Pan-Asian adapted ESMO Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with early breast cancer.

The European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with early breast cancer were updated and published online in 2023, and adapted, according to previously established standard methodology, to produce the Pan-Asian adapted (PAGA) ESMO consensus guidelines for the management of Asian patients with early breast cancer. The adapted guidelines presented in this manuscript represent the consensus opinions reached by a panel of Asian experts in the treatment of patients with breast cancer representing the oncological societies of China (CSCO), Indonesia (ISHMO), India (ISMPO), Japan (JSMO), Korea (KSMO), Malaysia (MOS), the Philippines (PSMO), Singapore (SSO), Taiwan (TOS) and Thailand (TSCO), co-ordinated by ESMO and KSMO. The voting was based on scientific evidence and was independent of the current treatment practices, drug access restrictions and reimbursement decisions in the different Asian regions represented by the 10 oncological societies. The latter are discussed separately in the manuscript. The aim is to provide guidance for the optimisation and harmonisation of the management of patients with early breast cancer across the different regions of Asia, drawing on the evidence provided by both Western and Asian trials, whilst respecting the differences in screening practices, molecular profiling, as well as the age and stage at presentation. Attention is drawn to the disparity in the drug approvals and reimbursement strategies, between the different regions of Asia.

Hypoalbuminaemia as a Marker of Severity of Patients of Community Acquired Pneumonia.

Community-acquired pneumonia (CAP) is a common presentation with an acute infection of the pulmonary parenchyma occurring in the community level. Despite the availability of potent antibiotics, it remains as a serious illness with significant morbidity and mortality in both developed and developing countries. This study was undertaken to determine the relation between serum Albumin and severity of CAP. This was a cross sectional descriptive study which was carried out in the Department of Medicine of Mymensingh Medical College Hospital (MMCH), Bangladesh from July 2019 to December 2019. The sample size was 67. Purposive sampling technique was employed. Patients of community acquired pneumonia (CAP), aged ≥14 years of both sex with recently developed radiological pulmonary shadowing with compatible clinical symptoms and signs were included. Patients who were chronically immunosuppressed, with chronic starvation, advanced liver disease or chronic kidney disease with or without receiving haemodialysis were excluded. Data analysis was done by SPSS software for Windows (version 23.0). The mean age 65.7±15.3 years, majority 13(19.4%) patients had chronic lung disease, 12(17.9%) had diabetes mellitus, 9(13.4%) had heart failure, 6(9.0%) had cerebrovascular disease, 6(9.0%) had neoplastic disease and 5(7.5%) had chronic renal failure. Majority 22(32.8%) patients had CURB-65 score 3, out of which 12(54.5%) had albumin level <20g/l, 9(40.9%) had albumin level 20.0-24.9g/l and 1(4.5%) had albumin level 25-29g/l. 17(25.4%) had score 4-5 out of which 10(58.8%) had albumin level <20g/l and 7(41.2%) had albumin level 20.0-24.9g/l, 15(22.4%) had score 2 and 13(19.4%) had score 0-1. Negative significant correction (r=-0.782; p=0.001) was found between CURB-65 score and albumin level. Significant number of patients with severe CAP show low serum albumin level at admission which is statistically significant when compared with CURB-65 score. Thus hypoalbuminaemia may be a good marker of severity of patients with CAP.

Intraoperative high-dose-rate brachytherapy: An American Brachytherapy Society consensus report.

PURPOSE: This report presents recommendations from the American Brachytherapy Society for the use of intraoperative high-dose-rate (IOHDR) brachytherapy. METHODS AND MATERIALS: Members of the American Brachytherapy Society with expertise in IOHDR formulated this document based on their clinical experience and a review of the literature. This report covers the use of IOHDR in colorectal cancer, soft tissue sarcoma, gynecologic cancers, head and neck cancers, and pediatric cancers. This report does not cover intraoperative brachytherapy for breast cancer. Details about treatment planning and delivery are emphasized so this document can serve as a guide to practices implementing this technique. RESULTS: IOHDR brachytherapy is generally most beneficial for patients with either close or positive margins and/or recurrent disease in a previous resection bed or previously irradiated area. IOHDR brachytherapy requires a well-coordinated multidisciplinary team. IOHDR brachytherapy is recommended in the treatment of both recurrent and primary locally advanced disease for colorectal and gynecologic malignancies, soft tissue sarcoma, and selected head and neck and pediatric malignancies. Other techniques such as perioperative fractionated brachytherapy are also acceptable in many cases with some advantages and disadvantages compared to IOHDR. CONCLUSIONS: IOHDR brachytherapy is a specialized technique in radiation therapy with unique properties and advantages in cancer control. Special considerations for treatment planning and delivery are outlined herein.

