Post-treatment mortality after definitive chemoradiotherapy versus resection for esophageal cancer.

In efforts to better characterize incidence and predictors of 30- and 90-day mortality following operative versus nonoperative approaches for locally advanced esophageal cancer (EC), we conducted a novel investigation of a large, contemporary US database. The National Cancer Database was queried for newly-diagnosed T1-3N0-1 squamous cell or adenocarcinoma receiving surgical-based therapy (esophagectomy alone or preceded by chemotherapy and/or radiotherapy) versus definitive chemoradiotherapy (dCRT). Statistics included graphing cumulative incidences of mortality before and following propensity score matching (PSM), based on age-based intervals. Cox regression determined factors independently predictive of 30- and 90-day mortality. Of 15,585 patients, 9,278 (59.5%) received surgical-based therapy and 6,307 (40.5%) underwent dCRT. In the unadjusted population, despite nonsignificant differences at 30 days (3.3% dCRT, 3.6% surgical-based), the dCRT cohort experienced higher 90-day mortality (11.0% vs. 7.5%, P < 0.001). Following PSM, however, dCRT patients experienced significantly lower 30-day mortality (P < 0.001), with nonsignificant differences at 90 days (P = 0.092). Surgical-based management yielded similar (or better) mortality as dCRT in ≤70-year-old patients; however, dCRT was associated with reduced mortality in subjects > 70 years old. In addition to the intervention group, factors predictive for 30- and 90-day mortality included age, gender, insurance status, facility type, comorbidity index, tumor location, histology, and T/N classification. In summary, surgical-based therapy for EC is associated with higher 30-day mortality, which becomes statistically similar to dCRT by 90 days. Differences between surgery and dCRT were most pronounced in patients > 70 years of age. These data may better inform shared decision-making between multidisciplinary providers and patients.

The impact of postmastectomy and regional nodal radiation after neoadjuvant chemotherapy for clinically lymph node-positive breast cancer: a National Cancer Database (NCDB) analysis.

BACKGROUND: Following neoadjuvant chemotherapy (NAC), the optimal strategies for postmastectomy radiotherapy (PMRT) and regional nodal irradiation (RNI) after breast-conserving surgery (BCS) are controversial. In this analysis, we evaluate the impact of these radiotherapy (RT) approaches for women with clinically node-positive breast cancer treated with NAC in the National Cancer Database (NCDB). PATIENTS AND METHODS: Women with cT1-3 cN1 M0 breast cancer treated with NAC were divided into four cohorts by surgery [Mastectomy (Mast) versus BCS] and post-chemotherapy pathologic nodal status (ypN0 versus ypN+). Overall survival (OS) was estimated using the Kaplan-Meier method and RT approaches were analyzed using the log-rank test, multivariate Cox models, and propensity score-matched analyses. RESULTS: From 2003 to 2011, 15 315 cases were identified including 3040 Mast-ypN0, 7243 Mast-ypN+, 2070 BCS-ypN0, and 2962 BCS-ypN+ patients. On univariate analysis, PMRT was associated with improved OS for both Mast-ypN0 (P = 0.019) and Mast-ypN+ (P < 0.001) patients. On multivariate analyses adjusted for factors including age, comorbidity score, cT stage, in-breast pathologic complete response, axillary surgery, ypN stage, estrogen receptor status and hormone therapy, PMRT remained independently associated with improved OS among Mast-ypN0 [hazard ratio (HR) = 0.729, 95% confidence interval (CI) 0.566-0.939, P = 0.015] and Mast-ypN+ patients (HR = 0.772, 95% CI 0.689-0.866, P < 0.001). No differences in OS were observed with the addition of RNI to breast RT for BCS-ypN0 or BCS-ypN+ patients. Propensity score-matched analyses demonstrated identical patterns of significance. On subset analysis, OS was improved with PMRT in each pathologic nodal subgroup (ypN0, ypN1, and ypN2-3) (all P < 0.05). CONCLUSIONS: In the largest reported analysis of RT for cN1 patients treated with NAC, PMRT was associated with improved OS for all pathologic nodal subgroups. No OS differences were observed with the addition of RNI to breast RT.

Natural history of asymptomatic gallstones: differential behaviour in male and female subjects.

