tbuckley/cabot-search huggingface dataset:
Influence of dose adjustment on afatinib safety and efficacy in patients (pts) with advanced <i>EGFR</i> mutation-positive (<i>EGFRm</i>+) non-small cell lung cancer (NSCLC).
Authors: James Chih-Hsin Yang, Myung-Ju Ahn, Nicolas J. Dickgreber, Balazs Halmos, Vera Hirsh, Maximilian J. Hochmair, Benjamin Philip Levy, Filippo De Marinis, Tony Mok, Kenneth O'Byrne, Isamu Okamoto, Martin H. Schuler, Martin Sebastian, Riyaz N.H. Shah, Eng-Huat Tan, Nobuyuki Yamamoto, Angela Marten, Dan Massey, Sven Wind, David Paul Carbone
Journal: Journal of Clinical Oncology (2015)

8073 Background: Afatinib 40 mg/day (oral) is approved for the treatment of pts with advanced EGFRm+ NSCLC. Dose adjustment is recommended according to pre-defined tolerability criteria. We performed post-hoc analyses on the influence of afatinib dose reduction on adverse events (AEs), pharmacokinetics (PK) and progression-free survival (PFS) in the Phase III LUX-Lung 3 (LL3) trial, and analyzed dose reduction data collected in clinical practice. Methods: All pts treated with afatinib in LL3 were included in the analyses (n = 229). Pts experiencing drug-related grade 3 or selected prolonged grade 2 AEs on the initial 40 mg dose could dose reduce by 10 mg decrements to 30 mg or a final dose of 20 mg. Frequency and severity of the most common AEs before and after dose reduction were analyzed. Final PK data collected as part of the standard visit schedule (Day 43) were used to compare plasma afatinib concentrations in pts who reduced to 30 mg vs those remaining at 40 mg. PFS was compared between pts who dose reduced within the first 6 months of treatment and those who did not. Real-world data were collected by practicing experts. Results: Dose reductions occurred in 53% (122/229) of pts; the majority (86%) within the first 6 months of treatment. In pts who dose reduced, decreases in the incidences of drug-related all grade (grade ≥ 3) AEs were 99.2% (20.5%) to 46.7% (4.1%) for diarrhea, 88.5% (26.2%) to 38.5% (3.3%) for rash/acne, 77.0% (12.3%) to 27.9% (0%) for stomatitis, and 44.3% (16.4%) to 36.9% (4.9%) for nail effects. Dose reduction was more likely in pts with higher plasma concentrations of afatinib. On Day 43, pts who dose reduced to 30 mg ≥ 4 days previously (n = 38) had geometric mean plasma afatinib concentrations of 24.4 ng/mL, vs 23.7 ng/mL in pts who remained on the 40 mg dose (n = 126). Median PFS was 11.3 months in pts who dose reduced during the first 6 months of treatment, vs 11.0 months in pts who did not (HR = 1.25 [95% CI, 0.91–1.72]). Dose reduction outcomes from daily clinical practice will also be presented. Conclusions: Tolerability-guided dose adjustment of afatinib is an effective measure to reduce treatment-related AEs without reducing therapeutic efficacy. Clinical trial information: NCT00949650.
Nitric Oxide–Induced Motor Neuron Disease in a Patient with Alcoholism
Authors: Guochuan E. Tsai, David R. Gastfriend
Journal: New England Journal of Medicine (1995)

To the Editor: Nitric oxide is a gas neurotransmitter involved in multiple physiologic and pathologic processes.1 We report a case in which the use of nitric oxide for the treatment of pulmonary hypertension after lung transplantation may have caused extensive lower motor neuron disorder. Nitric oxide activates guanylate cyclase, which is a transduction mechanism for the glutamatergic N-methyl-d-aspartate (NMDA) receptor. Glutamate and other excitatory amino acids can damage neurons if they persistently or excessively stimulate their receptors. They have been implicated in degenerative motor neuron diseases such as amyotrophic lateral sclerosis and Guam motor neuron . . .
Selective Loss of the Suppressor-Inducer T-Cell Subset in Progressive Multiple Sclerosis
Authors: Chikao Morimoto, David A. Hafler, Howard L. Weiner, Norman L. Letvin, Margaret Hagan, John Daley, Stuart F. Schlossman
Journal: New England Journal of Medicine (1987)

