The immune response to a fungus in pancreatic cancer samples.

Pancreatic ductal adenocarcinoma (PDAC) is a poor prognosis cancer with an .aggressive growth profile that is often diagnosed at late stage and that has few curative or therapeutic options. PDAC growth has been linked to alterations in the pancreas microbiome, which could include the presence of the fungus Malassezia. We used RNA-sequencing to compare 14 paired tumor and normal (tumor adjacent) pancreatic cancer samples and found Malassezia RNA in both the PDAC and normal tissues. Although the presence of Malassezia was not correlated with tumor growth, a set of immune- and inflammatory-related genes were up-regulated in the PDAC compared to the normal samples, suggesting that they are involved in tumor progression. Gene set enrichment analysis suggests that activation of the complement cascade pathway and inflammation could be involved in pro PDAC growth.

Phase IB study of the combination of docetaxel, gemcitabine, and bevacizumab in patients with advanced or recurrent soft tissue sarcoma: the Axtell regimen.

BACKGROUND: To assess the response of patients with soft tissue sarcoma (STS) to the combination of docetaxel, bevacizumab, and gemcitabine. Vascular endothelial growth factor (VEGF)-A levels and expression of VEGF-A and VEGF receptors 1 and 2 were evaluated. PATIENTS AND METHODS: Thirty-eight chemotherapy-naive patients with STS were enrolled. A dose-finding study for gemcitabine from 1000, 1250, then 1500 mg/m(2) was done in nine patients (three cohorts), followed by an expansion cohort of 27 patients. Dose of docetaxel was 50 mg/m(2), bevacizumab was 5 mg/kg, and gemcitabine was 1500 mg/m(2), every 2 weeks. Serum VEGF-A was measured by enzyme-linked immunosorbent assay and tissue VEGF-A and its receptors by immunohistochemistry. RESULTS: The median follow-up was 36 months. The overall response rate observed was 31.4%, with 5 complete and 6 partial responses, and 18 stable diseases lasting for a median of 6 months. There was no significant hematologic toxicity. The adverse events with the highest grade were attributed to bevacizumab. There was no correlation of VEGF pathway biomarkers with outcome. CONCLUSIONS: The combination of gemcitabine, docetaxel, and bevacizumab is safe and effective in patients with STS. The most concerning adverse events were consequences of bevacizumab administration. The benefit of bevacizumab in this patient population remains unclear.

Basic knowledge of the medication regimen correlates with performance on cognitive function tests and diagnosis of dementia in elderly patients referred to a geriatric assessment unit.

BACKGROUND: Cognitive decline and dementia are highly prevalent amongst the elderly. Medication management problems are also prevalent in this population. Although both problems coexist, the quantitative association between them has not been comprehensively analyzed. METHOD: A prospective cross-sectional study of a successive cohort of 425 patients was performed in a community-based geriatric assessment unit. Personal information, results of cognitive function tests, a diagnosis of dementia and an examination of basic knowledge of the medication regimen were recorded and entered into a patient register at the end of each patient's assessment. RESULTS: Performance in cognitive function tests was significantly poorer in patients demonstrating lack of basic knowledge of the medication regimen. Mean Mini-Mental State Examination score: 19.1 versus 25.5 (p<0.001); mean number of words recalled on a 3-word recall test: 1.0 versus 1.84 (p<0.001); abnormal clock drawing test: 82 versus 57.7%, respectively (p<0.001). The number of patients diagnosed with dementia was greater among patients who demonstrated lack of basic knowledge of the medication regimen (46.8 vs. 6.9%, respectively; p<0.001). CONCLUSION: A strong association between lack of basic knowledge of the medication regimen and cognitive dysfunction was demonstrated in elderly patients referred to a geriatric assessment unit, suggesting that lack of basic knowledge of the medication regimen is indicative of cognitive dysfunction and vice versa.

Phase I study of capecitabine in combination with cisplatin and irinotecan in patients with advanced solid malignancies.

