Cardiotoxicity during long-term trastuzumab use in patients with HER2-positive metastatic breast cancer: who needs cardiac monitoring?

PURPOSE: Patients with HER2-positive metastatic breast cancer (MBC) usually receive many years of trastuzumab treatment. It is unknown whether these patients require continuous left ventricular ejection fraction (LVEF) monitoring. We studied a real-world cohort to identify risk factors for cardiotoxicity to select patients in whom LVEF monitoring could be omitted. METHODS: We included patients with HER2-positive MBC who received > 1 cycle of trastuzumab-based therapy in eight Dutch hospitals between 2000 and 2014. Cardiotoxicity was defined as LVEF < 50% that declined > 10%-points and was categorized into non-severe cardiotoxicity (LVEF 40-50%) and severe cardiotoxicity (LVEF < 40%). Multivariable Cox and mixed model analyses were performed to identify risk factors associated with cardiotoxicity. Additionally, we explored the reversibility of cardiotoxicity in patients who continued trastuzumab. RESULTS: In total, 429 patients were included. Median follow-up for cardiotoxicity was 15 months (interquartile range 8-31 months). The yearly incidence of non-severe + severe cardiotoxicity in the first and second year was 11.7% and 9.1%, respectively, which decreased thereafter. The yearly incidence of severe cardiotoxicity was low (2.8%) and stable over time. In non-smoking patients with baseline LVEF > 60% and no cardiotoxicity during prior neoadjuvant/adjuvant treatment, the cumulative incidence of severe cardiotoxicity was 3.1% after 4 years of trastuzumab. Despite continuing trastuzumab, LVEF decline was reversible in 56% of patients with non-severe cardiotoxicity and in 33% with severe cardiotoxicity. CONCLUSIONS: Serial cardiac monitoring can be safely omitted in non-smoking patients with baseline LVEF > 60% and without cardiotoxicity during prior neoadjuvant/adjuvant treatment.

A new diagnostic work-up for defining anemia etiologies: a cohort study in patients ≥ 50 years in general practices.

BACKGROUND: To study etiologies of anemia using an extensive laboratory analysis in general practices. METHOD: An extensive laboratory analysis was performed in blood of newly diagnosed anemia patients aged ≥50 years from the general population in the city of Dordrecht area, the Netherlands. Eight laboratory-orientated etiologies of anemia were defined. Patients were assigned one or more of these etiologies on the basis of their test results. RESULTS: Blood of 4152 patients (median age 75 years; 49% male) was analyzed. The anemia etiology was unclear in 20%; a single etiology was established in 59%; and multiple etiologies in 22% of the patients. The most common etiologies were anemia of chronic disease (ACD) (54.5%), iron deficiency anemia (IDA) (19.1%) and renal anemia (13.8%). The most common single etiologies were IDA (82%) and ACD (68%), while the multiple etiologies most commonly included folic acid deficiency (94%) and suspected bone marrow disease (88%). Older age was associated with a lower incidence of IDA and a higher incidence of renal anemia. Mild anemia was more often associated with ACD and uncertain anemia, while severe anemia was mainly seen in patients with IDA. CONCLUSION: Extensive laboratory analysis in anemic patients from the general population helped clarify the etiology of anemia and revealed many various combinations of etiologies in a significant proportion of patients. Age, sex and the severity of anemia are predictive of the underlying etiology.

Radiological complete remission in HER2-positive metastatic breast cancer patients: what to do with trastuzumab?

