet and drugs. Questions about the best way to tailor health interventions to individuals based on their nuanced genomic, physiologic, behavioral, etc. profiles have motivated the current emphasis on 'precision' medicine. This review's purpose is to describe how the design and execution of N-of-1 (or personalized) multivariate clinical trials can advance the field. Such trials focus on individual responses to health interventions from a whole-person perspective, leverage emerging health monitoring technologies, and can be used to address the most relevant questions in the precision medicine era. This includes how to validate biomarkers that may indicate appropriate activity of an intervention as well as how to identify likely beneficial interventions for an individual. We also argue that multivariate N-of-1 and aggregated N-of-1 trials are ideal vehicles for advancing biomedical and translational science in the precision medicine era since the insights gained from them can not only shed light on how to treat or prevent diseases generally, but also provide insight into how to provide real-time care to the very individuals who are seeking attention for their health concerns in the first place.

Lipophilic but not hydrophilic statins selectively induce cell death in gynaecological cancers expressing high levels of HMGCoA reductase.

Recent reports have suggested that statins induce cell death in certain epithelial cancers and that patients taking statins to reduce cholesterol levels possess lower cancer incidence. However, little is known about the mechanisms of action of different statins or the effects of these statins in gynaecological malignancies. The apoptotic potential of two lipophilic statins (lovastatin and simvastatin) and one hydrophilic statin (pravastatin) was assessed in cancer cell lines (ovarian, endometrial and cervical) and primary cultured cancerous and normal tissues. Cell viability was studied by MTS assays and apoptosis was confirmed by Western blotting of PARP and flow cytometry. The expressions of key apoptotic cascade proteins were analysed. Our results demonstrate that both lovastatin and simvastatin, but not pravastatin, selectively induced cell death in dose- and time-dependent manner in ovarian, endometrial and cervical cancers. Little or no toxicity was observed with any statin on normal cells. Lipophilic statins induced activation of caspase-8 and -9; BID cleavage, cytochrome C release and PARP cleavage. Statin-sensitive cancers expressed high levels of HMG-CoA reductase compared with resistant cultures. The effect of lipophilic statins was dependent on inhibition of enzymatic activity of HMG-CoA reductase since mevalonate pre-incubation almost completely abrogated the apoptotic effect. Moreover, the apoptotic effect involved the inhibition of synthesis of geranylgeranyl pyrophosphate rather than farnesyl pyrophosphate. In conclusion, lipophilic but not hydrophilic statins induce cell death through activation of extrinsic and intrinsic apoptotic cascades in cancerous cells from the human female genital tract, which express high levels of HMG-CoA reductase. These results promote further investigation in the use of lipophilic statins as anticancer agents in gynaecological malignancies.

Immunomodulation of innate immune responses by vasoactive intestinal peptide (VIP): its therapeutic potential in inflammatory disease.

Since the late 1970s a number of laboratories have studied the role of vasoactive intestinal peptide (VIP) in inflammation and immunity. These studies have highlighted the dramatic effect of VIP on immune cell activation and function, and studies using animal models of disease have indicated that VIP has significant therapeutic and prophylactic potential. This review will focus on the effects of VIP on innate immune cell function and discuss the therapeutic potential for VIP in inflammatory diseases of humans.

Agricultural Safety Education: Formative Assessment of a Curriculum Integration Strategy.

The purpose of this study was to assess an agricultural tractor and machinery safety curriculum for teacher training that focused on hands-on integration activities to assist with training youth in machinery safety skills. Teachers attended a single ten-hour summer training seminar hosted in Montana, South Dakota, or Utah during 2017. Teachers completed the National Tractor and Machinery Safe Operation (NSTMOP) exam to measure their existing knowledge prior to beginning the training. Upon seminar completion, teachers took an NSTMOP post-test to measure their knowledge gain of agricultural safety practices and hazard recognition associated with machinery and tractors. A total of 116 teachers completed the training. Fifty-three participants (45.7%) identified as female, and 63 (54.3%) identified as male. The average participant was 35 years old (SD = 11.3) and had 9.5 years of teaching experience (SD = 9.2). The average NSTMOP pre-test score was 35.2 out of 48 (SD = 3.3), and the average NSTMOP post-test score was 40.3 out of 48 (SD = 4.1). Participants' scores increased by ten percentage points. A paired-samples t-test was used to determine statistical significance. The difference between pre-test and post-test was significant (t(109) = 11.9, p < 0.001). Open responses indicated continuation of hands-on activities that focused on "how to teach" skills training that is relevant to the students. Teachers suggested developing new activities each year with a rotation of topics for upcoming seminars. Research is needed to determine the training's influence on the behaviors of young workers in agriculture.