OBJECTIVE: The natural history of asymptomatic (silent) gallstones has been inadequately studied. Existing information derives from studies based on oral cholecystography or relatively small sample sizes. We planned a retrospective cohort study in subjects with gallstones to determine conversion rates from asymptomatic to symptomatic. METHODS: We extracted data from computerised databases of one government hospital and two private clinics in Malaysia. Files were scrutinised to ensure that criteria for asymptomatic gallstones were fulfilled. Patients were called on telephone, further questioned to confirm that the gallstones at detection were truly asymptomatic, and asked about symptoms that were consistent with previously defined criteria for biliary colic. Appropriate ethical clearances were taken. RESULTS: 213 (112 males) patients fulfilled the criteria for asymptomatic gallstones and could be contacted. 23 (10.8%) developed pain after an average follow up interval of 4.02 years (range 0.1-11 years). Conversion rates from asymptomatic to symptomatic gallstones were high in the first two years of follow up, averaging 4.03±0.965 per year. Over time the conversion rates slowed, and by year 10 the annual conversion rate averaged only 1.38±0.29. Conversion rates were much higher for females compared to males (F:M hazard ratio 3.23, SE 1.54, p>z 0.014). The lifetime risks for conversion approached 6.15% for males, and 22.1% for females. CONCLUSION: In conclusion, asymptomatic gallstones are much more likely to convert to symptomatic in females than in males. Males in whom asymptomatic stones are discovered should be advised conservative treatment. Surgery may be preferable to conservative management if the subject is a young female.

Homozygous familial hypercholesterolemia.

We report a rare case of homozygous familial hypercholesterolemia (HoFH), a 22-year-old Malay woman who presented initially with minor soft tissue injury due to a cycling accident. She was then incidentally found to have severe xanthelasma and hypercholesterolemia (serum TC 15.3 mmol/L and LDL-C 13.9 mmol/L). She was referred to the Specialized Lipid Clinic and was diagnosed with familial hypercholesterolemia (FH) based on the Simon Broome (SB) diagnostic criteria. There was a family history of premature coronary heart disease (CHD) in that three siblings had sudden cardiac death, and of consanguineous marriage in that her parents are cousins. DNA screening of LDLR and APOB genes was done by Polymerase Chain Reaction (PCR), followed by Denaturing High Performance Liquid Chromatography (DHPLC). Homozygous mutation C255S in Exon 5 of her LDLR gene was found. There was no mutation was found in Exon 26 and Exon 29 of the APOB gene. This report is to emphasize the importance of identifying patients with FH and cascade screening through established diagnostic criteria and genetic studies in order to ensure early detection and early treatment intervention to minimize the risk of developing CHD and related complications.

Irreducible Hernia With Unusual Content.

Chronic increase in the intravesical pressure secondary to bladder outlet obstruction can lead to the formation of bladder diverticulum. Bladder diverticulum may get pulled into the hernial sac and may become a component of the hernia. Here, we report the case of an elderly male who had an unusual presentation of urinary bladder diverticulum as the content in an obstructed inguinal hernia. Upon exploration, the bladder diverticulum was released from the inguinal canal and returned to the peritoneal cavity, following which conventional hernioplasty was done. Inguinal herniation of bladder diverticulum is an uncommon condition and can be perilous during surgery if not diagnosed preoperatively.

Age, gender, and racial differences in incidence and survival in primary CNS lymphoma.

BACKGROUND: Primary central nervous system lymphoma (PCNSL) is a rare subtype of extranodal non-Hodgkin lymphoma that accounts for ~4% of newly diagnosed central nervous system (CNS) tumours. The objective of this study was to analyse the epidemiology, incidence, and outcome of these rare tumours. METHODS: Primary brain and CNS lymphoma cases were identified from the Surveillance, Epidemiology, and End Results (SEER) research data sets for the years 1980-2008 for analysis of trends in incidence and survival. SEER(*)Stat v. 7.0.4 software was used to analyse the data. RESULTS: The overall incidence rate of PCNSL was 0.47 per 100,000 person-years. The incidence was significantly higher in males compared with females, blacks aged 0-49 years at diagnosis compared with whites, and whites aged 50 years and older at diagnosis compared with blacks. After a significant decline in incidence between 1995 and 1999, incidence rates rose slightly; those aged 75+ years at diagnosis had the most dramatic increase in incidence rates over time. Five-year survival rates were significantly higher in whites compared with blacks aged 0-49 years at diagnosis, but was primarily driven by white women aged 0-49 years. CONCLUSION: There is an increase in incidence of PCNSL in the elderly, and elderly blacks have lower incidence compared with white population. Survival remains poor and is negatively dominated by factors associated with HIV infection and advanced age.

