Neratinib and Ado-Trastuzumab-Emtansine for Pre-treated and Untreated HER2-positive Breast Cancer Brain Metastases: Translational Breast Cancer Research Consortium Trial 022.

PURPOSE: Treatment options for HER2-positive breast cancer brain metastases (BCBM) remain limited. We previously reported central nervous system (CNS) activity for neratinib and neratinib-capecitabine. Preclinical data suggest that neratinib may overcome resistance to ado-trastuzumab-emtansine (T-DM1) when given in combination. In TBCRC 022's cohort 4, we examined the efficacy of neratinib plus T-DM1 in patients with HER2-positive BCBM. PATIENTS AND METHODS: In this multicenter, phase II study, patients with measurable HER2-positive BCBM received neratinib 160 mg daily plus T-DM1 3.6 mg/kg intravenously every 21 days in three parallel-enrolling cohorts (cohort 4A-previously untreated BCBM, cohorts 4B and 4C- BCBM progressing after local CNS-directed therapy without [4B] and with [4C] prior exposure to T-DM1). Cycle 1 diarrheal prophylaxis was required. The primary endpoint was the Response Assessment in Neuro-Oncology-Brain Metastases (RANO-BM) by cohort. Overall survival (OS) and toxicity were also assessed. RESULTS: Between 2018-2021, 6, 17, and 21 patients enrolled to cohorts 4A, 4B, and 4C. Enrollment was stopped prematurely for slow accrual. The CNS objective response rate in cohorts 4A, 4B, and 4C was 33.3% (95% confidence interval [CI]: 4.3-77.7%), 35.3% (95% CI: 14.2-61.7%), and 28.6% (95% CI: 11.3-52.2%), respectively; 38.1-50% experienced stable disease for ≥6 months or response. Diarrhea was the most common grade 3 toxicity (22.7%). Median OS was 30.2 months (cohort 4A; 95% CI: 21.9, not reached [NR]), 23.3 months (cohort 4B; 95% CI: 17.6, NR), and 20.9 months (cohort 4C; 95% CI: 14.9, NR). CONCLUSION: We observed Intracranial activity for neratinib plus T-DM1, including those with prior T-DM1 exposure, suggesting synergistic effects with neratinib. Our data provide additional evidence for neratinib-based combinations in patients with HER2-positive BCBM, even those who are heavily pre-treated.

Phase Ib dose-escalation trial of taselisib (GDC-0032) in combination with HER2-directed therapies in patients with advanced HER2+ breast cancer.

BACKGROUND: In most patients with advanced human epidermal growth factor receptor-2-positive (HER2+) breast cancer, anti-HER2 therapies fail due to the development of acquired resistance, potentially mediated through phosphoinositide-3-kinase (PI3K) signaling. We investigated adding taselisib, an α-selective potent oral inhibitor of PI3K, to different HER2-directed regimens in order to improve disease control. PATIENTS AND METHODS: Patients (n = 68) with advanced HER2+ breast cancer were enrolled to this open-label, dose-escalation phase Ib study. The primary endpoint was defining the maximal tolerated dose (MTD) for the various taselisib-containing combinations. The secondary endpoint was safety. Exploratory endpoints included circulating tumor DNA analysis. The study included four cohorts: (A) taselisib + trastuzumab emtansine (T-DM1), (C) taselisib + trastuzumab and pertuzumab (TP), (D) taselisib + TP + paclitaxel, and (E) taselisib + TP + fulvestrant. RESULTS: Following dose escalation, the taselisib MTD was defined as 4 mg once daily. Treatment was associated with significant toxicities, as 34 out of 68 patients experienced grade ≥3 adverse events (AEs) attributed to taselisib, the most common all-grade AEs being diarrhea, fatigue, and oral mucositis. At a median follow-up of 43.8 months, median progression-free survival (PFS) for the MTD-treated population in cohorts A, C, and E was 6.3 [95% confidence interval (CI) 3.2-not applicable (NA)] months, 1.7 (95% CI 1.4-NA) months, and 10.6 (95% CI 8.3-NA) months, respectively. The median PFS for patients in cohort A with prior T-DM1 use was 10.4 (95% CI 2.7-NA) months. CONCLUSIONS: PIK3CA targeting with taselisib in combination with HER2-targeted therapies was associated with both promising efficacy and substantial toxicities.

