Circulating tumor DNA in neoadjuvant-treated breast cancer reflects response and survival.

BACKGROUND: Pathologic complete response (pCR) to neoadjuvant chemotherapy (NAC) is strongly associated with favorable outcome. We examined the utility of serial circulating tumor DNA (ctDNA) testing for predicting pCR and risk of metastatic recurrence. PATIENTS AND METHODS: Cell-free DNA (cfDNA) was isolated from 291 plasma samples of 84 high-risk early breast cancer patients treated in the neoadjuvant I-SPY 2 TRIAL with standard NAC alone or combined with MK-2206 (AKT inhibitor) treatment. Blood was collected at pretreatment (T0), 3 weeks after initiation of paclitaxel (T1), between paclitaxel and anthracycline regimens (T2), or prior to surgery (T3). A personalized ctDNA test was designed to detect up to 16 patient-specific mutations (from whole-exome sequencing of pretreatment tumor) in cfDNA by ultra-deep sequencing. The median follow-up time for survival analysis was 4.8 years. RESULTS: At T0, 61 of 84 (73%) patients were ctDNA positive, which decreased over time (T1: 35%; T2: 14%; and T3: 9%). Patients who remained ctDNA positive at T1 were significantly more likely to have residual disease after NAC (83% non-pCR) compared with those who cleared ctDNA (52% non-pCR; odds ratio 4.33, P = 0.012). After NAC, all patients who achieved pCR were ctDNA negative (n = 17, 100%). For those who did not achieve pCR (n = 43), ctDNA-positive patients (14%) had a significantly increased risk of metastatic recurrence [hazard ratio (HR) 10.4; 95% confidence interval (CI) 2.3-46.6]; interestingly, patients who did not achieve pCR but were ctDNA negative (86%) had excellent outcome, similar to those who achieved pCR (HR 1.4; 95% CI 0.15-13.5). CONCLUSIONS: Lack of ctDNA clearance was a significant predictor of poor response and metastatic recurrence, while clearance was associated with improved survival even in patients who did not achieve pCR. Personalized monitoring of ctDNA during NAC of high-risk early breast cancer may aid in real-time assessment of treatment response and help fine-tune pCR as a surrogate endpoint of survival.

Variation in training requirements within general surgery: comparison of 23 countries.

Background: Many differences exist in postgraduate surgical training programmes worldwide. The aim of this study was to provide an overview of the training requirements in general surgery across 23 different countries. Methods: A collaborator affiliated with each country collected data from the country's official training body website, where possible. The information collected included: management, teaching, academic and operative competencies, mandatory courses, years of postgraduate training (inclusive of intern years), working-hours regulations, selection process into training and formal examination. Results: Countries included were Australia, Belgium, Canada, Colombia, Denmark, Germany, Greece, Guatemala, India, Ireland, Italy, Kuwait, the Netherlands, New Zealand, Russia, Saudi Arabia, South Africa, South Korea, Sweden, Switzerland, UK, USA and Zambia. Frameworks for defining the outcomes of surgical training have been defined nationally in some countries, with some similarities to those in the UK and Ireland. However, some training programmes remain heterogeneous with regional variation, including those in many European countries. Some countries outline minimum operative case requirement (range 60-1600), mandatory courses, or operative, academic or management competencies. The length of postgraduate training ranges from 4 to 10 years. The maximum hours worked per week ranges from 38 to 88 h, but with no limit in some countries. Conclusion: Countries have specific and often differing requirements of their medical profession. Equivalence in training is granted on political agreements, not healthcare need or competencies acquired during training.