PURPOSE: This phase I trial assessed the safety and the maximum tolerated dose of capecitabine given for 10 days prior to a combination of cisplatin and irinotecan in patients with advanced solid malignancies. It also evaluated the changes in cisplatin DNA adducts induced by capecitabine. PATIENTS AND METHODS: Patients with refractory solid tumors who had not failed 5-fluorouracil (5-FU) analogs or topoisomerase I inhibitors were eligible. All cohorts of patients first received a 28-day cycle of cisplatin and irinotecan. Both drugs were given at a dose of 50 mg/m(2) intravenously on day 1, followed by irinotecan on days 8 and 15 at the same dose. The first cycle served as an internal control. Starting from the second cycle, patients received increasing doses per cohort of capecitabine from day 1 to 10 of each cycle, followed by cisplatin on day 11 and irinotecan on days 11, 18 and 25, both at same doses as the first cycle. Cycles were repeated every 38 days. The starting dose of capecitabine was 500 mg/m(2)/day which was escalated by 250 mg/m(2)/day in the subsequent cohort of patients to reach the maximum tolerated dose (MTD). Later, additional patients were treated at the MTD of capecitabine to further evaluate the safety, pharmacodynamics, and tumor response. Patients blood was tested for cisplatin-DNA adducts to determine the impact of capecitabine on cisplatin-based therapy. RESULTS: Fifteen patients received at least 2 cycles of treatment. At 1,250 mg/m(2), two DLT of prolonged neutropenia of grade > or =3 were observed. The MTD for capecitabine was thus determined to be 1000 mg/m(2)/day. Fatigue and diarrhea of grade 1 or 2 were the most frequent toxicities at this dose level. No significant hematologic toxicity was observed at the MTD. Two complete and three partial remissions were observed. Four of the responders had received a platinum agent and/or 5-FU in the past. CONCLUSIONS: A sequential treatment with capecitabine followed by cisplatin and irinotecan is well tolerated and demonstrates clinical activity in patients with advanced solid malignancies. The influence of capecitabine, if any, on the efficacy of the cisplatin-irinotecan combination is not related to a variation in cisplatin-DNA adducts.

Molecular basis of von Willebrand disease type IIB. Candidate mutations cluster in one disulfide loop between proposed platelet glycoprotein Ib binding sequences.

Many variants of von Willebrand disease (vWD) with qualitatively abnormal von Willebrand factor (vWF) are recognized. In vWD type IIB, the abnormal protein displays enhanced affinity for a platelet vWF receptor, the glycoprotein Ib-IX complex. 14 patients from 7 unrelated families with vWD type IIB were studied to determine the molecular basis for this phenotype. Specific oligonucleotide primers were used to amplify portions of vWF exon 28 encoding a domain that interacts with the platelet glycoprotein Ib-IX complex. Candidate missense mutations were identified for all 14 patients by DNA sequencing, allele specific oligonucleotide hybridization, and restriction endonuclease digestion. These sequence changes occur in an 11 amino acid segment within a single disulfide loop bounded by Cys(509) and Cys(695). All of these sequence changes are C----T transitions within CG dinucleotides. Six patients from two unrelated families were heterozygous for the encoded sequence Arg(543)----Trp. Seven patients from four unrelated families were heterozygous for the encoded sequence Arg(545)----Cys; this sequence change appears to have occurred independently three times, once as a new spontaneous mutation. One patient with apparently sporadic vWD type IIB was heterozygous for the encoded sequence Val(553)----Met, and this appears to be a new mutation. None of these sequence changes was found in 100 normal alleles. These findings suggest that vWD type IIB may be caused by relatively few distinct mutations, that these mutations may cluster within a specific region of one disulfide loop in vWF domain A1, and that this region can modulate the affinity of vWF for the platelet glycoprotein Ib-IX complex.

Chronic myelogenous leukemia with acquired t(11;14)(q13;q32) CCND1-IGH: A case report and literature review.