Congenital disseminated neurofibromatosis type 1: a clinical and molecular case report.

Neurofibromatosis type 1 (NF1) is an autosomal dominant condition with a birth incidence of 1/3,500. Around 50% of cases are due to new mutations. The NF1 gene maps to 17q11.2 and encodes neurofibromin. NF1 is a "classical" tumor suppressor gene. Congenital disseminated NF1 is rare with just two cases previously reported. We present a deceased baby with congenital disseminated NF1 in whom we performed molecular studies. A germline mutation (R461X) in exon 10a of the NF1 gene was found. A 2 bp deletion (3508delCA) in codon 1170 of exon 21 was identified in DNA derived from some tumor tissue. Loss of heterozygosity in NF1 and TP53 was observed in other tumor samples. No microsatellite instability was observed in the tumor samples. This is the first report of molecular analysis of the NF1 locus in a patient with disseminated congenital neurofibromatosis. This case had a de novo germline mutation in NF1 and three documented somatic mutations in the NF1 and TP53 genes in tumor specimens.

A novel system for expansion and delivery of human keratinocytes for the treatment of severe cutaneous injuries using microcarriers and compressed collagen.

Cell therapy with autologous or allogeneic keratinocytes applied as a single-cell suspension is well established in clinical practice in the treatment of severe burn injuries to augment epithelial barrier restoration. Yet, the application of cell sprays can lead to significant cell loss owing to lack of adhesion of cell suspension to the wound bed. The development of a robust and controllable method of transplanting cells onto the wound bed is yet to be established. The ability to control adhesion and distribution of cells by using a cell carrier embedded in a biodegradable scaffold could significantly improve the treatment of cutaneous wounds with keratinocyte cell therapy. Several microcarrier-based systems for expanding keratinocytes already exist. A new method for expansion of human keratinocytes in a feeder-free, defined medium system on microcarriers has been developed. The cells retained their basal, proliferative phenotype after rapid expansion in a clinically relevant time-frame. The cell-laden microcarriers were further incorporated into collagen scaffolds fabricated by plastic compression. When cultured in vitro, cells continued to proliferate and migrate along the surface of the collagen scaffold. Using an in vitro wound bed model, cells were observed to form mostly single cell layers and in some areas multiple cell layers within 8 days, while retaining their basal, proliferative phenotype, indicating the suitability of this cell transplantation method to improve epithelial barrier restoration. This advanced cell expansion and delivery method for cutaneous cell therapy provides a flexible tool for use in clinical application. Copyright © 2017 John Wiley & Sons, Ltd.

Impact of postoperative radiation therapy and other perioperative factors on outcome after orthopedic stabilization of impending or pathologic fractures due to metastatic disease.

PURPOSE AND METHODS: We reviewed 64 orthopedic stabilization procedures in 60 consecutive patients diagnosed with metastatic disease to previously unirradiated femurs, acetabula, and humeri with pathologic or impending pathologic fracture. Thirty-five patients who received adjuvant postoperative radiation therapy were compared with 29 patients who were treated with surgery alone. Many potential perioperative and tumor prognostic variables were evaluated. RESULTS: On univariate analysis, surgery plus radiation therapy and prefracture functional status were the only significant predictors of patients who achieved normal use of the extremity (with or without pain) after surgery; on Cox multivariate analysis, only postoperative radiation therapy was significant (P = .02). Surgery-related factors such as use of methylmethacrylate, location of fracture, and type of surgery were not associated with improved functional status. The estimated probability of achieving normal use of the extremity (with or without pain) any time was 53% for postoperative radiation therapy versus 11.5% for surgery alone (P < .01). Second orthopedic procedures to the same site were more frequent in the group that received surgery alone. The actuarial median survival duration of the surgery-alone group was 3.3 months, compared with 12.4 months for the postoperative radiation therapy group (P = .02). CONCLUSION: While this study is limited by possible unaccountable selection biases, only postoperative radiation therapy was associated with patients regaining normal use of their extremity (with or without pain) and undergoing fewer reoperations to the same site. The improved overall survival associated with postoperative radiation therapy may represent selection bias.

