International Variation in Criteria for Internal Mammary Chain Radiotherapy.

AIMS: Evidence has emerged that internal mammary chain (IMC) radiotherapy reduces breast cancer mortality, leading to changes in treatment guidelines. This study investigated current IMC radiotherapy criteria and the percentages of patients irradiated for breast cancer in England who fulfilled them. MATERIALS AND METHODS: A systematic search was undertaken for national guidelines published in English during 2013-2018 presenting criteria for 'consideration of' or 'recommendation for' IMC radiotherapy. Patient and tumour variables were collected for patients who received breast cancer radiotherapy in England during 2012-2016. The percentages of patients fulfilling criteria stipulated in each set of guidelines were calculated. RESULTS: In total, 111 729 women were recorded as receiving adjuvant breast cancer radiotherapy in England during 2012-2016 and full data were available on 48 095 of them. Percentages of patients fulfilling IMC radiotherapy criteria in various national guidelines were: UK Royal College of Radiologists 13% (6035/48 095), UK National Institute for Health and Care Excellence 18% (8816/48 095), Germany 32% (15 646/48 095), Ireland 56% (26 846/48 095) and USA 59% (28 373/48 095). Differences between countries occurred because in Ireland and the USA, treatment may be considered in some node-negative patients, whereas in the UK, treatment is considered if at least four axillary nodes are involved or for high-risk patients with one to three positive nodes. In Germany, treatment may be considered for all node-positive patients. CONCLUSIONS: There is substantial variability between countries in criteria for consideration of IMC radiotherapy, despite guidelines being based on the same evidence. This will probably lead to large variations in practice and resource needs worldwide.

Cardiac Side-effects From Breast Cancer Radiotherapy.

Breast cancer radiotherapy reduces the risk of cancer recurrence and death. However, it usually involves some radiation exposure of the heart and analyses of randomised trials have shown that it can increase the risk of heart disease. Estimates of the absolute risks of radiation-related heart disease are needed to help oncologists plan each individual woman's treatment. The risk for an individual woman varies according to her estimated cardiac radiation dose and her background risk of ischaemic heart disease in the absence of radiotherapy. When it is known, this risk can then be compared with the absolute benefit of the radiotherapy. At present, many UK cancer centres are already giving radiotherapy with mean heart doses of less than 3 Gy and for most women the benefits of the radiotherapy will probably far outweigh the risks. Technical approaches to minimising heart dose in breast cancer radiotherapy include optimisation of beam angles, use of multileaf collimator shielding, intensity-modulated radiotherapy, treatment in a prone position, treatment in deep inspiration (including the use of breath-hold and gating techniques), proton therapy and partial breast irradiation. The multileaf collimator is suitable for many women with upper pole left breast cancers, but for women with central or lower pole cancers, breath-holding techniques are now recommended in national UK guidelines. Ongoing work aims to identify ways of irradiating pan-regional lymph nodes that are effective, involve minimal exposure of organs at risk and are feasible to plan, deliver and verify. These will probably include wide tangent-based field-in-field intensity-modulated radiotherapy or arc radiotherapy techniques in combination with deep inspiratory breath-hold, and proton beam irradiation for women who have a high predicted heart dose from intensity-modulated radiotherapy.

Estimating cardiac exposure from breast cancer radiotherapy in clinical practice.

PURPOSE: To assess the value of maximum heart distance (MHD) in predicting the dose and biologically effective dose (BED) to the heart and the left anterior descending (LAD) coronary artery for left-tangential breast or chest wall irradiation. METHODS AND MATERIALS: A total of 50 consecutive breast cancer patients given adjuvant left-tangential irradiation at a large U.K. radiotherapy center during 2006 were selected. For each patient, the following were derived using three-dimensional computed tomography (CT) planning: (1) mean dose and BED to the heart, (2) mean dose and BED to the LAD coronary artery, (3) MHD, (4) position of the CT slice showing the maximum area of the irradiated heart relative to the mid-plane slice, and (5) sternal and contralateral breast thickness (measures of body fat). RESULTS: A strong linear correlation was found between the MHD and the mean heart dose. For every 1-cm increase in MHD, the mean heart dose increased by 2.9% on average (95% confidence interval 2.5-3.3). A strong linear-quadratic relationship was seen between the MHD and the mean heart BED. The mean LAD coronary artery dose and BED were also correlated with the MHD but the associations were weaker. These relationships were not affected by body fat. The mid-plane CT slice did not give a reliable assessment of cardiac irradiation. CONCLUSION: The MHD is a reliable predictor of the mean heart dose and BED and gives an approximate estimate of the mean LAD coronary artery dose and BED. Doses predicted by the MHD could help assess the risk of radiation-induced cardiac toxicity where individual CT-based cardiac dosimetry is not possible.