Antecedentes: Existen muchas diferencias entre los programas de formación quirúrgica de posgrado del mundo. El objetivo de este estudio fue proporcionar una visión general de los requisitos formativos en cirugía general en 23 países diferentes. Métodos: En cada uno de los países participantes, un colaborador recopiló datos de la página web del organismo oficial encargado de la formación, si era posible. La información incluyó: gestión, formación, competencias académicas y operatorias, cursos obligatorios, años de formación de postgrado (que incluía el período de internado), regulaciones sobre las horas de trabajo, proceso de selección para la formación y existencia de un examen final. Resultados: Se incluyeron los datos de Australia, Bélgica, Canadá, Colombia, Dinamarca, Alemania, Grecia, Guatemala, India, Irlanda, Italia, Kuwait, Países Bajos, Nueva Zelanda, Rusia, Arabia Saudita, Sudáfrica, Corea del Sur, Suecia, Suiza, Reino Unido, Estados Unidos de América y Zambia. En algunos países existen los marcos normativos para definir los resultados del programa de formación, con ciertas semejanzas a los del Reino Unido e Irlanda. Sin embargo, algunos programas de formación, incluso en muchos países europeos, son muy heterogéneos con variaciones regionales. Pocos países describen el número mínimo de procedimientos quirúrgicos (rango 60 a 1.600), los cursos obligatorios o competencias quirúrgicas, académicos o de gestión exigidos. La duración de la formación postgraduada osciló de los 4 a los 10 años. El número de horas trabajadas máximas por semana oscilaron entre 38 y 88, sin límite en algunos países. Conclusión: Cada país tiene unos requisitos específicos, a menudo diferentes, para la formación de sus médicos. La convalidación se otorga por acuerdos políticos, más que por las necesidades médicas o por las competencias adquiridas durante la formación.

Survival of Pseudomonas aeruginosa in M-K preserved corneas.

AIM: To present seven eyes of suspected donor to host transmitted Pseudomonas sp corneal graft infection after corneal and scleral graft leading to corneal melting within 24 hours, in a span of 10 months. METHODS: Case series. Seven eyes, operated for either penetrating or lamellar keratoplasty or scleral patch graft for different indications and which developed massive corneal/corneoscleral infection within 24 hours, were studied prospectively. RESULTS: Pseudomonas aeruginosa, resistant to almost all antibiotics except polymyxin B in all and vancomycin in two, was identified as the causative organism from all the specimens obtained from the infected graft. CONCLUSION: Post-keratoplasty infection is a disaster. The source of early infection is invariably iatrogenic. Use of empirical antibiotics in the media is not always sufficient to prevent such infection. Thus, measures must be taken in the form of strict maintenance of asepsis and revision of antibiotics added to the storage medium. Further, early recognition and energetic therapy for such infection could reduce the ophthalmic morbidity.

A randomized controlled prospective study to assess the role of subconjunctival bevacizumab in primary pterygium surgery in Indian patients.

BACKGROUND: Pterygium is an ocular surface disorder with prevalence rates ranges from 0.3% to 29% in different parts of the world. Vascular endothelial growth factor (VEGF) has been detected in increased amounts in pterygium epithelium, compared with normal conjunctiva. Bevacizumab is a recombinant, humanized anti-VEGF antibody suggested as a possible adjunctive therapy for pterygium excision that appears to have a role in prevention of recurrence. We conducted this study to evaluate the role of subconjunctival bevacizumab in primary pterygium surgery in Indian patients. METHODS: In this randomized prospective clinical study, the patients were randomized into two groups of 30 patients each. Study group received 1.25 mg/0.05 ml subconjunctival bevacizumab 1 week before pterygium surgery with conjunctival autograft. Control group received 1.25 mg (0.05 ml) subconjunctival normal saline 1 week prior to pterygium surgery with conjunctival autograft. Patients were followed up at day 1, day 7, 1 month and 3 months. The main outcome measures were morphology of pterygium after injection, intra-operative ease, recurrence of pterygia, and any complications. RESULTS: After giving bevacizumab, there was statistically significant improvement in grade, color intensity, size of pterygium, and symptoms of patients. Intra-operatively, less bleeding was observed by the surgeon. No statistically significant difference regarding reduction in astigmatism, improvement of visual acuity, and complications were observed in two groups. Recurrence was noted in five patients (8.33%) in total study population at the end of 3 months. It was present in two patients (6.67%) in Group A and three patients (10%) in Group B. CONCLUSION: Single preoperative administration of subconjunctival injection bevacizumab given 1 week before the pterygium excision with conjunctival autograft decreases the vascularity of newly formed blood vessels, hence may decrease recurrence rate though not in our study.

Unidimensionality of alcohol dependence syndrome.

To evaluate the coherence of Alcohol Dependence Syndrome (ADS) as defined by DSM III-R criteria, 482 males were diagnosed as having ADS from a representative general population survey. Nine DSM III-R criteria were factor analyzed to assess unidimensionality. Unlike our earlier report on the same issue, a single-factor model, rather than a two-factor model, supports the coherence of the dependence syndrome explaining the relationship among the nine criteria for community data. When combining criteria into cumulative scales, they formed good approximation of Guttman scales and further supported unidimensionality. Withdrawal and withdrawal avoidance had maximum loading (0.9) and thus can be considered as highly central criteria in defining the syndrome, while preoccupation measured the most severe level of dependence (z = 0.21).