Radiotherapy as initial treatment for bulky stage II testicular seminomas.

Sixteen consecutive patients with bulky stage II seminoma were treated with primary radiotherapy from 1971 to 1982. Bulky stage II seminoma was defined as either Union Internationale Contre le Cancer (UICC) stage IIC (retroperitoneal metastases greater than 5 cm) or IID (palpable retroperitoneal metastases) with no evidence of visceral or supradiaphragmatic disease. The median age was 38 years (range, 26 to 52) and the median size of retroperitoneal disease was 11.5 cm (range, 5 to 25 cm). Patients were treated with generous radiation ports (such as wide hockey-stick or whole abdomen) often followed by boosts to the sites of bulky disease. Median tumor dose was 3,235 cGy (range, 2,700 to 5,668 cGy). Mediastinal (with or without supraclavicular) prophylactic radiation was administered to 15 of the 16 patients with a median dose of 2,590 cGy (range, 1,200 to 3,700 cGy). Treatment toxicity was mild. All 16 patients achieved a complete remission (CR) with radiotherapy. Median follow-up from the time of diagnosis was 60 months, and all patients are currently disease-free. Two patients recurred after therapy but were rendered disease-free with further radiation. These two relapsing patients have remained disease-free, following initial recurrence, for 8 years. The excellent results obtained with modern imaging and radiotherapeutic techniques justify radiotherapy as the initial treatment of choice for bulky stage II seminomas.

Effect of Cations on Effective Permeability of Leaf Cuticles to Sulfuric Acid.

Many plants are exposed to prolonged episodes of anthropogenic acid precipitation with pH values of 4 or less, but there is little evidence of widespread direct damage to the plant cells. Acids appear to permeate leaf cuticle via charged pores, which act as a fixed buffer that delays but does not stop acid movement. We investigated the effect of cations on the movement of protons through astomatous isolated leaf cuticles of pear (Pyrus communis L.) and rough lemon (Citrus limon [L.] Burm. fils cv Ponderosa). Chloride salt solutions of Na, K, Ca, Cd, Mg, Gd, or Y in a diffusion apparatus were applied to the morphological inner surface of the cuticle, while the outer surface faced a large volume of pH 3 or 4 sulfuric acid. Effective permeability was calculated from the change in the pH of the inner solution as measured with a pH microelectrode. Monovalent cations caused either no change (pear) or promotion (rough lemon) of proton movement. Divalent cations reduced proton movement in a concentration-dependent manner (both species), whereas trivalent cations (rough lemon only) caused the effective permeability to decrease to near zero. Inhibition by 10 mM CaCl2 was reversed with water. The effects of these cations on the permeability of cuticles to protons was used to elucidate mechanisms by which cations can protect leaves from acid precipitation in nature.

Autism and genetics. A decade of research.

The last ten years of research on the genetics of infantile autism were critically reviewed. Epidemiologic findings have shown that autism is a rare disorder with a prevalence of two to five per 10,000, a male-female ratio of 3:1, and an association with mental retardation (66% to 75% of autistic subjects have full-scale IQ scores [70]). Autism is familial, as reflected in an empiric sibling recurrence risk of 3% and pooled monozygotic and dizygotic concordance rates of 64% and 9%, respectively, which are much greater than the population prevalence of 0.02% to 0.05%. Genetic heterogeneity is pronounced with potential genetic subgroups, including autosomal recessive inheritance, X-linked inheritance, and sporadic chromosomal anomalies. Studies of subclinical markers in autism have elucidated potential markers at various levels of phenotypic expression from the DNA to the behavioral level. Linkage and cytogenetic studies point to two chromosome regions as putative markers, 9q34 and Xq27. Results of family studies support a putative biochemical marker, low levels of plasma dopamine-beta-hydroxylase, and a putative cognitive marker, ie, normal visuospatial but low verbal functioning, in autism. The frequency of minor physical anomalies and presence or absence of mental retardation are two dimensions of the physical and behavioral phenotype that may demark etiologically distinct subgroups. Genetic heterogeneity is offered as one explanation of the observed sex difference in the prevalence of autism. Directions for potentially fruitful research should be considered.