Approximately 5-10% of chronic myeloid leukemia (CML) patients are found to have structural or numerical additional chromosomal abnormality (ACAs) in addition to the characteristic t(9;22)(q34;q11.2) BCR/ABL1 at the time of diagnosis. The prognostic significance of such additional chromosomal abnormalities has been controversial. Translocation t(11;14)(q13;q32) CCND1-IGH is typically associated with mantle cell lymphoma or a subset of plasma cell myeloma and is exceedingly rare in myeloid neoplasm. Here we report a unique case describing a patient found at diagnosis of chronic phase CML to have both the Philadelphia chromosome as well as t(11;14)-a rare cytogenetic combination. The patient was treated with imatinib with appropriate hematologic response but persistent disease by FISH and RT-PCR. She was switched to dasatinib and eventually achieved cytogenetic remission in both translocations, but still with persistent RT-PCR evidence of BCR-ABL1 fusion. As cyclin D1 is a regulatory subunit of cyclin-dependent kinases CDK4 and CDK6 and is required for the cells to progress through the G1 phase of the cell cycle, overexpression of cyclin D1 will likely promote cells into cell cycle. This may further augment proliferation in addition to upregulated ABL1 kinase activity in the index case. It may also contribute to the resistance to imatinib, as imatinib only targets on BCR-ABL fusion. Therefore, the addition of t(11;14)(q13;q32) may have significant implication in patient management.

Physician compliance with warfarin prophylaxis for central venous catheters in patients with solid tumors.

PURPOSE: There is an established benefit of prophylactic warfarin in cancer patients with central venous catheters. This study assessed the compliance rate of prophylactic low-dose warfarin prescription in cancer patients with central venous catheters at a single institution. PATIENTS AND METHODS: Oncology patients with central venous catheters were identified by a retrospective chart review. Information retrieved included whether prophylactic warfarin had been prescribed and whether the patient had suffered a thrombotic or bleeding event. After the initial chart review, physicians were notified of the benefits of warfarin prophylaxis, and subsequently, a physician-independent mechanism of prescribing prophylactic warfarin was instituted. After each of these interventions, we retrospectively reviewed a further two cohorts of patients to assess compliance with warfarin prophylaxis. RESULTS: During the baseline study, only 10% of patients were prescribed prophylactic warfarin. After physician notification, the compliance rate increased to only 20% (P =.3). After instituting the physician-independent mechanism of prescribing prophylactic warfarin, the compliance rate increased to 95% (P <.001). The rate of catheter-related thrombosis was 11% for patients who were prescribed warfarin compared with 21% in those who were not anticoagulated (P =.2). CONCLUSION: At our institution, the rate of prescribing prophylactic warfarin was low in this patient population, and there was a reluctance of treating physicians to change their prescribing practice. Mechanisms exist to improve the rate of anticoagulant prophylaxis in this clinical setting. We recommend that institutions review their rate of compliance with prophylactic anticoagulation for patients with central venous catheters and solid tumors.

A randomized trial assessing the utility of a test-dose program with taxanes.

OBJECTIVE: Taxanes are commonly used anticancer agents with a potential of producing an allergic or hypersensitivity reaction (HSR). We performed a randomized study to evaluate the value of a test dose given prior to the full dose of either paclitaxel or docetaxel. RESEARCH DESIGN AND METHODS: Patients were randomly assigned to either the administration of the full dose or to the prior administration of a 1 mg intravenous test dose of either paclitaxel or docetaxel. The primary endpoints were severity of the HSR and the cost of drug wastage due to a HSR. RESULTS: Two hundred and eighteen patients were randomized from three different treatment sites. The overall incidence of HSR was 6.5% and there was no significant difference in the incidence of HSR in either group. The mean HSR severity grade was 2.8 for patients without a test dose and 2.3 for those receiving a test dose. There was, however, a reduction in the wastage of taxane in the test dose arm. Wastage avoided in the test dose arm was $1573 per patient who had a HSR and $104 per patient treated with a taxane. CONCLUSION: Although a test dose may not reduce the severity of a HSR with the administration of a taxane, it does reduce the cost associated with drug wastage.

The role of prostaglandin E, cyclic AMP, and cyclic GMP in the proliferation of guinea-pig ear skin stimulated by topical application of vitamin A acid.