Cardiac risks of breast-cancer radiotherapy: a contemporary view.

For some time, there has been compelling evidence both from randomised-controlled trials and from observational studies, that some of the breast-cancer radiotherapy regimens used in the past have led to increased risk of mortality from heart disease. There is also some evidence that the more recent regimens used in the USA are associated with lower risks than previous ones, but it is not clear whether current regimens are free from cardiac risk, especially in the light of recent evidence from the survivors of the bombings of Hiroshima and Nagasaki, in whom a clear relationship was observed between the risk of mortality from heart disease and radiation dose for doses in the range 0-4 Gy. Mortality from radiation-induced heart disease usually occurs at least a decade after irradiation. Symptomatic heart disease might have a much shorter induction period, but little information about it is available at present. Subclinical vascular abnormalities have been observed within months of irradiation, via myocardial perfusion imaging studies, but little is known about the relationship between these and later overt heart disease. At present, few data relate heart dose and other specific characteristics of breast radiotherapy to cardiac outcome. Further information on these topics is needed to enable estimation of the cardiac risk, that is likely to arise from radiotherapy regimens in current use and from those being considered for future use. Such knowledge would facilitate radiotherapy treatment planning and enable a reduction in cardiac risk while maintaining the known benefit in terms of breast cancer mortality.

Leukemic infiltration of the orbit: report of three cases and literature review.

Orbital infiltration by acute lymphoblastic leukemia is rare. The authors present 3 patients, 2 with optic nerve involvement and 1 with anterior chamber infiltration, treated by chemotherapy and radiotherapy. Two are in continuous remission at 64 and 59 months and 1 relapsed in the central nervous system 35 months after ocular relapse. Visual deterioration was prevented in two. Early diagnosis and treatment are important for preservation of vision.

Oncological aspects of breast reconstruction.

Breast reconstruction has become increasingly popular over the past 20 years. There is concern that it may mask locoregional recurrence or that immediate reconstruction may compromise adjuvant treatments. We review available evidence regarding its oncological safety. The literature consists almost entirely of single institution, small retrospective reviews with variable follow-up and varying conclusions. Most reviews suggest that breast reconstruction does not adversely affect disease-free or overall survival and that there is no significant delay in presentation with recurrent disease. Three retrospective series compared chemotherapy delivery after immediate breast reconstruction with controls having mastectomy alone. No delay in chemotherapy delivery or effect on dose intensity was demonstrated. Irradiation of a prosthetic implant has been shown to increase the rate of capsular contracture; irradiation of autogenous tissue reconstruction is usually well tolerated.

The effect of immediate breast reconstruction on adjuvant chemotherapy.

Immediate breast reconstruction is being increasingly offered to patients requiring mastectomy for breast cancer. An audit was carried out to determine whether it affected time to initiation of chemotherapy, delays during chemotherapy, percentage intended dose and need for support with antibiotics or granulocyte-colony stimulating factor. A total of 44 patients undergoing a variety of reconstructive procedures followed by chemotherapy were identified and patient records were reviewed. These were compared with a control group of 49 patients undergoing mastectomy alone and chemotherapy in the same 4-year period and institution. Patients undergoing transverse rectus abdominis myocutaneous flap reconstruction experienced an average of 5 more days delay to chemotherapy initiation than controls with the commonest reason being poor wound healing. Percentage intended dose, delays during chemotherapy and need for support with granulocyte-colony stimulating factor or antibiotics were comparable in all groups.

T-level downstaging and complete pathologic response after preoperative chemoradiation for advanced rectal cancer result in decreased recurrence and improved disease-free survival.