5-Fluorouracil modulation of radiosensitivity in cultured human carcinoma cells.

We evaluated conventional pulse exposure versus continuous exposure models of 5-fluorouracil (5-FU) radiosensitization in HT-29 (human colon adenocarcinoma) and DU-145 (human prostate cancer adenocarcinoma) cell lines. Cell survival following treatment with drug and/or radiation was determined by colony formation assays. Radiation was delivered either by itself, approximately midway through a 1-hr exposure to 5-FU (10 micrograms/ml), or at various times following initiation of exposure to 5-FU (0.5 microgram/ml) present throughout the entire period of incubation. Drug concentrations were selected to approximate those achieved in vivo in humans. HT-29 cells showed a plating efficiency of 87% and similar cytotoxicity (survival reduced to 0.57-0.71) for all 5-FU conditions. The Do's of the radiation survival curves were not different for 1 hr of 5-FU exposure versus radiation alone. However, continuous exposure conditions demonstrated statistically significantly different Do's from radiation alone and pulse 5-FU exposure. DU-145 cells displayed a plating efficiency of 17% and cytotoxicities of 0.10-0.91 for the 5-FU conditions. DU-145 cells showed different radiation 5-FU interactions: 5-FU produced statistically significant changes in Do well as the differences between cell lines insofar as their radiosensitization by 5-FU underscore the caution required in extrapolating these radiobiologic models to the clinical setting.

Role of postoperative radiation therapy after stabilization of fractures caused by metastatic disease.

PURPOSE: Although orthopedic stabilization is frequently performed for pathological fractures caused by metastatic disease, no data is available to support the value of postoperative radiation therapy (S+RT) in this setting. METHODS AND MATERIALS: We reviewed 64 orthopedic stabilization procedures in 60 consecutive patients with metastatic disease to previously unirradiated weight-bearing bones with pathological or impending pathological fracture (femur 91%). Thirty-five sites that received adjuvant S+RT were compared to 29 sites that were treated with surgery alone (SA). Many potential prognostic variables were evaluated. Endpoints were: functional status (FS) of the extremity (1 = normal pain free use; 2 = normal use with pain, 3 = significantly limited use; 4 = nonfunctional extremity), subsequent orthopedic procedures to the same site, and survival following surgery. RESULTS: At the univariate level, S+RT (p = 0.02) and prefracture FS (p = 0.04) were the only significant predictors of patients achieving an FS of 1 or 2 after surgery. On multivariate analysis, only postoperative RT was significantly (p = 0.02) associated with attaining FS of 1 or 2 after surgery. The predicted probability of achieving FS 1 or 2 at any time was 53% for S+RT vs. 11.5% or SA (multiple logistic regression, p < 0.01). Evaluation of FS following surgery revealed that S+RT group had significantly better function in the 1-3, 3-6, and 6-12 month postoperative periods (chi-square, p < 0.04 for each time period). Second orthopedic procedures to the same site were more common in the SA group than the S+RT group (log rank, p = 0.03). Actuarial median survival of S group was 3.3 months compared with 12.4 months for the S+RT group (log rank, p = 0.02), confirming the beneficial association with survival shown by the multivariate Cox regression analysis (p = 0.025). CONCLUSION: Although this retrospective study is subject to possible biases, several analyses adjusting for numerous prognostic factors uniformly indicate S+RT is the most important factor in patients achieving and maintaining normal functional status (+/- pain). Further, the S+RT group was associated with fewer orthopedic procedures as well as an improved overall survival. The improved survival may be due to (a) more favorable patients being referred for RT (possible section bias), or (b) improved functional status in the S+RT group. This study quantitatively supports the benefit of postoperative RT in this setting.

Adjuvant radiotherapy in high stage transitional cell carcinoma of the renal pelvis and ureter.