The T4+ lymphocyte population includes a subset that induces suppressor T lymphocytes (T8+ cells) and can be distinguished by dual-color fluorescence analysis with anti-2H4 and anti-T4 monoclonal antibodies. To investigate the possible role of these cells in multiple sclerosis, we used anti-2H4 antibody to characterize peripheral-blood lymphocyte subsets in 63 patients with multiple sclerosis that was progressive, stable, or acute (relapsing-remitting). Twenty-three of 37 patients with progressive multiple sclerosis had a selective decrease in the number and percentage of peripheral-blood T cells that induce suppressor cells (T4+2H4+ cells), whereas only 3 of 16 patients with stable disease and 2 of 10 patients in the midst of an acute attack had a significant decrease. These selective decreases of circulating T4+2H4+ cells occurred in only 1 of 34 patient controls with other neurologic diseases and in 2 of 50 healthy controls (P less than 0.0001 by Fisher's exact test). The absolute number of T4+2H4+ cells and the percentage of reactivity in the populations studied were 187 +/- 28 per cubic millimeter and 8.3 +/- 1 percent in patients with progressive multiple sclerosis; 353 +/- 60 per cubic millimeter and 14.5 +/- 2 percent in patients with stable disease; 368 +/- 72 and 14.6 +/- 2.1 percent in patients with acute disease; 402 +/- 64 and 15.6 +/- 2 percent in controls with other neurologic diseases; and 519 +/- 44 and 19.7 +/- 1 percent in healthy controls. Functional studies using a pokeweed mitogen-driven IgG assay demonstrated a correlation between decreased numbers of T4+2H4+ cells and increased production of IgG in vitro. Family studies showed that the 2H4 antigen was not part of an inherited polymorphic antigenic determinant. Our results suggest that in progressive multiple sclerosis decreases in inducers of suppressor T cells may permit the activation of cells reactive with elements of the central nervous system.
Sulindac sulfide augments the response of HT-29 colon cancer cells to oxidative stress: Involvement of the actin cytoskeleton and the map kinase pathway
Authors: Irina Korichneva, Jae-Ho Lee, Steven J. Shiff
Journal: Cancer Research (2004)