Development of fluorescent peptide substrates and assays for the key autophagy-initiating cysteine protease enzyme, ATG4B.

An efficient assay for monitoring the activity of the key autophagy-initiating enzyme ATG4B based on a small peptide substrate has been developed. A number of putative small fluorogenic peptide substrates were prepared and evaluated and optimized compounds showed reasonable rates of cleavage but required high enzyme concentrations which limited their value. A modified peptide substrate incorporating a less sterically demanding self-immolative element was designed and synthesized and was shown to have enhanced properties useful for evaluating inhibitors of ATG4B. Substrate cleavage was readily monitored and was linear for up to 4h but enzyme concentrations of about ten-fold higher were required compared to assays using protein substrate LC3 or analogs thereof (such as FRET-LC3). Several known inhibitors of ATG4B were evaluated using the small peptide substrate and gave IC50 values 3-7 fold higher than previously obtained values using the FRET-LC3 substrate.

Development of fluorescent substrates and assays for the key autophagy-related cysteine protease enzyme, ATG4B.

The cysteine protease ATG4B plays a role in key steps of the autophagy process and is of interest as a potential therapeutic target. At an early step, ATG4B cleaves proLC3 isoforms to form LC3-I for subsequent lipidation to form LC3-II and autophagosome membrane insertion. ATG4B also cleaves phosphatidylethanolamine (PE) from LC3-II to regenerate LC3-I, enabling its recycling for further membrane biogenesis. Here, we report several novel assays for monitoring the enzymatic activity of ATG4B. An assay based on mass spectrometric analysis and quantification of cleavage of the substrate protein LC3-B was developed and, while useful for mechanistic studies, was not suitable for high throughput screening (HTS). A doubly fluorescent fluorescence resonance energy transfer (FRET) ligand YFP-LC3B-EmGFP (FRET-LC3) was constructed and shown to be an excellent substrate for ATG4B with rates of cleavage similar to that for LC3B itself. A HTS assay to identify candidate inhibitors of ATG4B utilizing FRET-LC3 as a substrate was developed and validated with a satisfactory Z' factor and high signal-to-noise ratio suitable for screening small molecule libraries. Pilot screens of the 1,280-member library of pharmacologically active compounds (LOPAC(™)) and a 3,481-member library of known drugs (KD2) gave hit rates of 0.6% and 0.5% respectively, and subsequent titrations confirmed ATG4B inhibitory activity for three compounds, both in the FRET and mass spectrometry assays. The FRET- and mass spectrometry-based assays we have developed will allow for both HTS for inhibitors of ATG4B and mechanistic approaches to study inhibition of a major component of the autophagy pathway.

Activation of a Gq-coupled membrane estrogen receptor rapidly attenuates α2-adrenoceptor-induced antinociception via an ERK I/II-dependent, non-genomic mechanism in the female rat.