Pancreatic cancer and sugar diabetes.

The link between pancreatic cancer and diabetes mellitus is well recognized. Controversy still exists, however, as to whether the pancreatic cancer is the cause of abnormal glucose metabolism or if hyperinsulinemia predisposes the person to pancreatic cancer. A recent article offers strong data supporting diabetes as a risk factor for pancreatic cancer. Patients with abnormal glucose metabolism, as determined by elevated serum glucose 1 hour after an oral glucose challenge, were found to have an increased risk of developing pancreatic carcinoma even if patients dying from that disease during the first 5 years of follow-up were excluded from consideration.

Anticholinergic poisoning with adulterated intranasal cocaine.

In recent years, emergency physicians have encountered a growing number of patients who present with anticholinergic toxicity after using adulterated heroin. Anticholinergic poisoning caused by adulterated cocaine is far less common. This report describes the case of a 39-year-old man who arrived in the emergency department several hours after the nasal insufflation of cocaine. Classic symptoms of anticholinergic toxicity were evident on examination, including dry, flushed skin, agitation, tachycardia, mydriasis, and absence of bowel sounds. Treatment included intravenous fluids and lorazepam, with resolution of symptoms over several hours. Urine samples revealed the presence of cocaine metabolites as well as the anticholinergic drug atropine, and infrequently encountered adulterant of cocaine. Anticholinergic poisoning is reviewed, and the physical examination findings that distinguish this syndrome from the closely related sympathomimetic syndrome typical of cocaine are detailed. Current treatment recommendations for anticholinergic poisoning are summarized.

Beneficial effect of a bile acid resin binder on enteral feeding induced diarrhea.

OBJECTIVES: Diarrhea is a complication of enteral feeding, occurring in up to 68% of critically ill patients. We hypothesized that prolonged fasting results in abnormal bile acid homeostasis. Subsequent enteral feeding then causes a relative luminal excess of bile acids, which leads to choleretic diarrhea. Hence, diarrhea induced by enteral feeding should improve with the use of a bile acid binding agent, such as Colestid Granules. METHODS: We evaluated the effect of Colestid on enteral feeding-induced diarrhea in a double-blind placebo-controlled study. Nineteen patients who were nil per os (NPO) for 5 days before initiation of enteral feeding were enrolled in the study and treatment continued for 7 days. The severity and frequency of diarrhea were quantified. Fecal bile acids were measured enzymatically. Stool nutrient loss was measured by fat extraction, microkjeldahl determination of nitrogen, and bomb calorimetry of dried fecal specimens. RESULTS: Enteral feeding resulted in a high frequency of diarrhea (95%) at some time during the observation period. The majority of episodes of diarrhea in both groups were of low volume. Colestid significantly decreased the prevalence and severity of diarrhea. Colestid had no significant effect on fecal calorie or nutrient losses. The average bile acid concentration in the stool increased significantly after enteral feeding. CONCLUSION: Enteral feeding-induced diarrhea is, at least in part, due to malabsorption of bile acids. The bile acid resin binding agent Colestid improves diarrhea induced by enteral feeding.

Three cases of comprehensive dietary therapy and pharmacotherapy of patients with complex obesity-related diseases.

The effect of weight loss with anorectic medications on sleep apnea, non-insulin-dependent diabetes, and steatohepatitis is illustrated in three cases from practice in a clinical nutrition setting. Prevention of obesity, a chronic disorder, is preferable, but when obesity becomes a major obstacle in the care of patients with respiratory, cardiovascular, and metabolic disorders and osteoarthritis, an intense course of weight reduction using anorectic medications under medical and dietetic guidance is essential for patients' survival and reduction of medical cost.

Randomized, double-blind study of intravenous human albumin in hypoalbuminemic patients receiving total parenteral nutrition.

