Myelopreservation with the CDK4/6 inhibitor trilaciclib in patients with small-cell lung cancer receiving first-line chemotherapy: a phase Ib/randomized phase II trial.

BACKGROUND: Chemotherapy-induced damage of hematopoietic stem and progenitor cells (HSPC) causes multi-lineage myelosuppression. Trilaciclib is an intravenous CDK4/6 inhibitor in development to proactively preserve HSPC and immune system function during chemotherapy (myelopreservation). Preclinically, trilaciclib transiently maintains HSPC in G1 arrest and protects them from chemotherapy damage, leading to faster hematopoietic recovery and enhanced antitumor immunity. PATIENTS AND METHODS: This was a phase Ib (open-label, dose-finding) and phase II (randomized, double-blind placebo-controlled) study of the safety, efficacy and PK of trilaciclib in combination with etoposide/carboplatin (E/P) therapy for treatment-naive extensive-stage small-cell lung cancer patients. Patients received trilaciclib or placebo before E/P on days 1-3 of each cycle. Select end points were prespecified to assess the effect of trilaciclib on myelosuppression and antitumor efficacy. RESULTS: A total of 122 patients were enrolled, with 19 patients in part 1 and 75 patients in part 2 receiving study drug. Improvements were seen with trilaciclib in neutrophil, RBC (red blood cell) and lymphocyte measures. Safety on trilaciclib+E/P was improved with fewer ≥G3 adverse events (AEs) in trilaciclib (50%) versus placebo (83.8%), primarily due to less hematological toxicity. No trilaciclib-related ≥G3 AEs occurred. Antitumor efficacy assessment for trilaciclib versus placebo, respectively, showed: ORR (66.7% versus 56.8%, P = 0.3831); median PFS [6.2 versus 5.0 m; hazard ratio (HR) 0.71; P = 0.1695]; and OS (10.9 versus 10.6 m; HR 0.87; P = 0.6107). CONCLUSION: Trilaciclib demonstrated an improvement in the patient's tolerability of chemotherapy as shown by myelopreservation across multiple hematopoietic lineages resulting in fewer supportive care interventions and dose reductions, improved safety profile, and no detriment to antitumor efficacy. These data demonstrate strong proof-of-concept for trilaciclib's myelopreservation benefits. CLINICAL TRAIL NUMBER: NCT02499770.

Is there a benefit for health care workers in testing HIV, HCV and HBV in routine before elective arthroplasty?

INTRODUCTION: Occupational infection of clinical health care workers with blood-borne viruses (BBVs) like human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV) is a current and often emotionally discussed issue. HCV and especially HIV are still stigmatized. The consequence is a broad and maybe irrational fear of professional health care workers being infected occupationally. Therefore, we assessed preoperative screening to: (1) answer whether this can detect not previously diagnosed blood-borne virus infections to a great extent, (2) calculate a cost-benefit ratio to find out, if the screening's potential ability to prevent occupational transmission of BBVs to health care workers faces unjustifiable high costs. HYPOTHESIS: Preoperative routine screening is limited suitable for enhancement of detecting fomites compared to interview the patient. MATERIALS AND METHODS: Retrospective cohort study of preoperative screening for HIV, HBV and HCV (HBsAg, anti-HCV and HIV-Ab/Ag-Combination) for every patient who was admitted to the traumatologic department for elective arthroplasty between 01/01/1997 and 31/12/2008. RESULTS: Among the 1534 patients who underwent elective prosthetic surgery [total hip (879) and knee arthroplasty (508), followed by shoulder, elbow and upper ankle joint], 693 (45.2%) patients were male and 841 (54.8) female. Mean age was 64.2±13.8 years. Screening tests were available for 1373 patients (89.5%). Among all screened patients, we found 21 HCV, 10 HBV and 1 HIV infections. 5 HBV (0.5%) and 7 HCV infections (0.7%) were unknown before. Every newly detected infectious patient occasions screening costs about 7250€. Considering this data, the risk of HCV transmission from an index patient with unknown status of infectiousness to health care worker after percutaneous contact to blood is 0.08 ‰ and of HIV transmission is 0.00054 ‰ in our study population. DISCUSSION: Routine preoperative screening for BBVs of patients undergoing elective arthroplasty, who were asked for HBV, HCV and HIV, should be reconsidered and is, in times of sparse funds, overpriced. LEVEL OF EVIDENCE: IV.