Revisions in TB programme - boon or bane? A qualitative study exploring barriers and facilitators among health care workers in private and public sector, Kerala.

BACKGROUND: Despite many serious and organized efforts worldwide, Tuberculosis (TB) remains one of the major public health concerns in many countries. India accounts for more than one quarter of global TB cases and deaths each year. India's National Tuberculosis Elimination Programme (NTEP) is the largest TB control program in the world, placing more than 100,000 patients on treatment every month. There have been so many revisions in the programme guidelines in the last 5 years. As we are gearing up for TB elimination in India, knowledge regarding the barriers is very crucial in the successful undertaking of these revised guidelines. Exploring perceptions of health care workers, both from the private and public sector will help to design appropriate strategies at the field level. OBJECTIVE: To explore the barriers and facilitators among health care workers in the implementation of revised NTEP guidelines in a selected district of central Kerala. METHODOLOGY: This qualitative study was conducted among health care workers from all levels involved in the implementation of NTEP from private and public sector. Qualitative data was collected through Focus Group Discussions (FGD) and Key Informant Interviews using a topic guide till data saturation. All discussions were audio recorded with the consent of participants. Sociogram was plotted to confirm equal participation of interviewees. A total of 4 FGDs (2 from each sector) and 12 Key informant interviews (7 from public sector and 5 from private sector) were conducted after obtaining written consent from the participants. RESULTS: Overall awareness about revisions was found to be good. However, the study identified a "Gap between planners and implementers". Frequent nature of revisions without understanding the practical difficulties in the field, additional job responsibilities, inadequate knowledge among grass root level workers/private practioners in small clinics and increased side effects were the major barriers identified. In addition to that, insufficient logistics, not enthusiastic in learning revisions, fear of losing patients, delay in communication, decreased compliance with new regimen, increased out of pocket expenditure and grey areas in the current guidelines were also adversely affecting the successful implementation At the same time, facilitators like positive attitude and commitment of health care workers, introduction of M-health technology, strong public private partnership, inclusion of costly investigations in the revised guidelines, good administrative support, financial assistance, innovative initiatives like Treatment Support Groups (TSGs) and concept of Family Directly Observed Treatment Short-Course increased the effectiveness of the programme to a large extent. CONCLUSION: The study identified gaps in knowledge, attitude and practice of revised guidelines at the field level. Gap between 'Planners and implementers could impede the successful implementation of TB Elimination programme and needs to be addressed.

Assessment of Squalor in Migrant Colonies of Thiruvalla Province of Kerala, India using Rapid Survey Technique.

BACKGROUND: Domestic squalor refers to households that are extremely cluttered, in a filthy condition, and where the accumulation of items such as personal possessions, rubbish, excrement and decomposing food creates an environment that jeopardizes the health and wellbeing of the occupant(s). In India, an estimated 258 million are migrants. They are more likely to live in squalor due to inferior socio-economic status and no permanent residence. This poses a threat to the health of the migrants and the neighbors. OBJECTIVE: To assess the squalor and morbidity pattern among the migrants of Migrant colonies in Thiruvalla using Rapid survey technique. METHODOLOGY: The state of squalor in migrant colonies was assessed by Lot Quality Assurance Sampling Methodology using the Environment Cleanliness and Clutter Scale (ECCS). The sample size for each lot/colony was '14' dwellings according to LQAS table. The details were collected from 14 inhabitants of different dwellings of the same colony. The inhabitants were selected randomly and were excluded if he belonged to the same dwelling. Fifteen colonies were randomly selected to achieve the sample size of 210 (15*14). The study was done in Tiruvalla municipality. RESULTS AND CONCLUSION: Only two colonies (n = 15) were squalor free. Majority of the dwellings (n = 210) were having an ECCS score between 13 and 15. Common ailments affecting migrants include Common cold, Skin disorders, and dental caries and gastritis. Squalor was found in most of the migrant colonies as they are living in inhuman conditions.