OBJECTIVE: To determine whether replacement of human albumin will improve a patient's prognosis. DESIGN: A randomized, double-blind, controlled study in which 25 g of human albumin vs. placebo was administered intravenously daily. SETTING: A university-affiliated hospital. PATIENTS: Thirty-six patients with hypoalbuminemia (serum albumin of <2.5 g/dL), receiving total parenteral nutrition. None of the patients had known cancer, cirrhosis, or nephrotic syndrome. INTERVENTIONS: Each patient received at least 6 days of therapy (6 to 24 days of albumin; 7 to 32 days of placebo). Four subjects were excluded from the study since they received therapy for <6 days. One patient was excluded from the study after nephrotic syndrome was identified. Albumin metabolic rates for those patients receiving albumin were estimated using the formula: Metabolism of albumin = 25 g/day + (albumin 1 - albumin 2)(Vd)/days, where albumin 1 and 2 are the serum albumin concentrations (g/L) at the beginning and end of the serum sampling intervals, respectively; Vd is the volume of distribution (L); and days relates to the number of days of the sampling interval. MEASUREMENTS AND MAIN RESULTS: Sixteen patients received albumin; 15 patients received placebo. One patient receiving placebo and two patients receiving albumin died within 30 days. One patient who received placebo and three patients who received albumin developed sepsis or bacteremia; four patients who received placebo and seven patients who received albumin developed pneumonia during the study (NS). The serum albumin increased in all patients receiving intravenous albumin, but one patient received intravenous albumin for only 6 days. The mean serum albumin concentration increased by 1.42 g/dL in the albumin patients, and increased by 0.29 in the placebo patients (p < .0001 by unpaired t-test). Mean initial albumin metabolism was 17.4 g/day (0.3 g/kg/day). At the end of therapy, albumin metabolism was 20.5 g/day (0.36 g/kg/day) (paired t-test, p = .4, NS). CONCLUSIONS: a) The administration of intravenous albumin to hypoalbuminemic patients receiving total parenteral nutrition does not improve morbidity or mortality. b) Albumin metabolic rates, initially related to the catabolic state, are high; later, these rates are high related to filling of the albumin space and gluconeogenesis. c) On the basis of the high albumin catabolic rates at the end of the infusion, doses of albumin of <25 g/day might be sufficient to replace albumin stores.

Methemoglobinemia from perineal application of an anesthetic cream.

A 34-year-old woman presented with cyanosis and a methemoglobin level of 23.2% after perineal application of a topical anesthetic cream containing 20% benzocaine. Many commonly used products contain high levels of benzocaine, and their use can lead to life-threatening methemoglobin levels. This case reinforces the need for stricter guidelines for product use and warning labels to alert consumers to this potential side effect of topical benzocaine-containing products sold over the counter.

Blunted serotonergic responsivity in depressed inpatients.

We found a 38% lower maximal prolactin response to an oral challenge dose of 60 mg of dl-fenfluramine relative to placebo in younger (< 30 years) depressed inpatients compared with the response in age-matched healthy controls (p < .03). Severity of depression did not correlate with prolactin response. Prolactin responses in older depressed patients (> or = 30 years) did not differ from older controls. Younger depressed patients differed from older depressed patients in terms of earlier age of onset of first lifetime episode of major depression, greater degree of suicidal intent during a recent suicide attempt, double the level of hopelessness on admission to hospital, and a higher rate of comorbid borderline personality disorder. A blunted prolactin response to fenfluramine may be interpreted as evidence for reduced serotonergic function in younger depressed patients and may underlie their observed greater suicidality and hopelessness.

Diarrhea induced by enteral feeding.

Diarrhea is reported as a major complication of enteral feeding. Recent studies show that there is a staggering amount of confusion in defining diarrhea in this setting. This causes major problems both in estimating the incidence of diarrhea, as well as determining its clinical impact. In many cases, careful review of the patients' records and evaluation of the diarrhea may lead to its accurate diagnosis and treatment. The frustration involved in the management of these patients may lead investigators to measure quantitatively the patient's fecal output and to come up with a standardized definition of diarrhea. We describe here three cases that show various forms of enteral feeding-induced diarrhea. Subsequently we will review the important issues regarding the definition of related diarrhea and attempt to understand its pathogenesis.

Sucrose permeability as a marker for nonsteroidal anti-inflammatory gastroduodenal injury: how sweet is it?