1392   Evidence continues to accumulate that non steroidal anti-inflammatory drugs (NSAIDs), in addition to their well-known beneficial effects, reduce the risk of colorectal cancer development. This so called cancer chemopreventive effect has been hypothesized to result, at least in part, from their ability to inhibit the proliferation of and induce apoptosis in colon cells. These antiproliferative effects may not be dependent upon their inhibitory actions on cyclooxygenase (COX) activity or prostaglandin production, as cells that do not express COX isoenzymes are still inhibited by these compounds. Several non COX molecular events are altered by these agents in mammalian cells. Nevertheless, the precise molecular mechanisms of action accounting for their growth inhibitory properties remains unclear.  Methods:  Cultured HT-29 colon adenocarcinoma cells were incubated with 50-75 μM Sulindac sulfide (SS) in serum-free medium for 16 hrs, oxidative stress was then induced by a sub lethal concentration (200 μM) of hydrogen peroxide (H 2 O 2 ) for 30 min. The cells were also stimulated by serum re-addition or phorbol ester (PMA)under similar conditions in the presence or absence of the MEK inhibitor U0126 (10 μM). The extent of apoptosis and the distribution of F-actin, visualized by phalloidin staining, were determined morphologically. MAPK activity was measured by Western blot using a phospho-specific anti-ERK monoclonal antibody.  Results:  HT-29 colon cancer cells pretreated for 16 hours with 50-75 μM SS undergo rapid cell death upon further treatment with 200 μM H 2 O 2 , a sub lethal amount of oxidative stress when used alone. This was accompanied by alterations in cell morphology including: cell rounding, blebbing, and F-actin network destruction. SS alone activated the MAPK pathway leading to sustained phosphorylation of ERK1/2, but, as described by others, SS reduced the stimulatory action of serum or PMA on the MAPK pathway. In addition, the cell morphological changes were prevented by the MEK inhibitor U0126.  Conclusions:  Pretreatment of HT-29 colon cancer cells with SS increases HT-29 colon cancer cell sensitivity to apoptosis induced by oxidative stress which was prevented by pharmacologic inhibition of the MAP kinase pathway. This effect of SS and extracellular stressors may be physiologically important for cancer chemoprevention in the colon, where the mucosa is ordinarily confronted by several factors simultaneously in an anaerobic and reduced redox environment. In addition, SS alters actin cytoskeleton stucture and induces MAPK activity. These results suggest that the MAP kinase signal transduction pathway and the actin cytoskeleton may be targets for SS’s antiproliferative action in HT-29 colon cancer cells.
Updated Os Analysis, Multivariate and Qtwist Analysis of a Randomized Sequential Open-Label Study (Switch) to Evaluate Efficacy and Safety of Sorafenib (So) / Sunitinib (Su) Versus Su/So in the Treatment of Metastatic Renal Cell Cancer (Mrcc)
Authors: C. Eichelberg, P.J. Goebell, W.L. Vervenne, M. De Santis, L. Fischer von Weikersthal, C. Lerchenmüller, U. Zimmermann, M.M.E.M. Bos, W. Freier, S. Schirrmacher-Memmel, M. Staehler, S. Pahernik, M. Los, M. Schenck, A. Floercken, C. van Arkel, K. Hauswald, M. Indorf, D. Gottstein, M. Michel
Journal: Annals of Oncology (2014)
Endothelin A receptor mediates functional but not structural damage in chronic cyclosporine nephrotoxicity.
Authors: T E Hunley, A Fogo, S Iwasaki, V Kon
Journal: Journal of the American Society of Nephrology (1995)

Chronic treatment with cyclosporine (CsA) is limited not only by glomerular hypofiltration but also by structural damage. The pathogenesis of these nephrotoxicities was studied in a model of chronic CsA-induced renal damage. Salt-depleted rats were treated with daily CsA (15 mg/kg sc) for approximately 3 weeks, at which time renal function was measured and kidneys were harvested for morphologic assessment. A separate group of rats (CsA + BQ123) were identically treated with CsA but in addition also received simultaneous treatment with a specific endothelin A (EtA) receptor antagonist, BQ123, which was continuously delivered via sc osmotic pump (1 mg/kg per hour) and maintained throughout the study. Chronic CsA treatment caused profound functional and structural damage, although blood pressure was normal (102 +/- 6 mm Hg); GFR was 0.05 +/- 0.02 mL/min per 100 g body wt, and RPF was 0.15 +/- 0.06/100 g body wt. Renal injury was scored on a scale of 0 to 4 and showed dilation/vacuolization of 1.07 +/- 0.29 and tubulointerstitial fibrosis of 0.78 +/- 0.17. Arteriolopathy was present in 78 +/- 4% of arterioles. Chronic antagonism of the EtA receptor preserved renal function: GFR was 0.15 +/- 0.03 mL/min per 100 g body wt, and RPF was 0.32 +/- 0.08/100 g body wt (P < 0.05 for GFR versus CsA). Blood pressure was not affected: 104 +/- 8 mm Hg.(ABSTRACT TRUNCATED AT 250 WORDS)
When Physicians Treat Members of Their Own Families
Authors: John La Puma, Carol B. Stocking, Dan LaVoie, Cheryl A. Darling
Journal: New England Journal of Medicine (1991)