This review was undertaken to assess the influence of adjuvant radiation therapy on failure patterns and survival in high stage transitional cell carcinoma of the renal pelvis or ureter. Ninety-four patients with transitional cell carcinoma of the renal pelvis or ureter were retrospectively reviewed. Twenty-six had American Joint Commission stage T3 or T4 N0/+, M0 disease and underwent curative resections (median follow-up 13.5 months, range 3-311). Local failure was defined as recurrence in the tumor bed, regional nodes, or ureteral stump. Time to recurrence and survival were calculated from the time of pathologic diagnosis. Variables associated with local failure, distant metastasis, and survival were analyzed using univariate and multivariate analysis. Seventeen received surgery only, nine received adjuvant radiation therapy (median dose 50 Gy). Local failure occurred in 9 of 17 without and 1 of 9 with adjuvant radiation therapy (p = 0.07). Actuarial 5-year local control was 34% without and 88% with adjuvant radiation therapy. Cox step-wise regression confirmed adjuvant radiation therapy (p = 0.006) and grade (p = 0.006) as significantly associated with local failure. No patients with low grade lesions suffered local failure either with or without adjuvant radiation therapy. High grade lesions had an local failure rate of 15% with and 71% without adjuvant radiation therapy. Metastatic disease occurred in 4 of 9 and 8 of 17 with and without radiation therapy. No significant factors influencing distant failure were identified. Five-year actuarial survival was 44% with and 24% without adjuvant radiation therapy. The survival differences were not statistically significant on univariate or multivariate analysis. High staged transitional cell carcinoma of the renal pelvis or ureter has a substantial local failure risk after surgery alone. Adjuvant radiation therapy markedly reduces this risk but has no impact on distant disease which occurs in approximately 50%. Effective adjuvant therapy will require effective systemic therapy in addition to adjuvant radiation therapy.

Heterogeneity of 5-fluorouracil radiosensitivity modulation in cultured mammalian cell lines.

There is ample evidence that 5-fluorouracil (5-FU) improves both local control and survival of a variety of gastrointestinal tumors when added to radiotherapy. However, the modulation of radiosensitivity by 5-FU is incompletely understood and some reports are apparently contradictory. Therefore, we have reevaluated the modulation of radiosensitivity by 5-FU in a variety of mammalian cells. HT-29 and WiDr (human colon adenocarcinoma), DU-145 (human prostate adenocarcinoma), V-79 (Chinese hamster lung fibroblast), and HeLa cell lines were maintained in exponential growth as monolayer cultures. Cell survival following treatment with drug and/or radiation was determined by colony formation assay. Radiation was delivered either alone; midway through a 1 hr exposure to 7-25 micrograms/ml 5-FU (pulse); or following initiation of 0.1-1.5 micrograms/ml 5-FU present throughout the entire incubation for assay of colony forming ability (continuous exposure). These 5-FU levels were selected to approximate those achieved in vivo in humans. The results indicate that mammalian cell lines may vary substantially insofar as modulation of their radiosensitivity by 5-FU is concerned. Radiosensitization, defined by reduction in D0, was observed for continuous exposure only in V-79, WiDr, and HT-29 cell lines, was observed for both pulse exposure and continuous exposure in DU-145, and was not present in HeLa cells. Radioenhancement, defined by reduction in n, was observed in V-79, WiDr, and HT-29 but not in the other cell lines. This effect, characterized by reduction in the shoulder portion of the curve, is naturally accompanied by a decrease of Dq. This indicates that mammalian cell lines may have different responses to radiosensitivity modulation by 5-FU. Though the cell lines may exhibit radiosensitivity by either alterations in the slope or shoulder of the cell survival curve, the mechanisms responsible for both the heterogeneity as well as the radiosensitization itself are completely unknown at this time. Insight into the mechanisms for both the heterogeneity and the radiosensitization will be important areas for further investigation.

Adjuvant radiation therapy after surgical resection of solitary brain metastasis: association with pattern of failure and survival.