PURPOSE: Patients with HER2-positive metastatic breast cancer (MBC) treated with trastuzumab may experience durable tumor response for many years. It is unknown if patients with durable radiological complete remission (rCR) can discontinue trastuzumab. We analyzed clinical characteristics associated with rCR and overall survival (OS) in a historic cohort of patients with HER2-positive MBC and studied the effect of stopping trastuzumab in case of rCR. METHODS: We included patients with HER2-positive MBC treated with first or second-line trastuzumab-based therapy in eight Dutch hospitals between 2000 and 2014. Data were collected from medical records. We used multivariable regression models to identify independent prognostic factors for rCR and OS. Time-to-progression after achieving rCR for patients who continued and stopped trastuzumab, and breast cancer-specific survival were also evaluated. RESULTS: We identified 717 patients with a median age of 53 years at MBC diagnosis. The median follow-up was 109 months (IQR 72-148). The strongest factor associated with OS was achievement of rCR, adjusted hazard ratio 0.27 (95% CI 0.18-0.40). RCR was observed in 72 patients (10%). The ten-year OS estimate for patients who achieved rCR was 52 versus 7% for patients who did not achieve rCR. Thirty patients with rCR discontinued trastuzumab, of whom 20 (67%) are alive in ongoing remission after 78 months of median follow-up since rCR. Of forty patients (58%) who continued trastuzumab since rCR, 13 (33%) are in ongoing remission after 68 months of median follow-up. Median time-to-progression in the latter group was 14 months. CONCLUSIONS: Achieving rCR is the strongest predictor for improved survival in patients with HER2-positive MBC. Trastuzumab may be discontinued in selected patients with ongoing rCR. Further research is required to identify patients who have achieved rCR and in whom trastuzumab may safely be discontinued.

Digital microscopy as a screening tool for the diagnosis of hereditary hemolytic anemia.

INTRODUCTION: Evaluation of red blood cell (RBC) morphology is an important first step in the differential diagnosis of hereditary hemolytic anemia. It is, however, labor intensive, expensive, and prone to subjectivity. To improve and standardize the analysis of RBC morphology as a screening tool in the diagnosis of hereditary hemolytic anemia, we studied its automated analysis by digital microscopy (DM). METHODS: Blood from 90 patients with hereditary hemolytic anemia and 32 normal control subjects was analyzed by the CellaVision DM96 Digital Microscope. RESULTS: All hemolytic RBC abnormalities could be distinguished by the presence of at least one aberrant red cell type. In particular, the percentage of microcytes was highly sensitive and specific (AUCROC  = 0.97) for RBC membrane disorders, and a cut-off of 5.7% microcytes was calculated to be optimal to distinguish patients from healthy controls. Subgroup analysis of patients with RBC membrane disorders revealed additional distinct differences according to the underlying gene defect. A number of cell types were significantly elevated in sickle cell anemia patients, such as polychromatic cells, macrocytes, and poikilocytes. The increase in helmet cells (AUCROC  = 0.96) and hypochromic cells (AUCROC  = 0.91) was specific for ß-thalassemia, whereas patients with pyruvate kinase deficiency showed a significant increased polychromatic cells, macrocytes, and ovalocytes. Patients with hereditary xerocytosis showed significantly higher numbers of polychromatic cells, macrocytes, and target cells. CONCLUSION: DM holds a promise as a useful screening tool in the diagnosis of hereditary hemolytic anemia by detecting and quantifying distinct morphological changes in RBCs in patients with various forms of hereditary hemolytic anemia.

Microbiological outcomes and antibiotic overuse in Emergency Department patients with suspected sepsis.

OBJECTIVE: To study the presence of bacterial disease and antibiotic use in patients in the emergency department (ED) included in the local sepsis protocol. METHODS: An observational retrospective cohort study. Adults aged > 18 years, presenting to the ED of a large teaching hospital, from 1 January to 1 June 2011, with more than two SIRS criteria and a clinical suspicion of sepsis were included. RESULTS: Bacterial disease was suspected or confirmed in only 71% of all the patients with suspected sepsis (2008 definition) and consequently treated with antibiotics. Most of these patients (58%) suffered from systemic inflammatory response syndrome (SIRS) without signs of organ dysfunction, hypotension or hypoperfusion. Despite absence of bacterial disease in 29% of the patients after rigorous diagnostics, median antibiotic treatment in this group was still seven days (IQR 4-10). CONCLUSIONS: Standard sepsis detection using SIRS criteria and clinical suspicion identified patients with suspected or confirmed bacterial disease in 71% of the cases. A significant proportion of patients were exposed to prolonged antibiotic use without proof of bacterial disease. This study illustrates the difficulties in correctly identifying bacterial disease and sepsis, and shows that overuse of antibiotics may be the consequence.