Though sex differences in pain and analgesia are known, underlying mechanisms remain elusive. This study addresses the selective contribution of membrane estrogen receptors (mERs) and mER-initiated non-genomic signaling mechanisms in our previously reported estrogen-induced attenuation of α2-adrenoceptor-mediated antinociception. By selectively targeting spinal mERs in ovariectomized female rats using ß-estradiol 6-(O-carboxy-methyl)oxime bovine serum albumin (E2BSA) (membrane impermeant estradiol analog), and ERα selective agonist 4,4',4″-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol (PPT), ERß selective agonist 2,3-bis(4-hydroxyphenyl)-propionitrile (DPN), G-protein-coupled estrogen receptor 30 (GPR30) agonist G1 and Gq-coupled mER (Gq-mER) agonist STX, we provide strong evidence that Gq-mER activation may solely contribute to suppressing clonidine (an α2-adrenoceptor agonist)-induced antinociception, using the nociceptive tail-flick test. Increased tail-flick latencies (TFLs) by intrathecal (i.t.) clonidine were not significantly altered by i.t. PPT, DPN, or G1. In contrast, E2BSA or STX rapidly and dose-dependently attenuated clonidine-induced increase in TFL. ICI 182,780, the ER antagonist, blocked this effect. Consistent with findings with the lack of effect of ERα and ERß agonists that modulate receptor-regulated transcription, inhibition of de novo protein synthesis using anisomycin also failed to alter the effect of E2BSA or STX, arguing against a contribution of genomic mechanisms. Immunoblotting of spinal tissue revealed that mER activation increased levels of phosphorylated extracellular signal-regulated kinase (ERK) but not of protein kinase A (PKA) or C (PKC). In vivo inhibition of ERK with U0126 blocked the effect of STX and restored clonidine antinociception. Although estrogen-induced delayed genomic mechanisms may still exist, data presented here indicate that Gq-mER may solely mediate estradiol-induced attenuation of clonidine antinociception via a rapid, reversible, and ERK-dependent, non-genomic mechanism, suggesting that Gq-mER blockade might provide improved analgesia in females.

Targeting MDM2-p53 interaction for cancer therapy: are we there yet?

Inactivation of the tumor suppressor p53 and/or overexpression of the oncogene MDM2 frequently occur in human cancers, and are associated with poor prognosis, advanced forms of the disease, and chemoresistance. MDM2, the major negative regulator of p53, induces p53 degradation and inactivates its tumor suppressing activity. In turn, p53 regulates MDM2 expression. This MDM2-p53 negative feedback loop has been widely studied and presents an attractive target for cancer therapy, with a few of the inhibitors of this interaction already having advanced into clinical trials. Additionally, there is an increasing interest in understanding MDM2's p53-independent activities in carcinogenesis and cancer progression, which may also have implications for cancer therapy. This review aims to highlight the various roles that the MDM2-p53 interaction plays in cancer, the p53 independent oncogenic activities of MDM2 and the various strategies that may be used to target MDM2 and the MDM2-p53 interaction. We will summarize the major preclinical and clinical evidences of MDM2 inhibitors for human cancer treatment and make suggestions to further improve efficacy and safety of this interesting class of cancer therapeutics.

Activation of membrane estrogen receptors attenuates opioid receptor-like1 receptor-mediated antinociception via an ERK-dependent non-genomic mechanism.

To our knowledge, the present data are the first to demonstrate that activation of membrane estrogen receptors (mERs) abolishes opioid receptor-like 1 (ORL1) receptor-mediated analgesia via extracellular signal-regulated kinase (ERK)-dependent non-genomic mechanisms. Estrogen was shown previously to both attenuate ORL1-mediated antinociception and down-regulate the ORL1 gene expression. The present study investigated whether non-genomic mechanisms contribute to estrogen-induced attenuation of ORL1-mediated antinociception by the mERs GPR30, Gq-coupled mER, ERα, and ERß. E2BSA [ß-estradiol-6-(O-carboxymethyl)oxime: bovine serum albumin] (0.5mM), a membrane impermeant analog of estradiol, injected intrathecally immediately prior to orphanin FQ (OFQ;10 nmol), the endogenous ligand for the ORL1 receptor, abolished OFQ's antinociceptive effect in both male and ovariectomized (OVX) female rats, assessed using the heat-induced tail-flick assay. This effect was not altered by protein synthesis inhibitor, anisomycin (125 µg), given intrathecally 15 min prior to E2BSA and OFQ. Intrathecal application of selective receptor agonists permitted the relative contributions of various estrogen receptors in mediating this blockade of the antinociceptive response of OFQ. Activation of GPR30, Gq-mER, ERα, but not ERß abolished ORL1-mediated antinociception in males and OVX females. E2BSA produced a parallel and significant increase in the phosphorylation of ERK 2 only in OVX females, and pre-treatment with MEK/ERK 1/2 inhibitor, U0126 (10 µg), blocked the mER-mediated abolition of ORL1-mediated antinociception in OVX females. Taken together, the data are consistent with the interpretations that mER activation attenuates ORL1-mediated antinociception through a non-genomic, ERK 2-dependent mechanism in females.