Increased expression of CD40 ligand on systemic lupus erythematosus lymphocytes.

The specificity of T cell help for B cell activation and differentiation is maintained by the brief expression on the T cell surface, following T cell receptor-mediated triggering, of CD40 ligand (CD40L). Interaction of T helper (Th) cell CD40L with B cell CD40 induces B cell activation, cell surface expression of activation antigens, proliferation, and initiation of immunoglobulin isotype switch. We predicted that in patients with systemic lupus erythematosus (SLE), in whom Th cell-dependent production of autoantibodies results in immune complex-mediated tissue damage, CD40L expression might be augmented, prolonged, or abnormally regulated. Baseline expression of CD40L was increased in some SLE patients studied, when compared with control subjects. While Th cells from normal subjects (n = 14) and rheumatic disease control patients (n = 9) showed maximal expression of CD40L, after in vitro activation with phorbol myristate acetate (PMA) and ionomycin, at 6 h of culture with diminished levels observed at 24 and 48 h, Th cells from SLE patients (n = 19) maintained high level cell surface expression of CD40L through 24 and 48 h of culture. The prolonged expression of CD40L was functionally significant, as 24 h-activated SLE T cells, when cocultured with target B cells, induced greater B cell surface CD80 (B7-1) expression than did 24 h-activated normal T cells. These results document impaired regulation of CD40L expression in SLE T cells and identify an important potential target for therapy in this systemic autoimmune disease.

Hemoglobin F Lódz (G gamma I 44 Ser replaced by Arg). A newly identified variant from an American infant of Polish descent.

An electrophoretically slowly migrating hemoglobin variant was identified in a neonate of Polish parents from a cord blood hemoglobin survey. Structural analysis of the gamma chain of the mutant hemoglobin, with fractionation of the tryptic peptides by means of high-performance liquid chromatography, demonstrated a substitution of serine-44 by arginine. Glycine was identified at position 136 of the gamma chain and isoleucine at position 75. Serine residue 44 appears not to be a heme contact site, but as a result of the substitution in this mutant hemoglobin, the possibility exists for formation of a salt bridge between the arginine and a heme propionate group. The infant's hematologic findings suggested the possibility of mild hemolysis, but these changes may have been due to isoimmune disease.

Urate crystal degradation for treatment of gout: a nanoparticulate combination therapy approach.

The objective of the present work was to develop polymeric nanoparticles of uricase and aceclofenac (NSAID) and to incorporate them into gel, for delivering drugs to synovial joints, for effective treatment of Gout. Nanoparticles containing uricase and aceclofenac were prepared by double emulsion solvent evaporation method and emulsion solvent evaporation, using PLGA (50:50) as carrier, respectively. Process parameters were optimized using Taguchi L4 orthogonal array and L9 array, respectively. The formulations were characterized for particle size, entrapment efficiency, surface charge, in vitro drug release, ex vivo drug permeation, and urate crystal degradation activity. The particle size and entrapment efficiency for optimized batch was found to be 228.8 nm and 81.26% for uricase nanoparticles and 288.5 nm and 85.36% for aceclofenac nanoparticles, respectively. The developed nanoparticles formulations displayed zero order and Higuchi release kinetics with non-Fickian diffusion, respectively. The in vivo studies were performed in rabbit model. Topical application of gel containing polymeric uricase nanoparticles alone and a combination of both, uricase nanoparticles and aceclofenac nanoparticles in rabbit model test groups, provided complete removal of urate crystals and inflammation within 40 and 25 days of treatment, respectively. The combination treatment therapy resulted in effective treatment of gout due to degradation of crystals and anti-inflammatory response.

Sickle cell disease and pregnancy.