[Sphincter Ochsner dyskinesia as a cause of superior mesenteric artery syndrome].

OBJECTIVE: to investigate the pathological physiology of superior mesenteric artery syndrome (SMAS). MATERIAL AND METHODS: We selected 35 articles devoted to SMAS, which were published from 1990 to 2014, and performed radiometric analysis of X-rays, CT scans and MRI slices found in these articles. In pictures the narrowing in the third part of the duodenum was measured from the boundary of the expanded segment to the level of the superior mesenteric artery (SMA). RESULTS: Only in 6 (17%) of 35 cases the narrowing portion of duodenum was located directly between aorta and SMA, and its length was about 1 cm. In the remaining 29 cases, the beginning of the narrow segment was 2.5-4.6 cm (average 3.30 ± 0.15 cm) proximal to SMA, ie, most of the narrowed duodenum was out of aortomesenteric angle. Location and length of the narrowed segment of duodenum corresponded to the location and length (3.2 ± 0.15 cm) (P > 0.2) of the functional Ochsner sphincter. CONCLUSION: These data indicate that in most cases of SMAS the sphincter Oclisner dyskinesia causes the disease. It is likely that the disease is triggered by heavy stressful conditions that cause a sharp and sustained reduction in the pH of gastric secretions, which in turn leads to the spasms of the sphincter Ochsner. With time this condition progresses to hypertrophy of the contracted wall of the duodenum with subsequent replacement of the muscle fibers by connective tissue. This can lead to the rigidity of the wall.

[Duodenal motility in norm and in some diseases. Hypothesis]. / Dvigatel'naya funktsiya dvenadtsatiperstnoi kishki v norme i pri nekotorykh zabolevaniyakh (gipoteza).

AIM: to investigate the duodenal motility on the basis of radiological studies. PATIENTS AND METHODS: We tested our hypothesis that sphincters of Kapandji and Ochsner are contracted in response to stimulation of duodenum by hydrochloric acid. These sphincters are not found in standard X-ray studies because barium does not contain hydrochloric acid when it coming from the stomach into the duodenum. The retrospective analysis of radiological studies of the upper digestive tract of 116 patients aged 55 to 92 years was done. The first group consisted of 83 patients in whom the study was conducted using conventional barium suspension. The second group consisted of 8 patients who received 200 ml of barium with the addition of 3 grams of vitamin C. The third group was comprised of 25 patients with primary duodenal diverticula. The fourth group included radiographs from 35 articles devoted to the superior mesenteric artery syndrome (SMAS). We measured the width of the duodenum and the length of the sphincters on these radiographs. RESULTS AND CONCLUSION: We found an important role of the sphincters (bulbo-duodenal, Kapandji, Ochsner) in the duodenal physiology. On this basis, we proposed the hypothesis defining basic patterns of the duodenal motor function. Proposed hypothesis allows us to understand how the duodenum performs important functions and provides new avenues for understanding the pathogenesis of acquired diseases of the upper gastrointestinal tract. The different forms dyskinesia of these sphincters play an important role in the pathogenesis of the SMAS, primary duodenal diverticula and sphincter Oddi dyskinesia.

THE PATHOGENESIS OF ACUTE APPENDICITIS. THE NON-SPECIFIC RESPONSE OF THE DIGESTIVE TRACT IN ACUTE INFLAMMATION IN THE ABDOMEN.