Natural product MDM2 inhibitors: anticancer activity and mechanisms of action.

The mdm2 oncogene has recently been suggested to be a valuable target for cancer therapy and prevention. Overexpression of mdm2 is often seen in various human cancers and correlates with high-grade, late-stage, and more treatment-resistant tumors. The MDM2-p53 auto-regulatory loop has been extensively investigated and is an attractive cancer target, which indeed has been the main focus of anti-MDM2 drug discovery. Much effort has been expended in the development of small molecule MDM2 antagonists targeting the MDM2-p53 interaction, and a few of these have advanced into clinical trials. However, MDM2 exerts its oncogenic activity through both p53-dependent and -independent mechanisms. Recently, there is an increasing interest in identifying natural MDM2 inhibitors; some of them have been shown to decrease MDM2 expression and activity in vitro and in vivo. These identified natural MDM2 inhibitors include a plethora of diverse chemical frameworks, ranging from flavonoids, steroids, and sesquiterpenes to alkaloids. In addition to a brief review of synthetic MDM2 inhibitors, this review focuses on natural product MDM2 inhibitors, summarizing their biological activities in vitro and in vivo and the underlying molecular mechanisms of action, targeting MDM2 itself, regulators of MDM2, and/or the MDM2-p53 interaction. These MDM2 inhibitors can be used alone or in combination with conventional treatments, improving the prospects for cancer therapy and prevention. Their complex and unique molecular architectures may provide a stimulus for developing synthetic analogs in the future.

Management of primary and metastatic triple negative breast cancer: perceptions of oncologists from India.

BACKGROUND: In order to document the understanding of current evidence for the management of triple negative breast cancer and application of this knowledge in daily practice, we conducted an interactive survey of practicing Indian oncologists. MATERIALS AND METHODS: A core group of academic oncologists devised two hypothetical triple negative cases (metastatic and early breast cancer, respectively) and multiple choice options under different clinical circumstances. The respondents were practicing oncologists in different Indian cities who participated in either an online survey or a meeting. The participants electronically chose their preferred option based on their everyday practice. RESULTS: A total of 152 oncologists participated. Just over half (53.8%) preferred taxane based chemotherapy as first-line chemotherapy in the metastatic setting. In the adjuvant setting, a taxane regimen was chosen by 61%. Over half of respondents (52.6%) underestimated the baseline survival of a patient with node positive triple-negative tumor and 18.9% overestimated this survival compared to the estimate of the Adjuvant! program. DISCUSSION: This data offers insight into the perceptions and practice of a diverse cross-section of practicing oncologists in India with respect to their therapeutic choices in metastatic and adjuvant settings in triple negative breast cancer.

Optimising management of cancer related anemia.

This review article provides the current recommendations and evidence for the correct management of anemia in cancer patients. The various options available include transfusions, iron and erythropoiesis stimulation. The indications, pros and cons of each option are discussed.

Review: molecular pathogenesis of blood-brain barrier breakdown in acute brain injury.

Historically, the blood-brain barrier (BBB) was considered to be at the level of cerebral endothelium. Currently, the interaction of endothelium with other components of the vessel wall and with neurones and glial cells is considered to constitute a functional unit, termed the neurovascular unit that maintains cerebral homeostasis in steady states and brain injury. The emphasis of this review is on cerebral endothelium, the best-studied component of the neurovascular unit, and its permeability mechanisms in health and acute brain injury. Major advances have been made in unravelling the molecular structure of caveolae and tight junctions, both of which are components of the structural barrier to the entry of plasma proteins into brain. Time course studies suggest that caveolar changes precede junctional changes in acute brain injury. Additional factors modulating BBB permeability in acute brain injury are matrix metalloproteinases-2 and 9 and angiogenic factors, the most notable being vascular endothelial growth factor-A and angiopoietins (Ang) 1 and 2. Vascular endothelial growth factor-A and Ang2 have emerged as potent inducers of BBB breakdown while Ang1 is a potent anti-leakage factor. These factors have the potential to modulate permeability in acute brain injury and this is an area of ongoing research. Overall, a combination of haemodynamic, structural and molecular alterations affecting brain endothelium results in BBB breakdown in acute brain injury.