Sickle cell disease refers to a group of genetic disorders characterised by the predominance of hemoglobin S. This includes sickle cell anemia (SS) sickle hemoglobin C disease (SC), sickle beta thalassemia plus (S beta + Thal), sickle beta thalassemia zero (beta zero Thal), sickle with alpha thalassemia (SS alpha Thal) and rare combinations of sickle hemoglobin with Hb D, Hb O, etc. While pregnancy does carry risk for the woman with sickle cell disease (SCD) and for the fetus, pregnancy can be well tolerated by the major genotypes. Infants born from these pregnancies may tend to be small for gestational age and undergo premature delivery. While complications for both sickle-related events and for pregnancy are seen, data to date state that women are able to complete their pregnancies successfully. Counselling, regular prenatal visits and aggressive treatment of acute events are always indicated. There is no proof that prophylactic transfusion alters the outcome of pregnancy. Transfusion therapy should be reserved for those patients with previous perinatal mortality, pre-eclampsia, acute chest syndrome, new onset neurological event, severe anemia and in preparation for surgical intervention. Thus, blood transfusion will continue to have a role in management of obstetrical and medical indications accompanied by meticulous prenatal care and early detection of complications. In addition, newborn screening should be recommended for the early detection of infants with disease.

Stem cell transplantation eliminates alloantibody in a highly sensitized patient.

Highly sensitized patients are forced to stay on transplant waiting lists for many years and ultimately may never find a donor. Peripheral blood stem cell (PBSC) transplantation may provide a strategy to decrease host alloreactivity through the production of a chimeric state. We investigated alloreactivity and chimerism in a highly sensitized 40-year-old patient with sickle cell disease who underwent a nonradiation based conditioning regimen consisting of fludarabine, ATG, and high dose melphalan, for allogeneic stem cell transplant. Host monocytes and lymphocytes became donor in origin by day 14. PRA, initially 100% pretransplant, fell to 0 by day 263. Anti-red blood cells antibody became undetectable by day 152. The use of a new nonradiation-based conditioning regimen enabled successful engraftment of allogeneic donor PBSCs and the elimination of alloantibody. As new less toxic conditioning regimens are developed, PBSC transplantation might provide a new solution to allosensitization.

Allogeneic stem cell transplantation for sickle cell disease. A study of patients' decisions.

Allogeneic stem cell transplantation is increasingly considered as a curative though risky treatment option for adults with sickle cell disease. Little is known about attitudes of adult patients and their health care providers regarding the risks and benefits of transplantation. A survey of 100 patients and their health care providers was undertaken. Assessment of risk was by a reference gamble paradigm. Comparison was made of the characteristics of those accepting substantial risk vs those not accepting risk, as well as assessment of agreement on risks recommended by health care providers and accepted by patients. Sixty-three of 100 patients were willing to accept some short-term risk of mortality in exchange for the certainty of cure. Fifteen patients were willing to accept more than 35% mortality risk. No differences in patient or disease-related variables were identified between those accepting risk and those not accepting risk. There was no agreement between the recommendations of health care providers and the risk accepted by patients. A substantial proportion of adults with sickle cell disease are interested in curative treatment, at the expense of considerable risk. The decision to accept risk is influenced by individual patient values that cannot be easily quantified and that do not correlate with the assessment of the health care provider. Given the substantial interest in curative therapy, education about and consultation for allogeneic stem cell transplantation in sickle cell patients should be encouraged.

Fludarabine-based conditioning for allogeneic transplantation in adults with sickle cell disease.

Although allogeneic transplantation can be curative for patients with sickle cell disease, the toxicity of conditioning regimens has precluded its use in adults with significant end-organ damage. Newer conditioning regimens have been developed that are less toxic and that may broaden the applicability of allogeneic transplantation in this disorder. We report two adults with end-stage sickle cell disease, who underwent allogeneic transplantation from an HLA-identical sibling donor after conditioning with fludarabine/melphalan and ATG. Both patients had been extensively transfused and one had multiple RBC antibodies. One of the patients also had end-stage renal disease, and was dialysis dependent. Engraftment occurred promptly in both patients. Both achieved 100% donor chimerism and both were free of pain crises after transplant. The first patient died of a respiratory failure related to chronic graft-versus-host disease (GVHD) on day 335 after transplantation. The second patient developed severe gastro-intestinal GVHD and TTP and died on day 147 after transplantation. Conditioning with fludarabine/melphalan and ATG followed by allogeneic stem cell transplantation resulted in prompt and reliable engraftment in adults with end-stage sickle cell disease. The incidence of severe GVHD was unacceptably high and may be related to the ethnicity of the patients or to the inflammatory state associated with pre-existing sickle cell disease.

