Changes over time in the course of advanced pancreatic cancer treatment with systemic chemotherapy: a pooled analysis of five clinical trials from two decades of the German AIO study group.

BACKGROUND: Over the past two decades, our group has conducted five multicenter trials focusing on first-line systemic therapy for patients with advanced pancreatic cancer. The current pooled analysis was designed to evaluate prognosis over time and the impact of clinical characteristics on survival. PATIENTS AND METHODS: Individual patient data were derived from five prospective, controlled, multicenter trials conducted by the 'Arbeitsgemeinschaft Internistische Onkologie' (AIO): 'Gem/Cis', 'Ro96', 'RC57', 'ACCEPT' and 'RASH', which recruited patients between December 1997 and January 2017. RESULTS: Overall, 912 patients were included. The median overall survival (OS) for all assessable patients was 7.1 months. OS significantly improved over time, with a median OS of 8.6 months for patients treated from 2012 to 2017 compared with 7.0 months from 1997 to 2006 [hazard ratio (HR) 1.06; P < 0.004]. Eastern Cooperative Oncology Group performance status (HR 1.48; P < 0.001), use of second-line treatment (HR 1.51; P < 0.001), and Union for International Cancer Control (UICC) stage (III versus IV) (HR 1.34, P = 0.002) had a significant impact on OS. By contrast, no influence of age and gender on OS was detectable. Comparing combination therapy with single-agent chemotherapy did not demonstrate a survival benefit, nor did regimens containing epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) such as afatinib or erlotinib, compared with chemotherapy-only arms. Patients with early-onset pancreatic cancer (age at study entry of ≤50 years, n = 102) had a similar OS compared with those >50 years (7.1 versus 7.0 months; HR 1.13; P = 0.273). The use of a platinum-containing regimen was not associated with better outcomes in patients with early-onset pancreatic cancer. CONCLUSIONS: Within this selected group of patients treated within prospective clinical trials, survival has shown improvement over two decades. This effect is likely attributable to the availability of more effective combination therapies and treatment lines, rather than to any specific regimen, such as those containing EGFR-TKIs. In addition, concerning age and sex subgroups, the dataset did not provide evidence for distinct clinical behavior.

Cancer of unknown primary (CUP) through the lens of precision oncology: a single institution perspective.

PURPOSE: For patients with cancer of unknown primary (CUP), treatment options are limited. Precision oncology, the interplay of comprehensive genomic profiling (CGP) and targeted therapies, aims to offer additional treatment options to patients with advanced and hard-to-treat cancers. We aimed to highlight the use of a molecular tumor board (MTB) in the therapeutic management of CUP patients. METHODS: In this single-center observational study, CUP patients, presented to the MTB of the Comprehensive Cancer Center Munich LMU, a tertiary care center, were analyzed retrospectively. Descriptive statistics were applied to describe relevant findings. RESULTS: Between June 2016 and February 2022, 61 patients with unfavorable CUP were presented to the MTB, detected clinically relevant variants in 74% (45/61) of patients, of which 64% (29/45) led to therapeutic recommendation. In four out of 29 patients (14%), the treatment recommendations were implemented, unfortunately without resulting in clinical benefit. Reasons for not following the therapeutic recommendation were mainly caused by the physicians' choice of another therapy (9/25, 36%), especially in the context of worsening of general condition, lost to follow-up (7/25, 28%) and death (6/25, 24%). CONCLUSION: CGP and subsequent presentation to a molecular tumor board led to a high rate of therapeutic recommendations in patients with CUP. Recommendations were only implemented at a low rate; however, late GCP diagnostic and, respectively, MTB referral were found more frequent for the patients with implemented treatment. This contrast underscores the need for early implementation of CGP into the management of CUP patients.

Early clinical trial unit tumor board: a real-world experience in a national cancer network.

PURPOSE: Early clinical trials are the first step into clinical therapies for new drugs. Within the six Bavarian university-based hospitals (Augsburg, Erlangen, Regensburg, Munich (LMU and TU), Würzburg) we have enrolled a virtual network platform for patient discussion. METHODS: The virtual Early Clinical Trial Unit Tumor Board (ECTU Tumor Board) is a secured web-based meeting to evaluate early clinical trial options for patients, where representatives from local ECTUs participate. We retrospectively analyzed patient cases discussed between November 2021 and November 2022. RESULTS: From November 2021 to November 2022, a total of 43 patients were discussed in the ECTU Tumor Board. Median age at diagnosis was 44.6 years (range 10-76 years). The median number of previous lines of therapies was 3.7 (range 1-9 therapies) including systemic treatment, surgery, and radiation therapy. A total of 27 different tumor entities were presented and 83.7% (36/43) patients received at least one trial recommendation. In total, 21 different active or shortly recruiting clinical trials were recommended: ten antibody trials, four BiTE (bispecific T cell engager) trials, six CAR (chimeric antigen receptor) T-cell trials, and one chemotherapy trial. Only six trials (28.6%) were recommended on the basis of the previously performed comprehensive genetic profiling (CGP). CONCLUSION: The ECTU Tumor Board is a feasible and successful network, highlighting the force of virtual patient discussions for improving patient care as well as trial recruitment in advanced diseases. It can provide further treatment options after local MTB presentation, aiming to close the gap to access clinical trials.