Daily treatment of guinea-pig ear skin with topical 0.5% retinoic acid in acetone produced erythematous scaly dermatitis. Histologic sections revealed bandlike thickening of the epidermis on days 2 to 4, psoriasiform acanthosis, papillomatosis and increased mitotic activity on days 5 to 6. Also seen were dilatation of the upper dermal blood vessels and a fibroblastic, histiocytic reaction in the dermis. Prostaglandin E, cyclic AMP, and cyclic GMP levels were increased in the treated skin and thymidine incorporation was enhanced. Cyclic AMP and GMP levels peaked on day 5 simultaneous with maximal epidermal hyperplasia, increased mitotic activity and dermal reaction. Tritiated thymidine uptake peaked on days 4 and 5, and prostaglandin E levels continued to increase up to day 6. Cyclic AMP phosphodiesterase activity of treated skin on day 5 did not appear to be significantly different from control.

Accuracy of radiation field alignment in clinical practice.

We present an analysis of simulator and portal films of 71 patients. Twenty-five were analyzed retrospectively, 39 prospectively, but without changing routine filming practice, and 7 had daily portal films taken. Treatment-to-treatment variations in anatomy with respect to the field were determined by comparing sequential portal films. The standard deviation of the variations was approximately normally distributed with an average value of 3 mm independent of site and field shaping technique. Discrepancies between the portal and simulator films were greater and depended on the site of treatment. The mean worst-case discrepancy averaged over all sites was 7.7 mm; the lowest value was 3.5 mm in the head and neck region; the highest value was 9.2 mm in the thorax.

Characterization of three mutations causing von Willebrand disease type IIA in five unrelated families.

Von Willebrand disease (vWD) type IIA is characterized by decreased ristocetin-induced platelet aggregation, and by the absence from plasma of high molecular weight multimers of von Willebrand factor (vWF). Most mutations causing vWD type IIA are clustered within the A2 domain of the mature vWF subunit that is encoded by exon 28. Using the polymerase chain reaction (PCR), the entire exon 28 from patients with vWD type IIA and normal controls was amplified and sequenced. Three missense mutations were detected that result in the amino acid substitutions were detected that result in the amino acid substitutions Arg(834)----Trp, Gly(742)----Glu, and Ser(743)----Leu. The first mutation occurred independently in three unrelated families; each of the latter mutations was found in one family. By restriction endonuclease analysis and allele-specific oligonucleotide (ASO) hybridization the mutations were confirmed in affected family members and excluded in unaffected members and 50 normal controls. The apparently high frequency of identical independent mutations among patients with vWD type IIA suggests that a precise diagnosis may be possible in a majority of patients using relatively simple recombinant DNA screening assays.

Interviewing prepubertal children about suicidal ideation and behavior.

OBJECTIVE: Much of the literature on assessment of suicidal children has focused on identifying risk factors associated with suicidal ideation and behavior in this population. Unique problems encountered in interviewing prepubertal children about suicidal ideation and behavior are examined in this paper. METHOD: Observations of problems encountered in interviewing prepubertal children about suicidal ideation and behavior were gleaned in the context of interviews of children admitted to a child psychiatry inpatient unit and interviews of the parents of these children. RESULTS: Unique problems include difficulties in assessment of suicidal intent, impact of cognitive development, particularly of the concept of death, interaction between current emotional state and memory of previous suicidal episodes, characteristics of play associated with suicidal states, effects of parents' attitudes toward assessment on information gathering, and the impact of certain risk factors on cognition and behavior during the interview. CONCLUSION: Interviewing children about suicidal ideation and behavior necessitates that the clinician attend to multiple elements of the interview simultaneously. These interviews are further complicated by the stressful thoughts and feelings that can be raised in both clinician and child in reaction to exploring the child's suicidal ideation and behavior. Additional research is needed to refine the process of reliable interviewing of children about suicidal ideation and behavior and to develop instruments both to quantitate the different elements of these interviews and to guide the clinicians conducting them.

A patient with chronic lymphocytic leukemia and acquired angioedema: correlation of clinical and biochemical response to CLL therapy.