Effectiveness of pseudoephedrine plus acetaminophen for treatment of symptoms attributed to the paranasal sinuses associated with the common cold.

BACKGROUND: Little data exist on the cause and treatment of subfacial pain and pressure and other discomfort attributed to the paranasal sinuses that develop early during the course of the common cold. The purpose of this study was to determine the efficacy of the combination of pseudoephedrine hydrochloride with acetaminophen for the treatment of early symptoms during colds, which are attributed by the patient to the sinuses. METHODS: Four hundred thirty subjects (216, pseudoephedrine and acetaminophen recipients; 214, placebo recipients) with cold symptoms of 48 hours or less who reported overall "sinus" symptoms of at least moderate severity were enrolled in this randomized double-blind placebo-controlled 2-dose study. Self-reported symptoms were scored (0 to 4, absent to severe) before and at 2 hours after the first and second doses. The 2 primary were measured 2 hours after the second dose were the overall sinus symptom assessment and a weighted composite assessment of sinus pressure, pain, and congestion (sinus symptoms). RESULTS: Compared with baseline, 2 hours after the second dose, the mean +/- SEM overall sinus symptom assessment score had decreased by 1.30 +/- 0. 06 in the pseudoephedrine and acetaminophen-treated subjects compared with 0.93 +/- 0.06 in the placebo-treated subjects (P< or = .029). The mean +/- SEM weighted average of sinus symptoms 2 hours after the second dose of study medication had decreased by 1.14 +/- 0.06 in the pseudoephedrine and acetaminophen-treated subjects compared with 0.84 +/- 0.06 in the placebo-treated subjects (P< or = .029). Reductions in similar magnitude were also observed for each of the individual sinus symptoms, and headache and rhinorrhea. Nervousness occurred in 4% of the pseudoephedrine and acetaminophen recipients compared with 0% of placebo recipients (P =.007). CONCLUSION: Our results suggest that pseudoephedrine plus acetaminophen is effective for relief of symptoms attributable to the paranasal sinuses that may develop early in the course of a cold. Arch Fam Med. 2000;9:979-985

A multicentric comparison of transabdominal versus totally extraperitoneal laparoscopic hernia repair using PARIETEX meshes.

The authors report a series of 1972 inguinal hernias treated between 1993 and 1997 by the insertion of a PARIETEX mesh via either a transabdominal-preperitoneal (TAPP) (1,290 procedures) or a totally extraperitoneal TEP approach (682 procedures). Pain scores were equivalent in both groups, while the hospital stay and time to return to normal activity was lower in the TEP group than in the TAPP group (p<0.001). In both groups, the average incidence of the total reported events (complications) was around 10% with no statistical difference. This ratio seemed to compare favorably to previously published reports. Chronic pain was extremely rare (0.6% and 0.7% in the TAPP and TEP groups, respectively). Whatever the approach was, sepsis was also very rare (1/1,526 laparoscopic procedures). These findings illustrate the local tolerance of the mesh. Recurrence rates were below 1% with no statistical difference between groups. This retrospective study demonstrates the clinically apparent local tolerance of this type of mesh. Prospective and long-term clinical results will be necessary to demonstrate that the optimized short-term tolerance of PARIETEX mesh will influence the long term functional results.

[Assessment of quality of life after antireflux surgery]. / Evaluation de la qualité de vie après chirurgie antireflux.