Unidimensionality of alcohol dependence syndrome?

To evaluate the coherence of Alcohol Dependence Syndrome (ADS), as per DSM-III-R criteria, 72 and 223 subjects with alcohol dependence disorder from Hospital and Community settings, respectively, were interviewed. Nine DSM-III-R criteria assessing the dependence syndrome were factor-analysed. A single factor model provides an adequate description of the interrelationship among the nine criteria and supports the coherence of the dependence syndrome for the hospital sample but not for the community. A two factor model, namely 'withdrawal' and 'social', fits the community data. When the criteria were combined into cumulative scales, they formed good approximations of unidimensional Guttman scales for both the hospital and community settings. For hospital data, preoccupation was the highly central criterion (lambda = 0.95) in defining the dependence syndrome while 'can't stop' (v = 0.11) measured the most severe level of dependence. In the community the 'socially dysfunctional use' identified as a separate secondary factor measured the most severe level of dependence.

Agreement between head of household informant and self-report in a community survey of substance use in India.

This survey of 500 households in a New Delhi urban slum compared reports of substance use by the head of the household informant with individual self-report. Information from the two sources was compared for 1,132 people above the age of 15 years. The paired agreement regarding the use of substances was high (kappa=0.92; S.E.=0.01, z=92.0). The agreement regarding the presence of symptoms and classification of dependence for the use of alcohol, tobacco and opiates ranged from good to excellent and head of household reports had a high positive predictive value for the use of these substances. This method provides useful estimates of drug use and dependence for substances associated with observable physiologic withdrawal syndromes, and is less costly and quicker to perform than traditional self-report methodologies.

Hydrocephalus: comparison of clipping and embolization in aneurysm treatment.

OBJECT: In this retrospective study conducted at Atkinson Morley's Hospital and Middlesbrough General Hospital, the authors analyzed 100 matched patients who had suffered subarachnoid hemorrhage (SAH) to determine whether the technical procedure by which aneurysms are treated affects the development of chronic hydrocephalus. METHODS: Four hundred seventy-five patients presented with SAH between 1995 and 1998. Exclusion criteria included posterior circulation aneurysms, multiple aneurysms, electively clipped or embolized aneurysms, angiographically undetected SAH, patients who died within 1 month of neurosurgical intervention, and patients with the same aneurysm location but a different Fisher grade. The authors matched 50 patients who underwent embolization of their aneurysms with another 50 who had similar Fisher grades and aneurysm types and underwent clipping of their aneurysms. The maximum incidence of ruptured aneurysms occurred in patients who were between 41 and 60 years of age, with women preponderant in both study groups. In each group, 27 patients had anterior communicating artery aneurysm, 13 had posterior communicating artery aneurysm, seven had middle cerebral artery aneurysm, and three had internal carotid artery aneurysm. The lesions in three patients in each group were Fisher Grade I, in 23 patients they were Fisher Grade II, in 14 they were Fisher Grade III, and 10 patients had Fisher Grade IV SAH. Nine patients among those with clipped aneurysms and eight of the patients who underwent embolization had hydrocephalus for which they needed intervention. These interventions included lumbar puncture, ventricular drainage, and ventriculoperitoneal (VP) shunt placement; three patients in each group needed VP shunt placement. CONCLUSIONS: The technical procedure used to treat aneurysms, whether clipping or embolization, does not significantly affect the development of chronic hydrocephalus. However, a larger sample of patients is needed for accurate comparisons and stronger conclusions.

Incidence estimates of substance use disorders in a cohort from Delhi, India.

BACKGROUND & OBJECTIVES: There are no reports of incidence studies in the Indian setting on substance use disorders in the general population. This survey-resurvey carried out in metropolis Delhi estimated the incidence rates of substance use disorders. METHODS: A cross-sectional survey was carried out at two points of time with an interval of one year in a representative sample from the general population of metropolis, Delhi. The instrument was precoded, structured and based on DSM III-R operationalised criteria for use of tobacco, alcohol, cannabis and opioids (past one month). Matched data for two points of time were available for 5414 males and 4898 females. RESULTS: In the total cohort, the annual incidence rates (per 100 persons) among males for any drug use, alcohol, tobacco, cannabis and opioids were 5.9, 4.2, 4.9, 0.02 and 0.04 respectively. Among females, incidence of any drug use was 1.2/100 persons. INTERPRETATION & CONCLUSION: Results showed that males have higher incidence for both not-dependent and dependent use for all the drug categories. Females had a higher incidence of dependent tobacco use.