PURPOSE: Preoperative chemoradiation therapy is used widely in the treatment of rectal cancer. The predictive value of response to neoadjuvant remains uncertain. We retrospectively evaluated the impact of response to preoperative and, specifically, of T-level downstaging, nodal downstaging, and complete pathologic response after chemoradiation therapy on oncologic outcome of patients with locally advanced rectal cancer. METHODS: There were 88 patients with ultrasound Stage T3/T4 midrectal (n = 37) and low rectal (n = 51) cancers (63 males; mean age 62.6 years). All patients were treated by preoperative 5-fluorouracil-based chemotherapy and pelvic radiation followed by surgical resection in six weeks or longer (56 sphincter-preserving resections). RESULTS: T-level downstaging after neoadjuvant treatment was demonstrated in 36 (41 percent) of 88 patients, and complete pathologic response was observed in 16 (18 percent) of the 88. Of the 42 patients with ultrasound-positive nodes, 27 had no evidence of nodal involvement on pathologic evaluation (64 percent). The overall response rate (T-level downstaging or nodal downstaging) was 51 percent. At a median follow-up of 33 months, 86.4 percent of patients were alive. The overall recurrence rate was 10.2 percent (three patients had local and six had metastatic recurrences). Patients with T-level downstaging and complete pathologic response were characterized by significantly better disease-free survival (P = 0.03, P = 0.04) and better overall survival (P = 0.07, P = 0.08), according to Wilcoxon's test comparing Kaplan-Meier survival curves. None of the patients with complete pathologic response developed recurrence or died during the follow-up period. CONCLUSION: T-level downstaging and complete pathologic response after preoperative chemoradiation therapy followed by definitive surgical resection for advanced rectal cancer resulted in decreased recurrence and improved disease-free survival. Advanced rectal cancers that undergo T-level downstaging and complete pathologic response after chemoradiation therapy may represent subgroups that are characterized by better biologic behavior.

Functional properties of Drosophila inositol trisphosphate receptors.

The functional properties of the only inositol trisphosphate (IP(3)) receptor subtype expressed in Drosophila were examined in permeabilized S2 cells. The IP(3) receptors of S2 cells bound (1,4,5)IP(3) with high affinity (K(d)=8.5+/-1.1 nM), mediated positively co-operative Ca(2+) release from a thapsigargin-sensitive Ca(2+) store (EC(50)=75+/-4 nM, Hill coefficient=2.1+/-0.2), and they were recognized by an antiserum to a peptide conserved in all IP(3) receptor subtypes in the same way as mammalian IP(3) receptors. As with mammalian IP(3) receptors, (2,4,5)IP(3) (EC(50)=2.3+/-0.3 microM) and (4,5)IP(2) (EC(50) approx. 10 microM) were approx. 20- and 100-fold less potent than (1,4,5)IP(3). Adenophostin A, which is typically approx. 10-fold more potent than IP(3) at mammalian IP(3) receptors, was 46-fold more potent than IP(3) in S2 cells (EC(50)=1.67+/-0.07 nM). Responses to submaximal concentrations of IP(3) were quantal and IP(3)-evoked Ca(2+) release was biphasically regulated by cytosolic Ca(2+). Using rapid superfusion to examine the kinetics of IP(3)-evoked Ca(2+) release from S2 cells, we established that IP(3) (10 microM) maximally activated Drosophila IP(3) receptors within 400 ms. The activity of the receptors then slowly decayed (t(1/2)=2.03+/-0.07 s) to a stable state which had 47+/-1% of the activity of the maximally active state. We conclude that the single subtype of IP(3) receptor expressed in Drosophila has similar functional properties to mammalian IP(3) receptors and that analyses of IP(3) receptor function in this genetically tractable organism are therefore likely to contribute to understanding the roles of mammalian IP(3) receptors.

Destabilization of steroid receptors by heat shock protein 90-binding drugs: a ligand-independent approach to hormonal therapy of breast cancer.