AIM OF THE STUDY: To assess the quality of life (QoL) of patients operated for gastroesophageal reflux disease (GERD). PATIENTS AND METHODS: This prospective study included 82 consecutive patients submitted to antireflux surgery between October 1998 and January 1999. A new questionnaire was used to assess their QoL: the Gastrointestinal Quality of Life Index (GIQLI) that includes 36 items concerning 5 dimensions: symptoms, vitality, emotions, social relations and medical treatment. The series consisted of 44 men and 38 women with a mean age of 47 years (range: 18-78). QoL was assessed before and 6 months after surgery; the follow-up rate was 94% (77/82). The pre- and postoperative GIQLI scores of the study group and the GIQLY score of a control group of 110 healthy patients were compared. RESULTS: Before surgery, the GIQLI score (90 +/- 23) was greatly impaired compared to the score (123 +/- 13) observed in the control group (p < 0.001). After surgery, the GIQLI score (110 +/- 23) increased significantly (p < 0.001), but remained statistically lower than the score of the control group (p < 0.001). The postoperative score recorded in the symptoms dimension was lower than the control group score: 55 +/- 11 versus 66 +/- 6 (p < 0.001), while no significant difference was observed in the other 4 dimensions. Univariate statistical analysis revealed that the postoperative GIQLI score (y) was correlated with the preoperative GIQLI score (x) according to the formula: y = 0.43 x + 71 (p < 0.001) and the sex of the patients, as the postoperative GIQLI score was higher in male patients (115 +/- 19) than in female patients (103 +/- 23) (p < 0.02). CONCLUSION: The QoL of the patients was greatly improved after antireflux surgery, but remained lower than that of a control group of healthy subjects. Better patient selection should improve the results. In our series, male patients or patients with a high preoperative GIQLI score were the best candidates for antireflux surgery.

[Time off of work after inguinal hernia repair. Results of a multicenter prospective study]. / Arrêt de travail après cure de hernie inguinale. Résultats d'une étude prospective multicentrique.

A multicentre prospective study was conducted to evaluate the effective duration of time off work following inguinal hernia repair. From 1st October to 30 November 1997, 14 surgeons repaired 459 hernias in 359 patients, corresponding to 28.8% of salaried workers, 10.9% self-employed and 4.8% civil servants. 46% of patients were retired. Only 6.9% of patients were treated by reconstruction of the inguinal floor without mesh, 59.6% were operated by laparoscopy and a conventional prosthesis repair was performed in 33.2%. There were 0.6% of complications or modifications of the postoperative course. The mean effective time off work was 17.5 days after unilateral repair and 24.7 days after bilateral repair. For unilateral repairs, no significant difference was observed between occupational groups in terms of effective time off work, in the absence of complications. In contrast, patients of these occupational groups presented a shorter time off work following an uncomplicated TAPP repair than after plug-Lichtenstein repair. In the group of salaried workers, a significant difference was observed between patients undergoing TAPP or TEP repair and those undergoing plug-Lichtenstein repair.

Breakdowns on the path of chronic illness: opportunities for learning.

An unusual case of calciphylaxis, presenting at the onset of end-stage renal disease and evolving into an extended and arduous hospital stay, is described. The medical approach to this case is addressed briefly, but the main focus of this paper is to describe, in the words of various participants, the events and interactions that occurred and to learn from this description how our management of such cases breaks down. When confronted by difficult circumstances, it is common for us to react emotionally in ways that are automatic and based on our own personal histories and behavior patterns. Such automatic reactions prevent us from seeing and understanding what we really need to know about a given situation and leave us vulnerable to discouragement and internal suffering when clinical events do not go well (A. Nierenberg, personal communication, April 1998). The result is often exasperation with patients and families, as well as emotionally laden interactions that do not forward problem solving. In retrospect, the appearance of such breakdowns is not only predictable in the course of chronic illness, but offers us the opportunity to observe our automatic reactions, to re-evaluate our approach, and to redesign our actions. We have written this review, not to find error or blame, but rather to emphasize that we are learning to view these breakdowns as signals first to step back from our automatic reactions and then to listen and communicate clearly as a means to navigating the best pathway through difficult and discouraging clinical challenges.