Based on the analysis of literature and our own studies we propose hypothesis of the pathogenesis of acute appendicitis (AA), which differs from the following generally accepted provisions. Acute appendidtis develops as a result of immunological reaction and hyperplasia of the mucous membrane of the appendix. Frequency peaks related to age, sex, and seasonal changes of AA are due to increased excretion of sex hormones. Only a small percentage of cases of primary hyperplasia causes a complete occlusion of the lumen and destructive AA. Usually it is exposed to regression without causing the typical symptoms, but leaving the damaged nervous system and / or sclerotic changes that violate the peristalsis of the appendix. Faeces, lingering in appendix eventually harden, increasing in size and often get saturated with salts. In the next fit of hyperplasia, the walls are stretched over fecolithe, causing obstruction of the lumen, the formation of a closed cavity and the known mechanisms of inflammation. Inflammation leads to increased tone of the stomach and colon, but strong in the segments of intestine lay next to the A. This is accompanied by increased of the anal canal pressure. Increased tone of the digestive tract is a nonspecific response to acute inflammation. We can assume that the same reaction is observed at any localization of acute and chronic inflammation.

GASTRIC MOTILITY HYPOTESIS.

The publication is based on a retrospective analysis of 344 radiological studies of the upper digestive tract and analysis of the literature. We propose the hypothesis of the gastric motility, based on the following points: 1) The gastric cardia is the intra-abdominal portion of the lower esophageal sphincter (LES). Its tone increases in response to the increasing pressure in the stomach. 2) in gastroesophageal reflux disease (GERD), the cardia cannot withstand the pressure and subsequently opens. Depending on the degree of insufficiency of the LES and the force applied during provocative test, angular deformity of the stomach appears, due to the shortening of LES as well as a downsizing of the gas bubble in the stomach; 3) Pyloric sphincter (PS) is a true sphincter. Evacuation from the stomach is the result of the opening of the PS due to increase of antral pressure above the "threshold" level; 4) The evacuation starts in the upright position, when the liquid chyme above PS creates hydrostatic pressure above the threshold; 5) When hydrostatic pressure is reduced below the threshold level or in the recumbent position the antral pressure is created by the clamping of deep peristaltic wave and formation of the closed antral cavity; 6) The portioned evacuation is provided in two ways; a) the volume of antral cavity corresponds to the volume of duodenal bulb; b) in upright position after filling of the duodenal bulb the postbulbar sphincter is closed, whereby the pressure in the bulb rises, which leads to a reflex contraction of the PS and cessation of the e stomach emptying.

PATHOGENETIC SIGNIFICANCE OF DYSKINESIA OF THE SPHINCTER OF OKSNER IN THE DEVELOPMENT OF THE SYNDROME OF THE SUPERIOR MESENTERIC ARTERY.

The goal of this study is to investigate the pathological physiology of superior mesenteric artery syndrome (SMAS). MATERIALS AND METHODS: We selected 35 articles devoted to SMAS, which were published from 1990 to 2014, and performed radiometric analysis of X-rays, CT scans and MRI slices found in these articles. In pictures the narrowing in the third part of the duodenum was measured from the boundary of the expanded segment to the level of the superior mesenteric artery (SMA). RESULTS: Only in 6 (17%) of. 35 cases the narrowing portion of duodenum was located directly between aorta and SMA, and its length was about 1cm. In the remaining 29 cases, the beginning of the narrow segment was 2.5-4.6 cm (average 3.30 ±0.15 cm) proximal to SMA, ie, most of the narrowed duodenum was out of aortomesenteric angle. Location and length of the narrowed segment of duodenum corresponded to the location and length (3.2 ± 0.15 cm) (P> 0.2) of the functional Ochsner sphincter. CONCLUSION: These data indicate that in most cases of SMAS the sphincter Ochsner dyskinesia causes the disease. It is likely that the disease is triggered by heavy stressful conditions that cause a sharp and sustained reduction in the pH of gastric secretions, which in turn leads to the spasms of the sphincter Ochsner. With time this condition progresses to hypertrophy of the contracted wall of the duodenum with subsequent replacement of the muscle fibers by connective tissue. This can lead to the rigidity of the wall.

[Schatzki ring as a symptom of gastroesophageal reflux disease].