We reviewed patients treated by resection of solitary cerebral metastasis at the Mayo Clinic from January 1, 1972, to December 1, 1982. Eighty-five patients rendered clinically disease-free and who received intramural follow-up after craniotomy were studied. Adjuvant whole-brain radiation therapy (WBRT) was delivered to 34, and 51 were observed after craniotomy. Pattern-of-failure analysis showed a much smaller incidence of subsequent brain relapse in the adjuvant WBRT group than in the observation group (21% versus 85%, respectively). Multivariate analysis utilizing 17 patient, tumor, and treatment characteristics showed adjuvant WBRT to have the strongest association with brain control (p less than 0.0001). The only other variable which was significant (p less than 0.01) was multilobe involvement of the metastatic lesion, which was associated with a greater likelihood of brain failure. Systemic failures were more frequent (61% versus 37%), and the proportion of patients remaining disease-free (29% versus 4%) was higher in the adjuvant group. Those patients who received adjuvant WBRT to a dose of 39 Gy or greater manifested an 11% rate of subsequent brain failure versus a 31% rate when less than 39 Gy was delivered. The median survival was longer for the adjuvant WBRT group (21 months versus 11.5 months). Multivariate analysis indicated that adjuvant WBRT was one of several variables (including female gender, long disease-free survival, and good neurologic function prior to craniotomy) significantly associated with improved survival. This study suggests that adjuvant cranial irradiation may help prevent clinical recurrence of resected metastatic intracranial disease and that improved control of intracranial disease may be associated with an improved survival in patients without clinical evidence of systemic disease at the time of craniotomy.

Radiation therapy quality control in a clinical trial of adjuvant postoperative treatment for rectal cancer.

PURPOSE: Deviations from protocol can detract from the reliability of results obtained in prospective clinical trials. In an effort to decrease the number of deviations in a prospective trial of adjuvant treatment for rectal cancer, we undertook pretreatment review of the irradiated fields. METHODS AND MATERIALS: Before initiation of radiation therapy, patients' radiation therapy fields were simulated by their radiation oncologists and films were submitted for review. The treating physicians were then informed whether their fields were in compliance with the protocol or whether any modifications were needed. RESULTS: Among the 625 patients participating in this study who received radiation therapy as a component of protocol treatment, 419 (67%) had no radiation therapy deviations, 127 (20%) had minor deviations, and 51 (8%) had major deviations; 28 (4%) could not be evaluated or did not receive protocol treatment because of circumstances beyond the treating radiation oncologist's control. The pretreatment quality control review identified major deviations in the radiation portals for 57 cases; these findings were communicated to the radiation oncologists prior to initiation of treatment, and, on final review, 40 had no deviation or only minor deviation. CONCLUSION: In the absence of pretreatment quality control review, 40 additional patients would have had major deviations from their radiation therapy protocol. On the basis of these findings, it is estimated that pretreatment quality control reduced the rate of major deviation from 15% to 8%. Pretreatment review of radiation therapy parameters is an effective method of reducing the frequency of major deviations in prospective clinical trials.

Polymorphic reticulosis limited to the upper aerodigestive tract--natural history and radiotherapeutic considerations.

Polymorphic reticulosis (PMR) is a specific clinicopathological entity which commonly presents as an aggressive, necrotizing lesion of the upper airway. It is a separate nosologic entity from Wegener's granulomatosis, though its site and aggressive nature has lead to confusion in the distinction between these two different processes. Although radiotherapy has been acknowledged as the treatment of choice for limited upper airway PMR, little data exist to guide the radiation oncologist in the practical management of this disorder. We review our single institutional experience with PMR limited to the upper airway. Thirty-four patients (24 males, 10 females) with a median age of 44 years (range 19-80 years) are presented. Symptoms of nasal obstruction were present in 94%. Systemic symptoms such as fever, night sweats, and weight loss were noted in 62% and were often striking clinically. The nasal mucosa was most frequently involved (91%), although involvement of the paranasal sinuses (47%), palate (32%), as well as, other upper airway sites was not uncommon. Perforation of involved structures was recorded in 37%. All but 1 patient were treated with primary radiotherapy. Twelve relapsed with PMR and 3 additional patients manifested diffuse histiocytic lymphoma either within or adjacent to the original treatment field. The median survival relapse in these 15 patients was only 4 months, although 25% were salvaged at 5 years post-relapse. The overwhelming majority of relapses were noted within the first 3 years following treatment. An evaluation of radiotherapy parameters indicated that a minimum dose of 42 Gy or a TDF of 70 is necessary to achieve long-term local control. Pattern of failure analysis demonstrated in-field failure as the predominant failure site, and this problem should become much less significant with implementation of proper time-dose-fractionation schemes. Marginal failure was noted in 20% as a component of eventual failure sites suggesting the need for generous treatment volumes including clinically uninvolved adjacent structures at risk, such as palate, sinuses, and nasopharynx for nasal lesions. Finally, systemic failure occurred in 25%. Although this rate may be reduced by improved local treatment measures, ultimately effective systemic chemotherapy will be required to substantially impact on these patients' survival.