Effectiveness of clemastine fumarate for treatment of rhinorrhea and sneezing associated with the common cold.

Limited data support the use of first-generation antihistamines for treatment of the common cold. The purpose of this study was to test the effectiveness of clemastine fumarate, a first-generation antihistamine, for treatment of sneezing and rhinorrhea associated with naturally occurring common colds. Four hundred three subjects (202 clemastine fumarate recipients and 201 placebo recipients) who reported new onset (< 24 hours) of cold symptoms that included rhinorrhea or sneezing were studied. At baseline (day 1), the mean symptom-severity scores +/- SEM for the clemastine fumarate and placebo groups were not significantly different. The mean rhinorrhea-severity score +/- SEM was not different on day 2; however, on day 3, the mean rhinorrhea-severity score +/- SEM was 1.02 +/- 0.07 for the clemastine fumarate group and 1.39 +/- 0.07 for the placebo group (P < .001). This treatment effect persisted on day 4. A significant effect on sneezing was noted on days 2-4. Sedation occurred in 14% of the clemastine fumarate-treated subjects and 1.5% of the placebo-treated subjects (P < .0001).

Failure to screen newborns for inborn disorders: a potential consequence of changes in newborn care.

OBJECTIVES: To determine how changes in the structure of the hospital care of infants, such as shortened post-natal stays, affect the completeness of newborn screening. DESIGN: Cohort. SETTING: Two large maternity hospitals. PARTICIPANTS: 8751 consecutive births at the study hospitals during 1993. MAIN OUTCOME MEASURE: The completeness of initial specimen collection and processing as determined by matching of birth and screening records. RESULTS: At least one specimen was received by the screening program for 8675 (99.1%) of the births. Most non-screened patients (71/76, 93%) had been admitted to the neonatal intensive care unit (NICU). Of these, 53/71 (75%) were low birth weight infants who died within 48 h of birth. Even after excluding these non-survivors, NICU patients were 37 times more likely to be unscreened than their healthy counterparts (22 vs. 0.6 per 1000 infants, 95% C.I. 12.8, 92.8 P < 0.01). A common characteristic of non-screened NICU survivors, (12/18) was interhospital transfer for sub-specialty care. Among patients in the healthy-baby nursery, early discharge (i.e. < 24 h of age) accounted for 2/5 (40%) of the cases of non-screening. The non-screening rate among patients discharged early was 25 times higher than for those discharged after 24 h (9.8 vs. 0.4 per 1000 infants, 95% C.I. 4.2, 149 P < 0.01). CONCLUSIONS: Although the overall rate of screening was high, NICU patients, especially those requiring transfer, are disproportionately at risk for non-screening. Early discharge of healthy newborns was also significantly associated with non-screening. This latter finding is of special importance given the current trend toward shorter hospital stays for newborns. Increased attention to ensuring the collection of specimens from these two high-risk populations is warranted.

Low dose clemastine inhibits sneezing and rhinorrhea during the early nasal allergic reaction.