Steroid hormone receptors have become an important target in the management of breast cancers. Despite a good initial response rate, however, most tumors become refractory to current hormonal therapies within a year of starting treatment. To address this problem, we evaluated the effects of agents that bind the molecular chaperone heat shock protein 90 (Hsp90) on estrogen receptor function in breast cancer. Unstimulated estrogen and progesterone receptors exist as multimolecular complexes consisting of the hormone-binding protein itself and several essential molecular chaperones including Hsp90. We found that interaction of the Hsp90-binding drugs geldanamycin and radicicol with the chaperone destabilizes these hormone receptors in a ligand-independent manner, leading to profound and prolonged depletion of their levels in breast cancer cells cultured in vitro. Consistent with these findings, in vivo administration of the geldanamycin derivative 17-allylaminogeldanamycin (17AAG; NSC330507) to estrogen-supplemented, tumor-bearing SCID mice resulted in marked depletion of progesterone receptor levels in both uterus and tumor. Drug administration also delayed the growth of established, hormone-responsive MCF-7 and T47D human tumor xenografts for up to 3 weeks after the initiation of therapy. We conclude that in light of their novel mechanism of anti-hormone action, consideration should be given to examining the activity of 17AAG and other Hsp90-binding agents in patients with refractory breast cancer in future clinical trials, either alone or in combination with conventional hormone antagonists.

Xylopyranoside-based agonists of D-myo-inositol 1,4,5-trisphosphate receptors: synthesis and effect of stereochemistry on biological activity.

The synthesis of a series of tetrahydrofuranyl alpha- and beta-xylopyranoside trisphosphates, designed by excision of three motifs of adenophostin A is reported. The synthetic route features improved preparations of allyl alpha-D-xylopyranoside and its 2-O-benzyl ether, and gives access to four diastereoisomeric trisphosphates, which show a range of abilities to mobilise Ca2+ from the intracellular stores of hepatocytes. A comparison of the potencies of the four trisphosphates provides useful information relating to the effects of stereochemical variation on the recognition of carbohydrate-based trisphosphates by D-myo-inositol 1,4,5-trisphosphate receptors. 1-O-[(3'S,4'R)-3-hydroxytetrahydrofuran-4-yl] alpha-D-xylopyranoside 3,4,3'-trisphosphate (8) is the most active member of the series with a potency close to Ins(1,4,5)P3; a beta-linked analogue, 1-O-[(3'R,4'S)-3-hydroxytetrahydrofuran-4-yl] beta-D-xylopyranoside 3,4,3'-trisphosphate, is ca. 20-fold weaker than Ins(1,4,5)P3, and the other compounds are much less active. While no compound attained a potency close to that of adenophostin A, we believe that 8 represents the minimal structure for potent Ca2+-releasing activity in this type of carbohydrate-based analogue.

Bicyclic analogues of D-myo-inositol 1,4,5-trisphosphate related to adenophostin A: synthesis and biological activity.

The high affinity of adenophostin A for 1D-myo-inositol 1,4,5-trisphosphate [Ins(1,4,5)P(3)] receptors may be related to an alteration in the position of its 2'-phosphate group relative to the corresponding 1-phosphate group in Ins(1,4,5)P(3). To investigate this possibility, two bicyclic trisphosphates 9 and 10, designed to explore the effect of relocating the 1-phosphate group of Ins(1,4,5)P(3) using a novel fused-ring system, were synthesized from myo-inositol. Biological evaluation of 9 and 10 at the Ins(1,4,5)P(3) receptors of hepatocytes showed that both were recognized by hepatic Ins(1,4,5)P(3) receptors and both stimulated release of Ca(2+) from intracellular stores, but they had lower affinity than Ins(1,4,5)P(3). This finding may be explained by considering the three-dimensional structures of 9 and 10 in light of recent studies on the conformation of adenophostin A.

Structural determinants of adenophostin A activity at inositol trisphosphate receptors.