Prevalence and nature of anaemia in a prospective, population-based sample of people with diabetes: Teesside anaemia in diabetes (TAD) study.

AIMS: Anaemia occurs in 25% of people attending hospital diabetes clinics, but this may not be representative of all people with diabetes. We aimed to determine the prevalence of anaemia in a prospective population-based sample stratified by estimated glomerular filtration rate (eGFR) using the 4-point Modification of Diet in Renal Disease (MDRD) formula. METHODS: All 7331 patients on our district register were stratified by eGFR. Seven hundred and thirty were approached by letter on two occasions. Two hundred and thirty-four (32%) returned questionnaires and blood samples. Responders (R), non-responders (NR) and the whole cohort (C) were similar: mean +/- sd age R 61.7 +/- 12.7 years; NR 61.3 +/- 15.1 years; C 61.8 +/- 14.2 years; diabetes duration R 8.8 +/- 8.6 years; NR 8.2 +/- 7.9 years; C 7.5 +/- 7.8 years, Type 1 diabetes R 10.1%, NR 10.8%, C 9.4%. Anaemia was defined using World Health Organization criteria: haemoglobin < 13 g/dl for men, < 12 g/dl for women. RESULTS: Previously undiagnosed anaemia was present in 15% of the whole group, 36% with eGFR < 60 ml/min per 1.73 m(2) and 9% of those with eGFR > 60 ml/min per 1.73 m(2). Anaemia was as a result of erythropoietin deficiency in 34%, abnormal haematinics in 40% and was unexplained in 26% of patients. Five per cent of the patients had anaemia below the treatment threshold of 11 g/dl. CONCLUSIONS: The prevalence of unrecognized anaemia in population-based cohorts is lower than that in hospital-based studies. Current clinical surveillance in the UK is failing to detect anaemia in stage 3-5 chronic kidney disease (eGFR < 60 ml/min per 1.73 m(2)) and current guidelines will not detect 9% of diabetic patients with anaemia and an eGFR > 60 ml/min per 1.73 m(2).

Expression of endothelial phosphorylated caveolin-1 is increased in brain injury.

AIMS: Increased endothelial caveolae leading to transcytosis of plasma proteins is associated with blood-brain barrier (BBB) breakdown and cerebral oedema in brain injury. Increased expression of caveolin-1alpha (Cav-1), an integral caveolar membrane protein, was reported in endothelium of arterioles and veins with BBB breakdown to fibronectin post injury. In this study the phosphorylation state of Cav-1 and its association with BBB breakdown was determined in the rat cortical cold injury model over a period of days 0.5-6 post lesion. METHODS: Expression of phosphorylated Cav-1 was determined by immunoblotting and dual labelling immunofluorescence for phosphorylated caveolin-1 and fibronectin, a marker of BBB breakdown. A phospho-specific monoclonal antibody that selectively recognizes only tyrosine 14-phosphorylated Cav-1 (PY14Cav-1) was used. RESULTS: Immunoblots showed constitutive expression of PY14Cav-1 in cortex of control rats and a significant increase in PY14Cav-1 expression at the lesion site up to day 4 post lesion. PY14Cav-1 immunostaining was observed in the endothelium of lesion vessels at days 0.5-4 post lesion, in neutrophils at days 0.5 and 2 and in macrophages at day 6 post lesion. Dual labelling showed that 100% of vessels with BBB breakdown to fibronectin showed endothelial PY14Cav-1 on day 0.5, the percentage decreasing to 62% on day 4. On day 6, none of the vessels showed endothelial phosphorylated Cav-1. CONCLUSIONS: The presence of phosphorylated Cav-1 in endothelium of vessels showing BBB breakdown suggests that phosphorylated Cav-1 signalling may be one of the factors associated with early BBB breakdown and brain oedema in brain injury.