Pregnancy in sickle cell disease: experience of the Cooperative Study of Sickle Cell Disease.

OBJECTIVE: To determine the maternal and fetal outcomes of pregnancy in women with sickle cell disease. METHODS: The subjects were part of a cohort recruited from 19 centers for a prospective study of the clinical course of sickle cell disease. Each participant was evaluated using a structured protocol in which steady-state data and information on both sickle- and non-sickle-related events were collected. The rates of antepartum and intrapartum complications were tallied for pregnancies carried to delivery. Fetal outcome was assessed according to gestational age, birth weight, and Apgar score. Differences among genotypes in event rates were assessed using Fisher exact test. Differences in gestational age and birth weight, and predictors of these outcomes, were assessed using analyses of covariance. RESULTS: Two hundred eighty-six of the 445 reported pregnancies proceeded to delivery. Non-sickle-related antepartum and intrapartum complication rates were comparable with those of African-American women who did not have sickle cell disease. One of the two deaths observed during this study was directly related to the presence of sickle cell disease. Rates of maternal morbidity from sickle cell disease were the same during pregnancy as during the nonpregnant state. Ninety-nine percent of those pregnancies carried to delivery resulted in a live birth. Twenty-one percent of the infants born to women of the SS genotype were small for gestational age (SGA). Preeclampsia and acute anemic events were identified as risk factors for SGA infants. CONCLUSIONS: Those caring for women with sickle cell disease should support them if they desire to have children.

Immune-deficient bronchiectasis associated with X-linked lymphoproliferative disease.

Bronchiectasis may occur with various congenital and acquired immunodeficiency diseases. The association of bronchiectasis and the X-linked lymphoproliferative disease (XLP), also known as Duncan's disease is unknown. We describe the case of a 39-year-old man with XLP, the oldest surviving, who developed chronic bronchiectasis with hemoptysis and required a pneumonectomy to control his symptoms.

Management of pregnancy in sickle cell syndromes.

We have seen a marked decrease in maternal and perinatal morbidity and mortality among pregnant patients with sickle cell disease. This has been the result of coordinated efforts with the obstetric and hematologic teams. Patients are counseled prior to pregnancy regarding the risks and are given the opportunity to modify their life style to prepare for the additional metabolic burden of gestation. Once pregnant, they are instructed in the techniques to recognize and avoid complications. They are observed frequently for the appearance of pain crisis and other medical and obstetric complications. If complications are identified, they should be treated aggressively. Transfusion therapy is important in the management of patients; however, prophylactic transfusion does not change outcome. Although significant laboratory techniques aid in fetal and maternal supervision, the universal fundamentals of good clinical perinatal care provided through the combined efforts of the obstetrician and hematologist contribute to the framework for the modern management and successful outcome of patients with sickle cell disease during pregnancy.

Continuing care for adult patients with sickle cell disease.

Continuing services for patients with sickle cell disease focuses on holistic care. Participation in preventive medicine principles of health management, avoidance of risk behaviors and seeking appropriate counseling for education, employment, healthy lifestyles, and productive living are beneficial to the patient.

Subarachnoid hemorrhage in sickle-cell disease.

The neurological complications of sickle-cell disease include cerebral intracerebral hemorrhage; subarachnoid hemorrhage (SAH) has been infrequently reported. Among 325 patients with sickle-cell disease followed at the University of Illinois between 1975 and 1989, 11 cases of SAH were identified. Aneurysms were found in 10 of these patients, three of whom had multiple aneurysms. All of the patients had some degree of anemia and nine underwent craniotomy without hematological or neurological complications. From this review it appears that SAH is not uncommon in sickle-cell disease patients and tends to occur at a younger age and with smaller aneurysm size than in the general population. With proper perioperative management, including exchange transfusions to reduce the proportion of hemoglobin S to less than 30%, these patients can undergo angiography and craniotomy without an increased incidence of complications. The techniques used in managing sickle-cell disease patients with SAH are discussed.