Acquired angioedema (AAE) is a result of an acquired deficiency or inactivity of the C1 esterase inhibitor (C1-INH). There is a well-known link between AAE and lymphoplasmacytic disorders.A 65-year-old woman who was diagnosed with chronic lymphocytic leukemia (CLL), presented with recurrent episodes of angioedema. Although no association between the CLL and angioedema was initially recognized, further workup showed her to have low C1-INH levels. Chemotherapy helped prevent subsequent episodes, but three years later she redeveloped angioedema. She was then placed on ofatumumab maintenance and has since remained free of angioedema.Knowledge of this rare disease and anticipation of the link between CLL and AAE can prevent further attacks and associated morbidity.

An unusual reoccurrence of Waldenstrom's macroglobulinemia as pleural effusions that had a discordant response with treatment.

A 77-year-old female with a past medical history of Waldenstrom's macroglobulinemia presented with progressive shortness of breath and a newly diagnosed left pleural effusion. Numerous diagnostic studies were performed on the patient and finally a pleural biopsy confirmed pulmonary involvement of Waldenstrom's macroglobulinemia. As past studies have shown, Waldenstrom's involvement as a pulmonary process is uncommon. Unexpectedly, treatment with rituximab and fludarabine did decrease the patient's serum immunoglobulin M levels, but her pleural effusions never improved.

Calcium oxalate crystalluria: crystal size in urine.

Studies of calcium oxalate crystals in urine suggest similarities to crystal growth in calcium oxalate renal calculi. Previous reports indicate that urinary crystals in patients in whom stones form are larger than those in normal subjects. We report herein a study on crystal size by structure and habit (shape) based on direct microscopic measurement of crystals in urine of 27 normal subjects and in 6 of 22 patients in whom stones form. The mean size of all crystals in normal subjects is 12.0 plus or minus 7.8 micrometers. Calcium oxalate monohydrate crystals are significantly smaller than calcium oxalate dihydrate (p less than 0.01). In 22 patients with stones there was no correlation between crystalluria and severity or duration of disease. The mean crystal size in 6 patients did not support the conclusion that patients in whom stones form excrete larger crystals than normal subjects.

Bleeding in a patient with lupus anticoagulant without associated hemostatic abnormalities.

Bleeding is very rare in patients with lupus anticoagulants in the absence of associated hemostatic abnormalities. Few cases have been reported with attention given to work-up for other coagulation defects. We report a case of spontaneous hematoma in a patient with lupus anticoagulant, immunoglobulin (Ig)M anticardiolipin antibodies, and no other associated abnormalities.

Calcium oxalate crystalluria.

Calcium oxalate crystals were obtained from urine specimens submitted to a hospital laboratory. The incidence of crystalluria was 4.2 per cent of 42 times the maximum reported incidence of urinary calculi. In our opinion the crystalluria was real and not artifactual. The crystalline structure was determined by polarized light, x-ray diffraction and electron microprobe analysis. Calcium oxalate occurs in several forms--the dihydrate as bipyramidal and dodecahedral prisms, the monohydrate as biconcave ovals, dumbbell shapes and intermediate forms.

Topical steroid depression of the hypothalamic-pituitary-adrenal axis in psoriasis vulgaris.

Significant suppression of the hypothalamic-pituitary-adrenal axis has been found in patients hospitalized with psoriasis vulgaris and receiving topical fluorinated steroid therapy. Depression of thyroid function and involvement of autoimmune processes is also suggested by the data.

The effectiveness of a remote access hotline service for the handling of night shift calls.

In order to justify dedicated staff for night calls, improve the quality of our handling of these calls, and qualify for certification by the AAPCC, we sought an alternative to hiring dedicated night staff. We offered our certified staff members the opportunity to fulfill part of their regular duties answering night calls from home. We set them up with a computer system, dedicated telephone line, texts and consultant information. They were able to access the Poison Center hotline computer via a remote access program. A significant increase took place in the number of documented calls to the Poison Center during the midnight to 8:00 am shift. Quality of documentation also improved significantly and level of service has been complemented by callers. The remote access method is a viable way for a small Poison Center to cover the night shift with certified, reliable, capable staff. This method of call answering has solved our major problem of hiring night staff who would satisfy requirements and provide excellent service.