The co-occurrence of tobacco & alcohol in general population of metropolis Delhi.

BACKGROUND & OBJECTIVES: The association between tobacco and alcohol use behaviours has not been explored in India. This study reports on the co-occurrence of tobacco and alcohol use in a representative general population in metropolis Delhi at two points of time a year apart. METHODS: Matched data on 10,312 individuals from 2937 households above the age of 10 yr were available for survey I and survey II. Among them 5414 were males and 4898 females. The subjects were interviewed by non clinical staff using a structured proforma based on DSM III R criteria on the use of tobacco, alcohol, cannabis and opioids. RESULTS: Among women, use of only tobacco was reported. Among males, the prevalence of use of 'only tobacco', 'only alcohol' and concurrent smoking and drinking was 18.1, 3.3 and 9.6 per cent respectively. Concurrent use was higher in the age group 31-40 yr and dependence higher in the 41-50 yr age group. Both at surveys I and II current smokers had higher percentage of alcohol drinkers compared to tobacco abstainers; dependent smokers had higher percentage of dependent drinkers. The use of alcohol at survey II was higher among tobacco smokers compared to tobacco abstainers identified at survey I (OR = 5.77, 95% CI 4.3-7.7). INTERPRETATION & CONCLUSION: Our results demonstrate a positive correlation between smoking and drinking. The findings lend support to existing evidence suggesting associations between tobacco and alcohol use. Smoking proved to be a powerful predictor of alcohol use. It is suggested that professionals who treat alcoholism should pursue the cessation of smoking among their patients.

A rapid assessment study on prevalence of substance abuse disorders in metropolis Delhi.

BACKGROUND & OBJECTIVES: No studies in India have attempted to identify in the general population a 'dependent drug user' based on clinically used diagnostic criteria. This two point survey estimated the prevalence of substance use disorders and the change in the trends of drug use after a period of one year in metropolis Delhi. METHODS: A total of 72 colonies in five types of housing clusters were surveyed. The head of the household (HOH) was interviewed only for collecting information about family members (above 10 yr) on an instrument based on the DSM III R operationalised criteria. Trained non medical interviewers administered the precoded instrument to 6004 and 5599 HOH in the first and second surveys respectively. RESULTS: In the first survey, the prevalence of tobacco, alcohol, cannabis and opioids use among males was 27.6, 12.6, 0.3 and 0.4 per cent respectively. The rates were highest in resettlement clusters followed by urban villages, unauthorized, regularized and in 'others' clusters. The use rates remained unchanged during the re-survey. Dependent use (any drug) increased in the resettlement clusters only during the re-survey. INTERPRETATION & CONCLUSION: The results highlight that it is the legal drugs viz., tobacco and alcohol that could pose higher health and social consequences, both short and long term. The situation of illicit drug use (heroin) was higher in the resettlement clusters and urban villages. Need based programmes have to be evolved and executed to keep the drug dependent population stable. The rapid survey technique can be useful in developing countries like India, where resource crunch for survey research is acute. This technique is less costly, quicker to perform and can supplant traditional self-report methodologies.

A rapid survey on substance abuse disorders in the urban slums of New Delhi.

The results are presented of a rapid survey screening method of general population for identifying dependent and non dependent drug abusers, especially in vulnerable groups such as slum dwellers. The results showed that with the help of instrument with modified DSM III and interviewing only the heads of the households it was possible to get reliable estimates of dependence disorder in the community. This method can be of assistance to health planners for a quick assessment of the magnitude of the problem leading to better allocation of funds and developing services for the affected population. The method is an improvement on key informant technique and a full fledged survey.

Cost analysis of unilateral and bilateral pallidotomy for Parkinson's disease.

With the rapid increase in provision of deep brain stimulation for Parkinson's disease, the efficacy of pallidotomy in symptom alleviation appears to be increasingly ignored. We demonstrate that lesional surgery is effective with benefit over a significant period of time with very significant societal cost savings. Such studies are essential for future planning of services so that maximum numbers of patients can benefit from surgery, both lesional and neuromodulation, as deemed appropriate.