Lost in translation? English- and Spanish-speaking women's perceptions of gestational weight gain safety, health risks and counseling.

OBJECTIVE: To determine English- and Spanish-speaking women's perceptions on gestational weight gain (GWG) counseling. STUDY DESIGN: We administered a written survey to 279 pregnant women regarding GWG counseling and knowledge. We compared English- and Spanish-speaking women's responses using X(2)-tests and logistic regression analyses. RESULT: Seventy-four (27%) women completed the survey in Spanish and 205 (73%) in English. More Spanish compared with English speakers did not know if their provider recommended weight gain goals (26% vs 10%, odds ratio (OR) 3.2, confidence interval (CI) 1.5 to 6.5); if there are risks to excessive GWG for mother (27% vs 11%, OR 3.1, CI 1.5 to 6.4) or infant (38% vs 16%, OR 3.3, CI 1.7 to 6.3); or if exercise (15% vs 1%, OR 12.1, CI 3.0 to 69.1) or weight loss (35% v 12%, OR 4.0, CI 2.0 to 8.0) were safe during pregnancy. CONCLUSION: Significant differences exist between Spanish- and English-speaking women's perception of GWG counseling, which may be due to language or cultural barriers.

Long polymerase chain reaction amplification of heterogeneous HIV type 1 templates produces recombination at a relatively high frequency.

Studies of HIV molecular evolution and pathogenesis have relied on the polymerase chain reaction (PCR) to provide sequence information from infected tissues. Until recently, studies have been constrained by the limited length of fragments that can be reliably amplified. The addition of a thermostable 3'-exonuclease activity and altered cycling profiles has increased the length of target sequences that can be amplified by more than 10-fold. We have evaluated the fidelity of long PCR (LPCR). We determined that LPCR amplification maintains the distribution of sequences found in a heterogeneous sample and introduces nucleotide misincorporations at a rate comparable to that found with routine PCR. However, a significant proportion of the LPCR-amplified DNA fragments resulted from recombination events. This result suggests that LPCR amplification may have limited utility in the production and analysis of full-length HIV clones.

Characterization of V3 loop of HIV type 1 spreading rapidly among injection drug users of Manipur, India: a molecular epidemiological perspective.

PIP: Blood samples were obtained from six HIV-infected IV drug users attending the Indian Council for Medical Research Clinic at Imphal, the capital of Manipur state, as part of a study to analyze the sequences of the third variable region (V3) of the HIV envelope in that population. 18 sequences were obtained from the study participants, men aged 24-29 years. A fragment of the envelope gene encompassing the entire V3 loop and partial sequences from the third conserved region was sequenced, while amplifications were performed on DNA extracted directly from patient peripheral blood mononuclear cells to avoid the introduction of artifacts during cell culture. One set of viruses seems to be most closely related to a prototypical virus recovered from IV drug users in Thailand (Thai B), while the other sequences clustered more closely with a North American clade B virus (HXB). Sequences recovered from one person are rather diverse.^ieng

Use of the World Wide Web in research: randomization in a multicenter clinical trial of treatment for twin-twin transfusion syndrome.

OBJECTIVE: To describe the process involved in using the World Wide Web to coordinate a randomized, multicenter international trial of treatment for twin-twin transfusion syndrome. METHOD: A Web site was designed by members of the research team, a Web consultant, and a senior computer programmer. The original intent was to provide patient randomization only, but the Web site later was designed so that centers could download a data collection form. Data could be entered directly into the Web site and subsequently imported into a database at the coordinating center. EXPERIENCE: The Web site has been active for 3 years, with 13 participating centers and 31 patients enrolled. COMMENT: Use of the World Wide Web to coordinate an international, multicenter trial is an efficient method. Although there are many benefits, the most obvious is the capability to initiate and conduct a large international trial at minimal cost.

Influence of crystalloid versus colloid infusion on peripartum colloid osmotic pressure changes.