OBJECTIVE: To determine the importance of a symptom of Schatzki ring. MATERIAL AND METHODS: The results of examining 95 patients aged 62-92 years with the symptoms of dyspepsia in the Netanya State Geriatric Center (Israel) in 1994-2004 were analyzed. Standard X-ray study of the upper digestive tract was complemented by provocation tests. The length of an X-ray-negative area (XNA) between barium in the esophagus and stomach and the width in the lower esophagus were measured. RESULTS: Only 2 (2%) of the 95 patients were found to have normal function of the gastroesophageal junction (GEJ). Two patients with a drastic esophageal narrowing due to reflux esophagitis were excluded. The remaining (91) patients were divided into 2 groups. The width of the esophagus was less than 2 cm and 2 cm or more in 64 (70%) and 27 (30%) patients, respectively. In weak GEJ, there was esophageal dilatation above the XNA. When in a horizontal position, this portion of the esophagus evacuates its contents into the stomach as a result of ampullary function. It is proximally closed by contracting the functional proximal sphincter (PS). When the ampulla contracts, its pressure increases up to the threshold. This causes the XNA to be closed and the ampulla to inject its contents into the stomach. The wider was the ampulla, the shorter the XNA was. Schatzki ring was detected in 20 (22%) of the 91 patients with gastroesophageal reflux disease (GERD). It was always at the level of the PS. CONCLUSION: The so-called sliding esophageal hernia is an esophageal ampulla measuring more than 2 cm in wide. The presence of the esophageal ampulla despite its size suggests that the GEJ is incompetent and GERD is present. Schatzki ring occurs at the level of the PS due to reflux esophagitis.

[Descending perineum syndrome in children: Pathophysiology and diagnosis].

Objective: To propose a safer, simpler, and more exact method for the diagnosis of descending perineum syndrome (DPS). Material and Methods: A total of 194 patients aged 5 days to 15 years were examined and divided into 2 groups: Group 1 consisted of 65 patients without anorectal anomalies (AA); Group 2 comprised 129 patients, including 66 children with functional constipation, 55 with AA and visible fistulas, who were preoperatively examined, and 8 patients with anorectal angle (ARA), who were postoperatively examined. All the patients underwent irrigoscopy that was different from standard examination in the presence of X-ray CT contrast marker near the anus. Results and Conclusion: DPS is caused by puborectalis muscle dysfunction. A method was proposed to evaluate the status of the puborectalis muscle from the distance between the position of the ARA and the marker near the anus. This not only promotes an exacter estimate of DPS, but also allows refusal of defecography. The use of a barium enema with the minimum number of X-ray films decreases dose of ionizing radiation hazard and permits the use of this procedure not only in adults, but also in children with chronic constipation, fecal incontinence, and in AA for both pre- and postoperatively assessment of the causes of complications.

[The pathological physiology of the anorectal defects, from the new concept to the new treatment].

PURPOSE: To determine physiology of anorectal zone in norm and anorectal malformations (ARM) to optimize the surgical treatment. MATERIAL AND METHODS: Examination of 119 patients were selected, including 65 children without anorectal pathology and 54 patients with ARM. We performed barium enema with radiopaque marker placed near the anus. The manometric study of anorectal area was done using intubation tube with an inflatable cuff. RESULTS: The anal canal was detected in all of ARM patients with perineal and vestibular fistulas, as well as in most of the newborns without fistula. The well innervated internal anal sphincter (IAS) was located in the loop of the puborectal muscle (PRM) and connected to the levator ani muscle (LAM) which opens the anal canal during defecation. Anterior and posterior sagittal approaches use IAS excision, with PRM damage and cutting off the LAM from IAS, which leads to incontinence and/or chronic constipation. CONCLUSION: We describe two surgical approaches that allow preservation of all elements of the anal canal resulting in a normal post-operative continence and defecation.

[Pathological physiology of gastroesophageal reflux disease. Hypothesis (Literature review)].