The authors report that sucrose is a novel permeability marker in the evalution of proximal gastrointestinal (GI) injury. In patients undergoing endoscopy and in volunteers who were chronically taking nonsteroidal anti-inflammatory drugs (NSAIDs), the sucrose permeability test accurately identified patients with severe gastritis and gastric ulcer. The sucrose permeability test did not detect other types of proximal GI injury as reliably. Given the propensity of NSAIDs to cause upper GI injury, the authors suggest that this test can be used to identify people who might be at high risk from the sequelae of NSAID ingestion. This interesting marker deserves further evaluation in targeted prospective studies.

Monitoring exposure of hospital personnel handling cytostatic drugs and contaminated materials.

A study was undertaken to evaluate the urine mutagenicity of 63 individuals working in four hospital departments. The exposed group included 38 subjects who were exposed to various cytostatic drugs and/or contaminated material from treated patients. The control group included 25 individuals of the hospital personnel. Urine mutagenicity was monitored by the Ames test using tester strains TA 98 + S9 Mix and TA 102-S9 Mix. Urine samples were collected before and after the working periods. A total of 29/116 (25%) urine samples were mutagenic for either strain. Among the mutagenic samples, 24/29 were mutagenic for tester strain TA 98 exclusively. No significant correlation could be found between occupational exposure to cytostatic drugs and urine mutagenicity evaluated by the strain TA 98 + S9 Mix. Smoking was the main environmental factor that modulated urine mutagenicity with TA 98. Three subjects in the exposed group had mutagenic urine samples at the end of the working period with strain TA 102-S9 Mix. This mutagenicity was related to occupational exposure to cisplatin. In the control group, one individual had mutagenic samples before and after the working period. Assessing occupational exposure to cytostatic drugs with strain TA 102 requires additional studies to determine environmental mutagens which can be detected by this strain.

Effect of dietary oat and soy fiber on bowel function and clinical tolerance in a tube feeding dependent population.

OBJECTIVE: The role of fiber in tube feeding products has not clearly been defined. While some studies suggest that fiber can increase stool weight and bowel transit time in acutely ill patients, there is less information in stable patients receiving chronic enteral nutritional support. DESIGN: Using a crossover study design, we investigated the effect of 28.8 g/day of a 50% soy and 50% oat fiber combination in 10 medically stable residents of a chronic care facility. Subjects were randomized to initially receive 10 days of either Isocal HN or Ultracal, which are identical in composition except Ultracal contains 14.4 g/L of fiber. After the first 10-day study, subjects underwent a washout followed by a second 10-day study using the other product. Fecal dye markers were used to identify appropriate collection times. RESULTS: Fiber significantly increased the number of bowel movements per day (0.9 +/- 0.4 vs 0.5 +/- 0.2, p < 0.05) and fecal weights (57 +/- 31 vs 32 +/- 25 g/day, p < 0.05). Fiber also caused a significant increase in fecal nitrogen output (110 +/- 65 vs 75 +/- 74 mg/day, p < 0.05) and fecal energy (141 +/- 73 vs 76 +/- 62 kcal/day, p < 0.05). Fiber did not affect fecal moisture, gastric emptying, or intestinal transit time. CONCLUSION: We conclude that the addition of a combination of soy and oat fiber to tube feeding material is well tolerated, and promotes regular bowel movements without altering the rate of gastric emptying or intestinal transit time.

The relationship of platelet 5-HT2 receptor indices to major depressive disorder, personality traits, and suicidal behavior.