Plasma colloid osmotic pressure acts to retain fluid in the intravascular space. Intravenous crystalloids have been identified as one of the major factors contributing to the consistent peripartum decline in colloid osmotic pressure. This study was undertaken to compare the effect of two crystalloid infusions (1000 and 2000 mL Plasma-Lyte A) and a colloid infusion (1000 mL 5% albumin) on the peripartum colloid osmotic pressure. Before elective cesarean section, 45 parturients received one of the three infusions. The lowest mean maternal colloid osmotic pressure (16.6 +/- 1.1 mmHg, P less than .05 compared with baseline) occurred in the 2000-mL crystalloid infusion group eight to 16 hours postpartum. Although the colloid osmotic pressure fell in all groups postpartum, this reduction was significantly (P less than .05) less during the first 24 hours in the colloid infusion group. Minimizing this disruption of the colloid osmotic pressure to pulmonary capillary wedge pressure gradient may be clinically important in selected patients.

Plasma choline in normal newborns, infants, toddlers, and in very-low-birth-weight neonates requiring total parenteral nutrition.

Choline deficiency is associated with hepatic abnormalities in adult volunteers and patients administered total parenteral nutrition (TPN). Preliminary investigation has suggested that plasma-free choline concentration (PFCh) is greater in neonatal animals, including humans, than in adults. The aims of this study were to determine the normal PFCh and phospholipid-bound choline concentration (PPLBCh) for newborns, infants, and toddlers and to determine the change during TPN. We also sought to determine the degree of fetal choline extraction, the relation between maternal and newborn plasma choline concentrations, and the relation between plasma choline status and normal newborn length, weight, and gestational age. Blood samples were obtained from 104 full-term newborns in two centers (Ben Taub and Maimonides), 25 mothers, 21 normal infants aged 20.3 +/- 11.8 wk, 12 normal infants aged 62.4 +/- 3.9 wk, and 14 preterm infants (gestational age = 28.9 +/- 2.2 wk) who required TPN. The vein PFChs were 28.1 +/- 13.0 nmol/mL (Ben Taub) and 68.1 +/- 16.9 nmol/mL (Maimonides). The artery PFChs were 27.1 +/- 13.0 nmol/mL (Ben Taub) and 57.9 +/- 11.6 nmol/mL (Maimonides). The vein PPLChs were 1004.7 +/- 246.6 nmol/mL (Ben Taub) and 1121.2 +/- 289.6 nmol/mL (Maimonides). The artery PPLChs were 1065.7 +/- 469.3 nmol/mL (Ben Taub) and 1106.9 +/- 285.8 nmol/mL (Maimonides). The vein-minus-artery differences for PFCh were 1.0 +/- 9.7 nmol/mL (Ben Taub) and 10.2 +/- 10.9 nmol/mL (Maimonides). The vein-minus-artery differences for PPLCh were -51.9 +/- 398.2 nmol/mL (Ben Taub General Hospital, Houston, Texas) and 14.4 +/- 254.3 nmol/mL (Maimonides, New York, New York). Maternal venous PFCh was 8.4 +/- 3.1 nmol/mL. Maternal venous PPLCh was 2592.1 +/- 584.0 nmol/mL (range = 1227.8-3729.0). Maternal venous PFCh correlated with newborn arterial PFCh (r = 0.53, P < 0.05) but not with newborn venous PFCh. No correlation was seen between maternal venous and newborn PPLCh. No significant differences were seen in PPLCh or choline extraction in Ben Taub versus Maimonides patients, although PFCh was significantly greater in the newborns from Maimonides (P < 0.05). The mean venous PFCh and PPLCh in the preterm infants before beginning TPN was 21.2 +/- 6.3 and 1366.8 +/- 339.1 nmol/mL, respectively. Just before initiation of tube feeding (4.0 +/- 2.7 d after TPN had been started), mean venous PFCh and PPLCh was 18.4 +/- 5.3 and 2251.8 +/- 686.9 nmol/mL, respectively. When TPN was discontinued and tube feeding increased to goal, after 10.8 +/- 10.4 d, venous PFCh and PPLCh was 22.6 +/- 8.7 and 2072.5 +/- 540.6 nmol/mL, respectively. Venous PFCh and PPLCh was 13.4 +/- 2.5 and 1827.5 +/- 327.0 nmol/mL, respectively in the older infant group. In conclusion, newborn PFCh is significantly greater than PFCh in adults but falls to adult levels within the first year of life. Low maternal PFCh may be associated with low newborn PFCh. Normal newborn plasma choline status has no bearing on intrauterine growth, although the role of maternal choline deficiency in underweight newborns is unknown. Newborn PPLCh is substantially below that of adults, which suggests its use in membrane synthesis during growth.