A phase II study of sequential neoadjuvant gemcitabine plus doxorubicin followed by gemcitabine plus cisplatin in patients with operable breast cancer: prediction of response using molecular profiling.

This study examined the pathological complete response (pCR) rate and safety of sequential gemcitabine-based combinations in breast cancer. We also examined gene expression profiles from tumour biopsies to identify biomarkers predictive of response. Indian women with large or locally advanced breast cancer received 4 cycles of gemcitabine 1200 mg m(-2) plus doxorubicin 60 mg m(-2) (Gem+Dox), then 4 cycles of gemcitabine 1000 mg m(-2) plus cisplatin 70 mg m(-2) (Gem+Cis), and surgery. Three alternate dosing sequences were used during cycle 1 to examine dynamic changes in molecular profiles. Of 65 women treated, 13 (24.5% of 53 patients with surgery) had a pCR and 22 (33.8%) had a complete clinical response. Patients administered Gem d1, 8 and Dox d2 in cycle 1 (20 of 65) reported more toxicities, with G3/4 neutropenic infection/febrile neutropenia (7 of 20) as the most common cycle-1 event. Four drug-related deaths occurred. In 46 of 65 patients, 10-fold cross validated supervised analyses identified gene expression patterns that predicted with >or=73% accuracy (1) clinical complete response after eight cycles, (2) overall clinical complete response, and (3) pCR. This regimen shows strong activity. Patients receiving Gem d1, 8 and Dox d2 experienced unacceptable toxicity, whereas patients on other sequences had manageable safety profiles. Gene expression patterns may predict benefit from gemcitabine-containing neoadjuvant therapy.

Sex-specific modulation of spinal nociception by alpha2-adrenoceptors: differential regulation by estrogen and testosterone.

Sex-related differences in antinociception produced by the activation of alpha(2)-adrenoceptors (alpha(2)-ARs) have been reported, however, the precise role of gonadal steroids is still unknown. Hence, we hypothesized that estrogen and testosterone modulate antinociceptive effects of clonidine (an alpha(2)-AR agonist) on N-methyl-D-aspartate- (NMDA) and heat-induced spinal nociception. We also investigated whether estrogen or testosterone alters the expression of alpha(2A)-adrenoceptors in the spinal cord. Sprague-Dawley (SD) rats were implanted with PE10 cannulae in the intrathecal space of the lumbosacral spinal cord and divided into male, proestrous and diestrous female, ovariectomized (OVX), estradiol-treated OVX (OVX+E), castrated male (GDX), testosterone (GDX+T) and estradiol-treated castrated male (GDX+E) groups. Clonidine dose-dependently inhibited NMDA-induced scratching behavior in the male and OVX groups but to a significantly lesser extent in the OVX+E group. It also increased the tail withdrawal latency in the male, OVX, diestrous and GDX+T groups but not in the OVX+E, proestrous, GDX and GDX+E groups. Levels of alpha(2A)-AR mRNA were significantly higher in the OVX, estradiol-treated OVX, GDX and GDX+E animals. In contrast, alpha(2A)-AR protein levels were higher in estradiol-treated OVX, GDX, GDX+T and GDX+E animals as compared with the male. Indeed, no correlations were observed between changes in the mRNA or protein levels of alpha(2A)-AR and behavioral observations. These results support our hypothesis that sex-related differences in alpha(2)-AR-mediated modulation of spinal nociception are gonadal hormone-dependent: estrogen attenuates antinociceptive effects in females whereas testosterone is required for the expression of antinociception in males. In addition, results also revealed that the mechanism of action of gonadal hormones may not involve a global alternation in expression of alpha(2A)-AR in the spinal cord. Estrogen-induced attenuation of alpha(2)-AR-mediated inhibition of nociception could contribute to the higher prevalence of pain syndromes in women.

Transbronchial decompression of emphysematous bullae: a new therapeutic approach.