Little is known about the circumstances under which physicians care for family members. We sought to examine current practice and, in particular, to learn how often family members request medical care or treatment, whether physicians accede to such requests, and what concerns, if any, physicians have about caring for their family members.
HER2 overexpression and amplification in advanced ovarian cancer (AOC): Treatment with trastuzumab—A GINECO study
Authors: J. P. Guastalla, D. Allouache, M. Combe, B. Weber, J. Cretin, H. Curé, M. Mousseau, D. Paraiso, S. Camilleri-Broët, E. Pujade-Lauraine
Journal: Journal of Clinical Oncology (2007)

5559 Background: Variable rates of HER2 protein overexpression and gene amplification have been reported in AOC. Trastuzumab (Herceptin [H]) has been tested only as single agent and has shown a 7% response rate (RR) in heavily pre-treated AOC patients (pts) with 3+ and 2+ HER2 immunostaining (IHC) (Bookman MA et al, J Clin Oncol 2003). GINECO has explored the combination of H with paclitaxel (T) and carboplatin (C) in pts with resistant AOC (&lt; 6 months) and HER2 gene amplification. Methods: 321 AOC pts were centrally screened for HER2 status (243 pts in first-line and 78 relapsing pts). All positive (3+) and doubtful (2+) cases were screened by fluorescence in-situ hybridisation (FISH). Pts with HER2 gene amplification, normal left ventricular ejection fraction (LVEF) and resistant relapse after first or second line of chemotherapy including TC were treated with T (175mg/m 2 , 3h), C (AUC 5) and H (9mg/kg first course, 6mg/kg subsequent courses) every 3 weeks. Results: Of the 321 cases tested, 22 (6,7%) were HER2+ by IHC and FISH. Only 7 pts (32%) with a median age of 56 (range: 48–70) met the eligibility criteria of the trial. Pts had measurable lesions (n=4) or elevated CA 125 level + non-measurable lesions (n=3). Three pts had complete response (6, 7+ and 24+ months) and 2 had stable disease (3 months). Toxicity was moderate: febrile neutropenia, Gr3 infection, Gr2 neurotoxicity and decrease of LVEF after 23 cycles of H were observed in one patient respectively. Conclusions: HER2 overexpression/amplification is low in advanced ovarian carcinoma (6,7 %). In this small prospective cohort of resistant patients, 3 of 7 have achieved complete remission when adding Trastuzumab to conventional chemotherapy. No significant financial relationships to disclose.
Immunization of Adults
Authors: Jane F. Desforges, Pierce Gardner, William Schaffner
Journal: New England Journal of Medicine (1993)

In the United States, the immunization of adults does not receive the same priority as the immunization of children, although deaths from vaccine-preventable diseases occur predominantly in adults. About 50,000 to 70,000 adults die each year from pneumococcal infection, influenza, or hepatitis B (Table 1),1 as compared with about 1000 children who die from diseases targeted by childhood immunizations. Reasons for the poor record of immunization of adults include lingering doubts on the part of both the public and health care providers about the efficacy and safety of vaccines; uncertainty about specific recommendations; concern about liability; inadequate reimbursement; and poorly . . .
Respiratory Function of Hemoglobin
Authors: Connie C.W. Hsia
Journal: New England Journal of Medicine (1998)

Hemoglobin is essential for oxygen transport, and the study of its structure and function has led to numerous discoveries that have shaped modern biologic science.1 This review will examine how hemoglobin actively regulates oxygen transport and will illustrate the clinical and physiologic importance of this regulation.Oxyhemoglobin Dissociation CurveThe oxyhemoglobin dissociation curve describes the relation between the oxygen saturation or content of hemoglobin and the oxygen tension at equilibrium. Bohr2,3 first showed that the dissociation curve was sigmoid-shaped, leading Hill4 to postulate that there were multiple oxygen-binding sites on hemoglobin and to derive an empirical approximation of the . . .
PTH-326 Cytoreductive surgery and heated intraperitoneal chemotherapy with synchronous liver resection for metastases of colorectal origin
Authors: R Fish, R Deshpande, O Aziz, P Fulford, A Renehan, M Wilson, S O’Dwyer
Journal: Gut (2015)