Previous research has suggested that major depression and suicidal behavior may be associated with altered serotonin receptor function. In this study, platelet serotonin2 (5-HT2) receptor binding indices were measured in conjunction with serotonin-amplified platelet aggregation, a response mediated by the platelet 5-HT2 receptor complex, in depressed patients and normal controls. The magnitude of serotonin-amplified platelet aggregation was positively correlated with the number of platelet 5-HT2 receptor sites in both groups. Mean values for the receptor binding indices and the receptor-mediated response did not differ significantly between patients and controls, although patients exhibited a wider range of values for each parameter compared with controls. Exploratory analyses were undertaken to determine clinical variables that might contribute to the increased variance in depressed individuals. These analyses failed to reveal a statistically significant relationship between any of the platelet 5-HT2 receptor measures and the subtype or severity of depressive illness, or the presence of comorbid borderline personality disorder. Although the mean number of receptor sites did not differ between patients who had recently attempted suicide and those who had never attempted suicide, a strong positive correlation (p = 0.002) was found between receptor number and the degree of medical damage resulting from the suicidal act. Furthermore, the ratio of the serotonin-amplified platelet aggregation response to platelet 5-HT2 receptor number, an index of the mean responsivity of an individual receptor complex, was lower in suicide attempters versus nonattempters (p = 0.06) and normal controls (p = 0.01). Exploratory analyses also suggested that recent exposure to psychotropic medication may result in a significant increase in platelet 5-HT2 receptor number (p = 0.03). Thus, although the study did not show a consistent alteration in platelet 5-HT2 receptor indices in major depression, the data suggest that specific factors such as suicidality and drug exposure may explain some of the variance in depressed patients.

Nutrition in acute pulmonary disease.

Acutely stressed patients with chronic pulmonary disease have a particular need for accurate nutritional assessment and appropriate nutritional therapy. Loss of skeletal muscle, often extensive, can be paralleled by dramatic alterations in cellular function; inadvertent provision of excessive calories or of individual substrates may produce more harm than benefit. In the absence of a single "gold standard" for nutritional assessment and monitoring, no single value should take precedence over the entire clinical picture, which should be thoughtfully assessed and reassessed, with both the patient's nutritional needs and the consequences of their provision kept in mind. In the future, assessments of the impact of nutritional intervention will probably rely more heavily on functional tests of specific organs and of the immune system. Intervention will be based not only on provision of calories, individual substrates, vitamins, and minerals, but also on control of the inflammatory response in order that the nutrients may be properly utilized.

Relationship between central and peripheral serotonin indexes in depressed and suicidal psychiatric inpatients.

Serious suicidal behavior, affective disorders, and a variety of other psychopathologic behaviors and syndromes have been found to correlate with measures of the serotonin system. Clinical studies have employed a range of serotonin indexes, including the cerebrospinal fluid level of 5-hydroxyindoleacetic acid, the prolactin response to serotonin agonists, such as fenfluramine hydrochloride, and platelet serotonin-related proteins or serotonin content. Many of these indexes are correlated with suicidal behavior, but the interrelationship of these biologic measures has been uncertain. We studied the relationship of a series of serotonin indexes in patients in whom these measures were correlated with suicidal behavior. A positive correlation was found between cerebrospinal fluid 5-hydroxyindoleacetic acid and the maximal prolactin response to fenfluramine but not with platelet serotonin2 receptor indexes. The fenfluramine-stimulated maximal prolactin response correlated with platelet serotonin2 receptor number, particularly in older patients. We conclude that cerebrospinal fluid 5-hydroxyindoleacetic acid measurements cannot be replaced but can be complemented by less invasive procedures, such as a fenfluramine challenge test or platelet serotonin2 measures, in the study of the relationship of the serotonin system to psychiatric disorders.

Neuroendocrine and behavioral responses to challenge with the indirect serotonin agonist dl-fenfluramine in adults with obsessive-compulsive disorder.

Neuroendocrine and behavioral responses to a single 60-mg oral dose of the indirect serotonin agonist dl-fenfluramine were assessed in unmedicated adults with obsessive-compulsive disorder (OCD) and neuroendocrine results contrasted with those in normal control subjects. Net fenfluramine-induced prolactin release did not differ significantly between OCD patients and normal controls. Prolactin responses in the OCD group were not significantly correlated with baseline Yale-Brown Obsessive Compulsive Scale scores for either obsessions or compulsions, but were positively correlated with the baseline Hamilton Depression Scale score and Hamilton Anxiety Scale score. No clear difference in the severity of patients' obsessions or compulsions was found following challenge with fenfluramine versus placebo. Although the present study does not demonstrate a serotonergic abnormality in OCD, this may be more a reflection of limitations of the test procedures than evidence that central nervous system (CNS) serotonergic function is normal in the disorder.