Bullae are common accompaniments of chronic obstructive pulmonary disease especially emphysema. They contribute to increased lung volume and worsen the mechanical disadvantage of the inspiratory muscles by increasing the residual volume (RV) and RV/total lung capacity ratio. Thus effective decompression of a large bulla or bullae is thus important to improve the lung function of affected patients and also to provide symptomatic relief. Surgery and thoracoscopy are two commonly performed procedures used to treat bullae. Although bronchoscopic lung volume reduction has been successfully accomplished for emphysema, isolated decompression of bullae bronchoscopically has not been tried to date. A large emphysematous bulla in the left lower lobe of a surgically unfit patient was bronchoscopically punctured with a transbronchial aspiration needle; the position of the needle inside the bulla was confirmed and the air from the bulla was aspirated slowly to allow collapse. Finally, some autologous blood was instilled into the bulla before the needle was withdrawn. The patient had immediate and sustained symptomatic relief with significant improvement in lung function. Bronchoscopic transbronchial decompression of emphysematous bullae can be an effective therapeutic option and warrants further investigation.

Effects of seed migration on post-implant dosimetry of prostate brachytherapy.

Brachytherapy using permanent seed implants has been an effective treatment for prostate cancer. However, seeds will migrate after implant, thus making the evaluation of post-implant dosimetry difficult. In this study, we developed a computer program to simulate seed migration and analyzed dosimetric changes due to seed migration at various migration amounts. The study was based on 14 patients treated with Pd-103 at the James Cancer Hospital. Modeling of seed migration, including direction, distance as well as day of migration, was based on clinical observations. Changes of commonly used dosimetric parameters as a function of migration amount (2, 4, 6 mm respectively), prostate size (from 20 to 90 cc), and prostate region (central vs peripheral) were studied. Change of biological outcome (tumor control probability) due to migration was also estimated. Migration reduced prostate D90 to 99+/-2% of original value in 2 mm migration, and the reduction increased to 94+/-6% in 6 mm migration. The reduction of prostate dose led to a 14% (40%) drop in the tumor control probability for 2 mm (6 mm) migration, assuming radiosensitive tumors. However, migration has less effect on a prostate implanted with a larger number of seeds. Prostate V100 was less sensitive to migration than D90 since its mean value was still 99% of original value even in 6 mm migration. Migration also showed a different effect in the peripheral region vs the central region of the prostate, where the peripheral mean dose tended to drop more significantly. Therefore, extra activity implanted in the peripheral region during pre-plan can be considered. The detrimental effects of migration were more severe in terms of increasing the dose to normal structures, as rectum V50 may be 70% higher and urethra V100 may be 50% higher in the case of 6 mm migration. Quantitative knowledge of these effects is helpful in treatment planning and post-implant evaluation.

Salvage of isolated vaginal recurrences in women with surgical stage I endometrial cancer: a multiinstitutional experience.

The objective of this study was to evaluate the treatment outcomes and risk factors of women with surgical stage I endometrial adenocarcinoma who were initially treated with surgery alone and subsequently developed isolated vaginal recurrences. Patients with surgical stage I endometrial adenocarcinoma diagnosed from 1975 to 2002 were identified from tumor registry databases at seven institutions. All patients were treated with surgery alone including a total hysterectomy, bilateral salpingo-oophorectomy, pelvic (+/- para-aortic) lymph node dissection, and peritoneal cytology and did not receive postoperative radiation therapy. Vaginal recurrences were documented histologically. Metastatic disease in the chest and abdomen was excluded by radiologic studies. Overall survival was calculated by the Kaplan-Meier method. Sixty-nine women with surgical stage I endometrial cancer with isolated vaginal recurrences were identified. Of the 69 patients, 10 (15%) were diagnosed with stage IA disease, 43 (62%) were diagnosed with stage IB disease, and 16 (23%) were diagnosed with stage IC disease. Patients diagnosed with grade 1 disease were 22 (32%), grade 2 disease were 26 (38%), and grade 3 disease were 21 (30%). Among women, 81% with isolated vaginal recurrences were salvaged with radiation therapy. The mean time to recurrence was 24 months, and the mean follow-up was 63 months. Among women, 18% died from subsequent recurrent disease. The 5-year overall survival was 75%. The majority of isolated vaginal recurrences in women with surgical stage I endometrial cancer can be successfully salvaged with radiation therapy, further questioning the role of adjuvant therapy for patients with uterine-confined endometrial cancer at the time of initial diagnosis.