Radiotherapeutic considerations in the treatment of hemangioblastomas of the central nervous system.

Twenty-seven hemangioblastomas of the central nervous system were treated at the Mayo Clinic with radiation therapy from January 1963 to August 1983. Six patients had von-Hippel Lindau syndrome, and four presented with polycythemia. The median age among the 15 males and 12 females was 48 years (range 20-68). Two clinical groups were apparent: those that received postoperative radiation therapy for clinically suspect, or microscopically positive margins (6 patients) and those who underwent therapy for gross residual disease (20 patients). One patient did not fall into either group because his initially unresectable tumor was treated with planned pre-operative radiotherapy to 40 Gy and was subsequently successfully cured by surgery. Because the combined modality approach did not allow assessment of local control with radiation alone, he was excluded from the gross residual cohort in terms of time-dose relationship analysis. The cohort with gross residual disease was particularly unfavorable as 12 of these patients had developed 17 local recurrences prior to radiation. Three had multiple lesions, and four had the von-Hippel Lindau syndrome. In-field disease control appeared to be improved when patients were treated more aggressively. Patients treated to a dose of 50 Gy manifested local control in 4/7 (57%) vs 4/12 (33%) in patients treated to less than 50 Gy. In-field local control was also better if patients received a TDF greater than 75 (local control in 66%) vs a TDF of 65-75 (local control in 22%). Actuarial analysis of in-field disease control showed more aggressive treatment improved control whether analyzed by dose level (greater than or equal to 50 Gy vs less than 50 Gy, or TDF greater than 75 vs less than 75). Four of the six patients who received radiation therapy for microscopically positive or clinically suspect margins achieved local control. Both patients manifesting in-field relapse were successfully surgically salvaged. Overall survival for the entire group of 27 patients was 85%, 58%, 58%, and 46% at 5, 10, 15, and 20 years, respectively. Recurrence-free survival was 76%, 52%, and 42% at 5, 10, and 15 years, respectively. Half of all in-field recurrences had occurred by 2 years, but the remaining half recurred from 5.6 to 14.4 years. Patients who developed in-field failure usually died from disease with a median survival of only 1.5 years, but surgical salvage was accomplished in 4/12. Hydro-myelia developed in two patients and required operation. Surveillance for systemic tumors also was important and revealed seven benign and four malignant tumors.(ABSTRACT TRUNCATED AT 400 WORDS)

Dosimetric analysis in brachytherapy of carcinoma of the cervix.

Brachytherapy plays an essential role in the definitive radiation treatment of cervical carcinoma. The dosimetry of intracavitary irradiation is complex in that the optimum doses that can be delivered are dictated not only by the volume and extent of tumor but also by the close vicinity of dose-limiting structures, such as the small and large intestines, rectum, and bladder. To facilitate understanding of the relationships between the various dosimetric parameters involved, a retrospective analysis of 50 randomly chosen intracavitary insertions with Cesium-137 in 41 patients performed at our institution between 1975 and 1985 was carried out. All 50 cases utilized Fletcher-Suit-Delcos applicators and only the insertions using three sources in the tandem and one in each of the ovoids were included in this analysis. Using the AP and lateral radiographs and the lymphatic trapezoid, the reference points were obtained and transferred digitally to the treatment planning computer, and computerized dosimetry performed. In addition to the specified reference points, points were added and modified to obtain more complete information. The doses at the specified points were normalized to the average dose at AT, a reference point 2 cm superior to external os and 2 cm lateral to the tandem, and expressed as a percentage. It was noted that the average dose at the closest bladder point was 103 +/- 41% of the dose at AT, the maximum rectal dose 77 +/- 29% of the dose at AT and the maximum small bowel dose 65 +/- 16% of that at AT. The analysis of percent contribution of various sources to different reference points revealed that the dose to point AT was equally contributed to by all sources; bladder and rectal doses were mainly contributed to by the lowermost uterine and ovoid sources. Our analysis may provide a model for optimizing brachytherapy in cervical carcinoma.