Externalising deep brain electrodes: an increased risk of infection?

It is the practice in many centres to externalise deep brain electrodes in functional neurosurgery to confirm efficacy of therapy prior to full implantation of the pacemaker. It has been a concern that such practice might lead to an increased rate of infection. We report a retrospective study of the rates of infection in two major centres where all electrodes are externalised in one centre and directly implanted in the other. We have not found an increased rate of infection as a result of externalisation and feel, particularly in pain patients, that doing so can lead to significant cost savings by avoiding ineffective implantations.

A clinico-hematological study of iron deficiency anemia and its correlation with hyperviscosity symptoms in cyanotic congenital heart disease.

The present study was carried out in 33 cases of cyanotic congenital heart disease (CCHD) to determine the prevalence of iron deficiency anemia (IDA) and its correlation to hyperviscosity symptoms in terms of hematocrit levels. Furthermore, the study was aimed at assessing the response to low dose iron therapy (60 mg of elemental iron once daily) in relieving symptoms of hyperviscosity. All these cases were evaluated for presence of symptoms of hyperviscosity and later subjected to various hematological & biochemical parameters of iron deficiency anemia including hemoglobin (Hb), pack cell volume (PCV), mean corpuscular volume (MCV), mean corpuscular hemoglobin concentration (MCHC), serum iron, total iron binding capacity respectively. Results showed presence of IDA in 6/33 cases (18.2%) and hyperviscosity symptoms in 10/33 cases (30.3%). Amongst the group with symptoms of hyperviscosity, in the subset having IDA these symptoms were observed at PCV levels of 0.52 L/L to 0.58 L/L in contrast to the subset not deficient in iron where the symptoms occurred at a PCV 0.68 L/L. Relief of symptoms of hyperviscosity was evident with a minimal rise of mean hemoglobin by 2.1 gm/dl. It was concluded that IDA was not an uncommon finding in CCHD cases and that it leads to symptoms of hyperviscosity at a level of PCV much lower than those known to produce these symptoms. Finally low dose iron therapy was found effective in relieving the symptoms of hyperviscosity.

Phototherapy induced hypocalcemia.

Sixty neonates with hyperbilirubinemia were included in the study. There were 20 preterm (Group A) and 20 full term (Group B) neonates. Ten neonates from each group formed the control group. The study group neonates were managed with phototherapy while the control group neonates were not subjected to phototherapy. Serum calcium levels of the two groups were studied. Ninety per cent preterm neonates and seventy-five per cent full term neonates developed hypocalcemia after being subjected to phototherapy. There was a highly significant fall in the total as well as ionized calcium levels in the study group in contrast to the control group. It is recommended that neonates under phototherapy should be given supplemental calcium to prevent hypocalcemia.

Acute Budd-Chiari syndrome due to a simple liver cyst.

Simple liver cysts are common, rarely causing significant morbidity or mortality. Budd-Chiari syndrome (BCS) is caused by obstruction of hepatic venous outflow and is the leading cause of postsinusoidal liver failure. We present a rare case of BCS caused by a simple hepatic cyst. A 16 cm × 16 cm liver cyst was found on computed tomography of a 66-year-old woman presenting with abdominal pain. The cyst had become infected, thus enlarged, exerting mass effect with almost complete compression of the inferior vena cava. Shortly after admission, the patient developed acute liver failure, with deranged clotting and hepatic encephalopathy requiring full organ support on the intensive care unit. Cardiac output studies showed a low cardiac index of 1.4 l/min/m(2). An emergency laparotomy with fenestration of the cyst and drainage of 2l of purulent material led to a full recovery. Intraoperative cystic fluid aspirates later confirmed no evidence of Echinococcus. Histology confirmed a simple cyst. Liver biopsies showed severe, confluent, bridging necrosis, without background parenchymal liver disease. Acute BCS due to rapid compression of all major hepatic veins leading to fulminant hepatic failure is rare. Our case highlights a clinically significant complication of a simple liver cyst of which clinicians should be aware when managing these 'innocent' lesions.

Differential expressions of bilaterally unerupted supernumerary teeth.

This article presents a case of bilateral unerupted supernumerary teeth in the mandibular premolar region. Surgical removal of the right-sided supernumerary tooth had to be carried out as it was impeding the eruption of the mandibular first premolar. However, its supernumerary antimere, lay dormant.