UNLABELLED: Currently prolonged pH-monitoring is considered as Gold standard for diagnosis of Gastro Esophageal Reflux Disease (GERD). Criteria and norms based on prolonged pH-monitoring were the basic concepts of pathophysiology of GERD. For example, it is accepted that esophageal hernia (EG) can be present without GERD, as well as GERD without EG. X-ray diagnosis compared to the pH- monitoring has a low sensitivity (70%) and specificity (74%). Meanwhile, in recent decades, it has been found that the pH-metry is not effective in a non-erosive reflux disease. We figured that the criteria and norms of pH-monitoring are not accurate. The purpose of this study is to determine the radiological norms of gastroesophageal junction (EGJ) and, to clarify the pathological physiology of GERD according to the new criteria and analysis of the literature. MATERIAL AND METHOD: The analysis of the survey of 452 patients was done. Among them were 263 children aged from 1 day to 15 years who have applied to the Belarusian Center of Pediatric Surgery (BCPS) in 1983-1987 and 189 patients aged 15-92 years surveyed in the BCPC, as well as in the Government Geriatric Center (Israel) in 1994-2004. The standard radiography of the upper digestive tract was supplemented by provocative tests. In 21 children and 36 adults survey was carried out to locate space-occupying lesions of the chest or abdomen. Other patients had symptoms of GERD. RESULTS: The 21 children and 17 of 34 adult patients without of GERD symptoms had the same radiographic picture, indicating of the normal LES function: the width of the esophagus was the same all over and no more than 1.5 cm; in a horizontal position a peristaltic wave opens the LES and pushes its contents into the stomach without delay, despite the provocative tests. In 15 out of 34 adults with no symptoms of GERD radiographic findings show signs of LES weakness. In these patients, with a mild GERD, abdominal compression caused contraction of the GEJ with length of (3.60 +/- 0.8 cm) in adults which corresponds to the length of the LES, according to the manometric studies. A rounded cavity (phrenic ampoule) is formed above the contracted LES when the functional'proximal sphincter' (PS) is closed cranially. When, during the am ampoule contraction the pressure in it reaches a threshold level, LES is opened, and the ampoule injects its contents into the stomach. Inflammation of the esophageal wall leads to the gradual ampoule expansion. With a width of the ampulla 2 cm and more we found no evidence of the displacement of the stomach into the chest cavity. The radiological symptoms of GERD are described, the identification of which at rest and during provocation, can be used for grading the antireflux function impairment of LES. CONCLUSION: 1. In GERD the last peristaltic wave expands, forming a phrenic ampoule, which is closed cranially by the PS. 2. The width of the ampoule is proportional to the stages of GERD. This means that ampoule as well as the so-called esophageal hernia are symptoms of GERD. 3. During the ampoule formation the inner surface of it increases by at least to 11 cm2. The deficit of the mucosa is compensated by the motion of the mucosa from GEJ. The shortening of the longitudinal muscle during the ampulla contraction does not significantly affect the length of the esophagus. 4. Transient LES relaxation is caused by a deficiency of the LES capacity.

[The method of radiographic examination anorectal area].

PURPOSE: Puborectal muscle (PRM) plays an important role in the continence. Its function is impaired in chronic constipation, fecal incontinence, especially after anorectal surgery. Assessment of PRM condition by the measurement of anorectal angle is not precise, the defecography requires special equipment and is associated with high doses of radiation. The purpose of this study is to propose another method of evaluation of anorectal function free of the above mentioned disadvantages. MATERIAL AND METHODS: The analysis of 475 studies of patients of all ages, including 79 without pathology anorectal area and 396 patients with different pathologies was done. They were examined by a method that differs from the usual barium enema by placing of radiopaque marker near the anus. RESULTS AND DISCUSSION: The weakness of PRM manifested by penetration of barium into the anal canal behind the tip of the enema. The prominent shortening of the anal canal, compared to age-related normal figures indicates the PRM failure. The finding of the anal canal shortening has the same diagnostic value as the perineum distendion revealed by defecography. The proposed method is simple, accurate, and does not apply large dose of radiation.