Adenophostin A is the most potent known agonist of inositol 1,4,5-trisphosphate (InsP(3)) receptors. Ca(2+) release from permeabilized hepatocytes was 9.9 +/- 1.6-fold more sensitive to adenophostin A (EC(50), 14.7 +/- 2.4 nM) than to InsP(3) (145 +/- 10 nM), consistent with the greater affinity of adenophostin A for hepatic InsP(3) receptors (K(d) = 0.48 +/- 0.06 and 3.09 +/- 0.33 nM, respectively). Here, we systematically modify the structures of the glucose, ribose, and adenine moieties of adenophostin A and use Ca(2+) release and binding assays to define their contributions to high-affinity binding. Progressive trimming of the adenine of adenophostin A reduced potency, but it fell below that of InsP(3) only after complete removal of the adenine. Even after substantial modifications of the adenine (to uracil or even unrelated aromatic rings, retaining the beta-orientation), the analogs were more potent than InsP(3). The only analog with an alpha-ribosyl linkage had massively decreased potency. The 2'-phosphate on the ribose ring of adenophostin A was essential and optimally active when present on a five-membered ring in a position stereochemically equivalent to its location in adenophostin A. Xylo-adenophostin, where xylose replaces the glucose ring of adenophostin A, was only slightly less potent than adenophostin A, whereas manno-adenophostin (mannose replacing glucose) had similar potency to InsP(3). These results are consistent with the relatively minor role of the 3-hydroxyl of InsP(3) (the equivalent is absent from xylo-adenophostin) and greater role of the equatorial 6-hydroxyl (the equivalent is axial in manno-adenophostin). This is the first comprehensive analysis of all the key structural elements of adenophostin A, and it provides a working model for the design of related high-affinity ligands of InsP(3) receptors.

Dysphagia and thoracoabdominal aneurysm.

Two elderly patients who presented with gradually progressive dysphagia are described. Investigations excluded an intraluminal obstruction and showed extrinsic compression of the oesophagus by an aneurysmal aorta. Surgery was not performed and they were successfully managed with a liquid diet.

A phase I and pharmacodynamic evaluation of polyethylene glycol-conjugated L-asparaginase in patients with advanced solid tumors.

PURPOSE: To evaluate the in vitro activity of polyethylene glycol-conjugated L-asparaginase (PEG-Lasparaginase) against fresh human tumor specimens, using the human tumor clonogenic assay (HTCA), and to perform a phase I dose-escalation clinical trial of PEG-L-asparaginase. The goal of the clinical study was to determine the toxicity and optimum biologic dose of PEG-L-asparaginase based on depletion of serum L-asparagine in patients with advanced solid tumors. METHODS: A modified method for determination of serum L-asparagine is described. PEG-L-asparaginase was administered by intramuscular injection every 2 weeks to 28 patients with various types of advanced solid tumor malignancies. At least 3 patients were evaluated at each dose level: 250 IU/m2, 500 IU/m2, 1,000 IU/m2, 1,500 IU/m2, 2,000 IU/m2. RESULTS: The in vitro HTCA studies suggested good antitumor activity against malignant melanoma and multiple myeloma. Serum L-asparagine was most consistently and profoundly depleted (up to 4 weeks) in patients treated with 2,000 IU/m2. Patients receiving this dose level also showed more frequent grade 1, grade 2, and occasional grade 3 toxicities of fatigue/weakness, nausea/vomiting, and anorexia/ weight loss. Three patients developed hypersensitivity reactions, but these were not dose related. Two patients developed deep vein thromboses. We saw no episodes of clinical pancreatitis, but there were minor fluctuations of serum amylase and lipase. We saw no partial or complete responses in patients treated in this study, including 11 patients with malignant melanoma. CONCLUSIONS: We conclude that PEG-L-asparaginase is generally well tolerated in patients with advanced solid tumors, and a dosage of 2,000 IU/m2 by intramuscular injection every 2 weeks results in significant depletion of serum L-asparagine.

Rapid activation and partial inactivation of inositol trisphosphate receptors by adenophostin A.