<h3>Introduction</h3> The combination of peritoneal metastases (PMCR) and liver metastases in colorectal cancer (CRLM) has been considered a relative contra-indication to surgical treatment of either lesion. In the UK joint resection has not been widely undertaken and there is no published UK data. We present a cohort of eight synchronous liver resections with cytoreduction and heated intraperitoneal chemotherapy (CRS+HIPEC) at a single UK centre. <h3>Method</h3> All patients undergoing CRS+HIPEC with a hepatobiliary surgeon were identified from the prospectively kept PTS database. Patients who had only liver mobilisation were excluded. Outcome data was gathered from the electronic patient record and the PTS database. Post-hepatectomy liver failure was defined using International Study Group of Liver Surgery criteria. <h3>Results</h3> Seven patients underwent eight CRS+HIPEC procedures with synchronous liver resection for metastasis of colorectal origin over 5 years. Median PCI was 9 (range 3–17), with CC-0/1 resection in all patients. The median volume of resected liver was 90.6 cm<sup>3 </sup>(2760 cm<sup>3</sup>– 15 cm<sup>3</sup>). Median CCU stay was 2 (1–3) days and hospital stay 11 (8–20) days. Two patients experienced grade 3–4 complications: one grade-A post-hepatectomy liver failure and one sepsis. There was no 30 day mortality. Median CCU stay, inpatient stay, and grade 3–4 complication rate for patients undergoing CRS+HIPEC without liver resection for PMCR (n = 85) in our unit is 2 (0–16) days 12 (4–141) days and 21% respectively. Three patients are alive at a median follow-up of 59.2(39–61) months. All surviving patients had CC0 resections and PCI &lt;11. Median overall survival is 36.9 months. <h3>Conclusion</h3> In selected patients with metastatic colorectal cancer, synchronous liver resection with CRS+HIPEC is safe, with inpatient stay, CCU stay and complication rates comparable to CRS+HIPEC without liver resection in our unit. Our outcomes and survival figures are consistent with published data which suggests improved overall survival compared to modern systemic chemotherapy. <h3>Disclosure of interest</h3> None Declared.
Case 35-2006
Authors: Robert H. Brown, P. Ellen Grant, Christopher R. Pierson
Journal: New England Journal of Medicine (2006)

A 2-day-old boy was hospitalized because of hypotonia. Neurologic examination showed diffuse hypotonia, no tongue fasciculations, absent deep-tendon reflexes in the arms, trace reflexes at the knees, and bilateral ankle clonus. The serum creatine kinase level was 14,528 U per liter. A diagnostic procedure was performed.
Infections and Antibiotic Use among Patients at Boston City Hospital, February, 1967
Authors: Fred F. Barrett, Joan I. Casey, Maxwell Finland
Journal: New England Journal of Medicine (1968)

In a survey of infections and antibiotic use at the Boston City Hospital in February, 1967, 26.3 per cent of the patients had infections considered to be community-acquired, and 15.5 per cent had infections assumed to be acquired in the hospital. The prevalence rates of infections did not differ greatly from those found in a similar survey conducted at this hospital in 1964. Gram-negative bacilli were isolated much more often from nosocomial than from community-acquired infections. The frequency of isolation of Staphylococcus aureus in hospital-acquired infections has decreased by more than 50 per cent since 1964, whereas gramnegative bacilli and enterococci have increased appreciably. Antibiotic use at this hospital had changed very little in 1967 as compared with 1964.
NTCT-13VAGOGLOSSOPHARYNGEAL NEURALGIA PRESENTING AS FREQUENT SEIZURE-LIKE SPELLS IN A PATIENT WITH HEAD AND NECK CANCER TREATED WITH HIGH CUMULATIVE RADIATION DOSE
Authors: Alicia Zukas, David Schiff
Journal: Neuro-Oncology (2015)