An endothelial nitric oxide synthase gene polymorphism is associated with preeclampsia.

OBJECTIVE: We sought to test the hypothesis that a polymorphism of the endothelial nitric oxide synthase gene (NOS3) is associated with preeclampsia. METHODS: We collected and performed polymerase chain reaction (PCR) on genomic DNA from pregnant patients with and without preeclampsia. Patient history and clinical course were evaluated. MAIN OUTCOME MEASURE(S): Frequency of the intron 4 polymorphism of NOS3 (designated allele A) among patients with preeclampsia compared with controls. Clinical features of patients with preeclampsia and the A allele compared with those patients with preeclampsia who did not have the A allele. RESULTS: The frequency of the A allele was 0.10 among controls versus 0.39 among patients with preeclampsia (p < 0.01). The odds ratio of developing preeclampsia when at least one A allele was present was 6.5 [95% confidence interval (CI): 2.1-19.7]. After adjusting for ethnic variation, the odds ratio increased to 7.2 (95% CI: 2.0-25.5). Among patients with preeclampsia, systolic blood pressure at the time of admission was higher for patients with at least one A allele compared with patients homozygous for the B allele (168 versus 156 mm Hg; p = 0.03), independent of gestational age (p = 0.01). CONCLUSION: These data provide evidence for an association between NOS3 and preeclampsia. In defined ethnic groups, this NOS3 may offer predictive information regarding the subsequent development of preeclampsia and its clinical course.

Molecular cloning and sequencing of MHC class II beta 1 domain of turkey reveals high sequence identity with chicken.

We report the nucleotide sequences of turkey (Meleagris gallopavo) major histocompatibility complex (MHC) class II loci (beta 1 domain or exon 2 encoding the peptide-binding region). In the present investigation, three distinct sequences from the beta 1 domain of turkey MHC class II were isolated. A BLAST search and phylogenetic analysis revealed that turkey MHC sequences are most similar to chicken and peacock MHC. There was no strong evidence of recombination among the turkey MHC sequences or with other avian MHC, but diversity was high. The diversity in this peptide-binding region may be the result of point mutation and balancing selection or frequent gene conversion within turkey. However, more work and data are needed to understand the evolution of turkey and other avian MHC. Moreover, polymerase chain reaction-restriction fragment-length polymorphism analysis of exon 2 using the Hinf I restriction enzyme demonstrated three restriction patterns and a preliminary evidence of multiple beta loci in turkey. PCR-RFLP analysis of turkey MHC class II loci could be a promising method of MHC genotyping, when more sequences are available. Turkey MHC haplotypes identified earlier by RFLP analysis should be sequenced to standardize turkey MHC nomenclature and to develop DNA based method of haplotyping.

Binocular versus monocular acuity in a patient with latent nystagmus.

This is a case of latent nystagmus with a significant improvement in acuity with both eyes open rather than with either eye alone. If this patient's visual acuity was tested only O.D. alone and O.S. alone, the best visual acuity obtainable would have been 20/60. This might have had serious implications for A.F.'s work since a minimum visual acuity of 20/40 is needed to keep a driver's license in New York State. Since binocular acuity was 20/20, I assured him that driving is safe.

Mechanical ventilation during pregnancy.

Mechanical ventilatory support is a significant component in the delivery of critical care. With increasing frequency, obstetric critical care nurses face the challenge of caring for women who require mechanical ventilation during pregnancy. It is important that those caring for such patients understand fundamental principles of mechanical ventilation, associated complications, and specific nursing care measures.

Group therapy versus ward rounds.

In this paper we present the development of an open-ended, unstructured, voluntary, unselected group which has met twice a week over a nine-month period. We further evaluate the use of this group in lieu of ward rounds, concluding that observations in a small group afford an effective adjunct to assessing a patient's current mental status. The group further provides a unique, on-going evaluation of the patient's interaction with others and, therefore, a better understanding of his individual problems. Group observations and the post-group meetings proved to be helpful teaching devices. The authors propose the use of this type of group therapy as a modification to the traditional medical model used on psychiatric units in general hospitals.

Comparison of intraocular pressure between normotensive and preeclamptic women in the peripartum period.