Adenophostin A, the most potent known agonist of inositol 1,4, 5-trisphosphate (InsP(3)) receptors, stimulated (45)Ca(2+) release from the intracellular stores of permeabilized hepatocytes. The concentration of adenophostin A causing the half-maximal effect (EC(50)) was 7.1+/-0.5 nM, whereas the EC(50) for InsP(3) was 177+/-26 nM; both responses were positively co-operative. In rapid superfusion analyses of (45)Ca(2+) release from the intracellular stores of immobilized hepatocytes, maximal concentrations of adenophostin A or InsP(3) evoked indistinguishable patterns of Ca(2+) release. The Ca(2+) release evoked by both agonists peaked at the same maximal rate after about 375 ms and the activity of the receptors then decayed to a stable, partially (60%) inactivated state with a half-time (t(1/2)) of 318+/-29 ms for adenophostin A and 321+/-22 ms for InsP(3). Dissociation rates were measured by recording rates of InsP(3)-receptor channel closure after rapid removal of agonist. The rate of adenophostin A dissociation (t(1/2), 840+/-195 ms) was only 2-fold slower than that of InsP(3) (t(1/2), 436+/-48 ms). We conclude that slow dissociation of adenophostin A from InsP(3) receptors does not underlie either its high-affinity binding or the reported differences in the Ca(2+) signals evoked by InsP(3) and adenophostin A in intact cells.

Phase II evaluation of interleukin-4 in patients with non-Hodgkin's lymphoma: a Southwest Oncology Group trial.

We performed a phase II, Southwest Oncology Group (SWOG) clinical trial of recombinant human interleukin-4 (rhuIL-4) in patients with previously treated non-Hodgkin's lymphoma (NHL). We studied 18 eligible patients with low-grade and 21 patients with intermediate- or high-grade NHL. All patients had received prior chemotherapy. A protocol amendment after the first four patients reduced the frequency of s.c. rhuIL-4 administration from daily to 3 times per week at 3 microg/kg and limited the number of prior chemotherapy regimens allowed. We documented no complete or partial responses in the low-grade NHL group [0%; 95% confidence interval (CI) 0-19%]. One patient in the intermediate/high-grade NHL group developed a partial response lasting longer than 15 months (5%; 95% CI 0-24%). Median survivals for the low- and intermediate/high-grade NHL groups were 15 and 13 months, respectively. Common toxicities included: arhralgia/myalgia, fatigue/malaise/lethargy, fever, headache, nausea and rigors/chills. Cardiac toxicity, gastrointestinal ulceration and nasal congestion due to rhuIL-4 were not prominent toxicities in our patients. Our previously treated NHL patients tolerated s.c. rhuIL-4 at a dose of 3 microg/kg given 3 times per week, but objective response rarely occurred. Further evaluation of rhuIL-4 in these patient populations does not appear warranted.

Contribution of the adenine base to the activity of adenophostin A investigated using a base replacement strategy.

Syntheses of 3'-O-alpha-D-glucopyranosyl-1-beta-D-ribofuranosidoimidazole 2',3'', 4''-trisphosphate (7) and 3'-O-alpha-D-glucopyranosyl-9-beta-D-ribofuranosidopurine 2',3'',4''- trisphosphate (8), two analogues of the superpotent 1D-myo-inositol 1,4,5-trisphosphate receptor agonist adenophostin A (2), are described. 5-O-Benzyl-1, 2-O-isopropylidene-alpha-D-ribofuranose was prepared by an improved route from 1,2-O-isopropylidene-alpha-D-xylofuranose and was coupled with 3,4-di-O-acetyl-2,6-di-O-benzyl-D-glucopyranosyl dimethyl phosphite to give 3',4'-di-O-acetyl-2',5, 6'-tri-O-benzyl-3-O-alpha-D-glucopyranosyl-1, 2-O-isopropylidene-alpha-D-ribofuranose. Removal of the isopropylidene acetal and subsequent acetylation gave the central disaccharide 1,2,3',4'-tetra-O-acetyl-2',5, 6'-tri-O-benzyl-3-O-alpha-D-glucopyranosyl-D-ribofuranose. Vorbrüggen condensation with activated imidazole or purine gave the required beta-substituted derivatives which were further elaborated to 7 and 8, respectively. Radioligand binding assays to hepatic InsP(3) receptors and functional assays of Ca(2+) release from permeabilized hepatocytes gave a rank order of potency of the ligands 2 approximately 8 > 7 approximately Ins(1,4,5)P(3) indicating that the N(6)-amino group of 2 is of little importance for activity and that a minimum of a two-fused-ring nucleobase is required for activity to exceed that of Ins(1,4,5)P(3). The role of the adenine base in the activity of the adenophostins is discussed. This general method should facilitate ready access to nucleobase-modified adenophostin analogues for SAR studies.