BACKGROUND: Clemastine (1 mg) is currently available over-the-counter for the treatment of allergic rhinitis. OBJECTIVE: To evaluate the efficacy of half the standard dose of clemastine (0.5 mg) in inhibiting the nasal response to allergen and the cutaneous response to histamine. METHODS: Double-blind, placebo-controlled, crossover study of 20 allergic subjects out of season. The subjects received placebo or clemastine administered one, four, and six hours before the challenges. Filter paper discs were used both to challenge the nasal mucosa with diluent and allergen and collect generated secretions. Sneezes, secretion weights, nasal and ocular symptoms, and albumin levels in nasal secretions were monitored for the nasal challenge. Intradermal skin testing was performed with diluent followed by histamine and the wheal and flare reactions were measured. RESULTS: There was a significant reduction in the number of sneezes after clemastine administered one, four, and six hours prior to challenge compared with placebo (P < .01). Clemastine administered four and six hours before challenge reduced sneezing significantly more than clemastine administered one hour before challenge (P < .05). Antigen-induced increases in secretion weights and symptoms of rhinorrhea were significantly reduced compared with placebo only when clemastine was administered four and six hours prior to challenge (P < .05). Pretreatment with clemastine had no significant inhibitory effects on other nasal symptoms or on albumin levels in nasal secretions, an objective index of increased vascular permeability. Pretreatment with clemastine did not inhibit the histamine-induced wheal skin reaction but showed a tendency, when administered six hours prior to the intradermal challenge, to reduce the flare reaction induced by the lowest dose of histamine (P = .05). CONCLUSIONS: The data show that clemastine, given at half the usual dose four and six hours prior to allergen challenge, provides relief for sneezing and rhinorrhea and suggests that this dose might be useful in the treatment of allergic rhinitis.

Mother as shield: differential effects of contact and nursing on pain responsivity in infant rats--evidence for nonopioid mediation.

To determine how rat mothers protect their pups against pain, we applied focal heat (34-51 degrees C) to the ear or shoulder of 10-day-old rats that were isolated, in contact among themselves or with their mother, suckling nonnutritively, or in the hyperextension position normally caused by milk letdown. Relative to isolated rats, contact doubled withdrawal latencies from heat (43 or 45 degrees C) applied to the ear. Suckling quadrupled heat-escape latencies. During hyperextension, rats essentially did not escape from thermal stimulation of up to 48 degrees C. Protection provided by maternal contact, especially suckling, was not mediated by either mu or kappa opioid receptors: neither systemic injections of naltrexone nor norbinaltorphimine reduced heat-escape latencies. Morphine (0.125 and 0.250 mg/kg) added to the effects of contact but multiplied the effects of suckling to produce heat-escape latencies that were upward of 2 min.

Complete disappearance of a leiomyosarcoma of the lower extremity following preoperative hyperthermia and intra-arterial doxorubicin.

Leiomyosarcoma of the extremities is an unusual tumor. Herein we report a unique and what we believe is the first case of a patient in whom there was complete disappearance of such a tumor following regional hyperthermia and chemotherapy.

Otologic effects of interferon beta serine in experimental rhinovirus colds.

To evaluate the efficacy and otologic effects of recombinant interferon beta serine for experimental rhinovirus colds, 38 healthy adults received nasal drops of recombinant interferon beta serine, 12 x 10(6) U, or placebo three times daily for 4.3 days beginning 36 hours after infection. Illness rates and severity did not differ between the groups, but the frequency of virus shedding was reduced on the fourth (37% vs 74%) and sixth (11% vs 42%) postchallenge days in recipients of recombinant interferon beta serine. Abnormal eustachian tube function in at least one ear was identified by the inflation-deflation test during 44% of observations in 13 infected recipients of recombinant interferon beta serine compared with 62% of observations in five placebo recipients. Tympanometry revealed middle-ear pressure abnormalities (less than -50 or greater than 20 mm H2O) in at least one ear during 18% of observations in recipients of recombinant interferon beta serine compared with 38% of observations in placebo recipients. These results suggest that antiviral therapy may alter the course of middle-ear dysfunction associated with experimental colds.

Physiologic abnormalities in the paranasal sinuses during experimental rhinovirus colds.

Six (18%) of 34 healthy, asymptomatic young adults had mucosal thickening or fluid in the paranasal sinuses on screening magnetic resonance imaging (MRI) examination. When 19 of these subjects were challenged with rhinovirus, 18 became infected. Twelve of the 18 infected subjects had technically satisfactory serial MRI examinations, and four (33%) of these developed MRI abnormalities of the ethmoid or antral sinuses that were temporally associated with the acute infection. The mean total nasal secretion weights were 22 gm/5 days in the four subjects whose MRI abnormalities were associated with the acute infection compared with 5.5 gm/5 days in the eight subjects who had normal MRI examinations during the acute infection (p = 0.06). Abnormalities of the paranasal sinuses, which were associated with increased volumes of nasal secretion, were detected by MRI examination during rhinovirus infection. These abnormalities may have a role in the pathogenesis of acute sinusitis associated with colds.