OBJECTIVE: Our purpose was to determine whether intraocular pressure differs between preeclamptic and normotensive women in the peripartum period. STUDY DESIGN: Eighteen preeclamptic (defined as blood pressure > 140/90 mm Hg and > or = 1+ proteinuria) and 18 normotensive women were studied. Intraocular pressure was determined with a handheld tonometer. Each intraocular pressure determination was obtained by repeatedly touching the cornea until signal averaging produced a single measurement with a variance < 5%. Right and left intraocular pressure, heart rate, and blood pressure were obtained intrapartum and 24 hours post partum with the patient in the seated, supine, and left lateral positions. Data are reported as mean +/- SD or median (range) as appropriate. Significance was set at p < 0.05. RESULTS: No differences existed in race, age, weight, gravidity, parity, cervical dilatation, and heart rate between the preeclamptic and normotensive groups. Gestational age was lower (39 [34 to 42] vs 41 [34 to 42] weeks, p = 0.003), and intrapartum mean arterial pressure (100.2 +/- 9.8 vs 81.0 +/- 8.3 mm Hg, p < 0.001) and degree of proteinuria (3 [1 to 4] vs 0, p < 0.001) were higher in the preeclamptic group. There was no effect of position or delivery on intraocular pressure in either group. Intraocular pressure was higher in the preeclamptic group in the intrapartum (18.8 +/- 3.0 vs 15.3 +/- 2.7 mm Hg, p < 0.001) and postpartum periods (20.2 +/- 4.5 vs 15.7 +/- 3.6 mm Hg, p = 0.002). CONCLUSION: Compared with normotensive women, preeclamptic women have increased intraocular pressure in the peripartum period.

Cardiovascular alterations in severe pregnancy-induced hypertension: relationship of central venous pressure to pulmonary capillary wedge pressure.

The relationship between central venous pressure and pulmonary capillary wedge pressure was studied in 18 patients with severe pregnancy-induced hypertension. Although statistically a linear relationship for the group as a whole could be identified, analysis on a case-by-case basis revealed different results. In 10 patients, a linear correlation between central venous pressure and pulmonary capillary wedge pressure was observed. However, accurate prediction of pulmonary capillary wedge pressure from central venous pressure was not possible even in this group because of large interindividual variations. In seven patients no correlation between central venous pressure and pulmonary capillary wedge pressure could be identified. In the last patient a curvilinear relationship existed between central venous pressure and pulmonary capillary wedge pressure. Additionally, in five cases of pulmonary edema, a negative gradient of colloid osmotic pressure to pulmonary capillary wedge pressure gradient was observed. Our data suggest that central venous pressure is not a clinically reliable predictor of pulmonary capillary wedge pressure.

Cardiovascular alterations in severe pregnancy-induced hypertension: acute effects of intravenous magnesium sulfate.

The central hemodynamic effects of intravenous magnesium sulfate were studied in five patients with severe pregnancy-induced hypertension. All five patients had a Swan-Ganz and a radial artery catheter placed prior to initiation of magnesium sulfate therapy. Four grams of magnesium sulfate was given over 15 minutes followed by a continuous infusion of 1.5 gm per hour. There was a 12.5% increase in cardiac index immediately after the infusion but cardiac index returned to pretherapy values by 15 minutes after infusion. The mean arterial pressure was significantly (p less than 0.01) decreased 30 minutes after the 4 gm loading dose but had returned to baseline values by 1 hour. There were no other significant changes in any of the hemodynamic or oxygen-related variables measured. Our data confirm previous hemodynamic studies in patients with severe pregnancy-induced hypertension indicating a hyperdynamic state with large fluctuations in systemic and pulmonary vascular resistances. In addition, magnesium sulfate has been shown to have a transient hypotensive effect on mean arterial pressure, related to bolus infusion, that is not present with continuous infusion.

Cardiovascular alterations in severe pregnancy-induced hypertension seen with an intravenously given hydralazine bolus.

The acute cardiovascular effects of a 10 milligram bolus of hydralazine was found to cause a significant increase in heart rate and cardiac index while decreasing mean arterial pressure and systemic vascular resistance index. A wide spectrum of individual responses was seen in terms of peak effects and duration of effects. The role of hydralazine in patients with severe pregnancy-induced hypertension was discussed and possible alternative therapy is suggested.

A simple method to estimate volume for fetal intravascular transfusions.

We derived a constant termed the transfusion coefficient to simplify the estimation of the fetal intravascular transfusion volume. The product of the estimated fetal weight (g) and 0.02 (transfusion coefficient), estimates the transfusion volume (ml) required to increase the fetal hematocrit by approximately 10 percentage points. Our estimation was comparable to Mandelbrot's technique and better than Plecas' method for estimating fetal transfusion volumes. Utilizing the transfusion coefficient to estimate the intravascular transfusion volume for an anemic fetus is simple, rapid and accurate.