A 62-year-old man presented with six months of numerous seizure-like events with a sequence of light-headedness, tonic extension of the right arm, loss of consciousness, urinary incontinence and convulsion. He had been diagnosed with laryngeal cancer five years prior, treated with definitive radiotherapy 72Gy in 36 fractions to the left glottis. He had local cancer recurrence three years later and was treated with additional surgeries including bilateral neck dissection and a pectoralis major myocutaneous flap. The following year he required extensive surgery for local disease recurrence and additional reconstruction. He underwent a second course of radiation of 60Gy in 30 fractions with concomitant cisplatin as a radiosensitizer. He achieved complete disease remission, with symptoms related to radiation dermatitis, dysphagia, and left ear pain. More than 20 seizure-like spells were documented, beginning fourteen months after final treatment. Many episodes were heralded by acute jaw and throat pain. Physical examination revealed an iatrogenic left hypoglossal nerve deficit, soft palate scarring, and post-radiation changes to the free flap of the neck and throat. During target events, his heart rate was 20 beats per minute and mean arterial pressure was 40-45 mmHg. EEG, brain MRI, and transthoracic echocardiogram were normal. This phenomenology of seizure-like activity led us to consider the rare entity of radiation-related vagoglossopharyngeal neuralgia, given the very high cumulative local radiation dose. We treated him accordingly with midodrine and fludrocortisone after an incomplete response to atropine. Gabapentin, carbamazepine, and aggressive analgesia provided partial relief of his pain attacks. He remained syncope-free for four months and elected hospice at the time of cancer recurrence. There have been rare reported cases of cancer treatment-related glossopharyngeal neuralgia with convulsive syncope. Prompt diagnosis is necessary because it is a treatable life-threatening condition that could be confused for seizure presentation.
The role of infant observation in child psychiatry training
Authors: G W Greenman, R Benson, L Grapentine, C Legg, I Sherick
Journal: American Journal of Psychiatry (1978)

The authors discuss the role of infant observation in the training of child psychiatrists, emphasizing the overriding importance of the subtle but crucial interactions in the mother-infant relationship. Infant observation is valuable in preparing the student as an observer of behavior, and developmental concepts are taught and learned more easily in programs that provide opportunities for observing normal infants. The infant study program in the Department of Psychiatry of the University of Michigan Medical Center is presented as a model.
Sex-Linked Hereditary Thrombocytopenia as a Variant of Wiskott–Aldrich Syndrome
Authors: Luis Canales, A. M. Mauer
Journal: New England Journal of Medicine (1967)

SEX-linked, hereditary thrombocytopenia is a rarely reported disorder. Only 3 cases have been described.1 2 3 More commonly reported is the Wiskott–Aldrich syndrome,4 , 5 in which sex-linked, hereditary thrombocytopenia is associated with eczema, frequent infections and early death. In the family described below, sex-linked, recessive, hereditary thrombocytopenia was found on closer inspection to be related to the Wiskott–Aldrich syndrome in some respects.Family StudiesThe propositus (IV-8) was admitted to the Children's Hospital at the age of 18 months because of iron-deficiency anemia. On physical examination he was pale, and there were scattered ecchymoses. The hemoglobin concentration was 4.7 gm per 100 ml, . . .
Tumor priming using metronomic chemotherapy with neovasculature-targeted, nanoparticulate paclitaxel
Authors: Xin Luan, Ying-Yun Guan, Jonathan F. Lovell, Mei Zhao, Qin Lu, Ya-Rong Liu, Hai-Jun Liu, Yun-Ge Gao, Xiao Dong, Si-Cong Yang, Lin Zheng, Peng Sun, Chao Fang, Hong-Zhuan Chen
Journal: Biomaterials (2016)