Effects of naproxen on experimental rhinovirus colds. A randomized, double-blind, controlled trial.

OBJECTIVE: To determine whether naproxen, a propionic acid inhibitor of cyclooxygenase, alters the course of experimental rhinovirus colds. DESIGN: A randomized, double-blind, controlled trial. SETTING: Rhinovirus challenge model in volunteers cloistered in individual hotel rooms. VOLUNTEERS: Eighty-seven healthy young adults with serum neutralizing antibody titers of less than or equal to 1:2 to the challenge virus; 79 were evaluable. INTERVENTION: Thirty-nine participants received naproxen (loading dose, 400 mg or 500 mg followed by 200 mg or 500 mg three times daily for 5 days). Forty participants received placebo. Treatment was started 6 hours after viral challenge. MEASUREMENTS: Daily measurement of viral titers, symptoms, nasal mucus production, and nasal tissue use; incidence of infection and illness; and measurement of homotypic serum neutralizing antibody responses. RESULTS: Viral titers and serum homotypic antibody responses were similar in the naproxen and placebo groups. Significant reductions in headache, malaise, myalgia, and cough occurred in the naproxen group. A 29% reduction was noted in the total (5-day) symptom score in the naproxen group (95% CI, 16% to 42%). CONCLUSION: Naproxen treatment did not alter virus shedding or serum neutralizing antibody responses in participants with experimental rhinovirus colds, but it had a beneficial effect on the symptoms of headache, malaise, myalgia, and cough. Prostaglandins may be among the inflammatory mediators that play a role in the pathogenesis of rhinovirus colds.

Perspectives in colorectal cancer.

This paper presents an overview of recent developments pertaining to colorectal adenocarcinoma. It is aimed toward the practicing clinician. Topics discussed include epidemiologic observations; genetic predispositions; molecular biology findings; screening and early detection programs; endoscopy; principles of surgical resection; laser and radioimmunoguided surgery; staging; selection of patients for adjuvant chemotherapy; and considerations regarding biologic response modifiers and pain control in the advanced-disease setting.

A randomized controlled trial of glucocorticoid prophylaxis against experimental rhinovirus infection.

The effects of combined intranasal and systemic glucocorticoid steroids on the local inflammatory response, and symptoms due to experimental rhinovirus infection were studied in 45 adults randomized to prophylaxis with either placebo or steroids. Intranasal beclomethasone (168 micrograms twice a day) was begun 4 days before viral challenge and continued 5 days after challenge. Oral prednisone (30 mg twice daily) was given for 3 days beginning 1 day before challenge. During the first 48 h after viral inoculation, nasal obstruction, nasal mucus weights, and kinin concentrations in nasal lavages were lower in steroid recipients, but subsequent increases in these variables in the steroid group resulted in no significant cumulative differences between treatment groups. These data suggest that steroid prophylaxis may suppress nasal inflammation and cold symptoms during the first 2 days in experimental rhinovirus colds.

Ineffectiveness of recombinant interferon-beta serine nasal drops for prophylaxis of natural colds.

Two randomized, double-blind, placebo-controlled trials during early autumn of 1986 and 1987 evaluated the efficacy and tolerance of recombinant interferon-beta serine (rIFN-beta ser) nasal drops for prevention of natural rhinovirus colds. In 1986, 9 X 10(6) units of rIFN-beta ser (139 subjects) or placebo (157) were administered once daily except Sundays for 4 w. Rhinovirus colds occurred in 2.8% of rIFN-beta ser recipients and 6.0% of placebo recipients during the treatment period (52% reduction, P = .3). In 1987, 24 X 10(6) units of rIFN-beta ser (186) or placebo (197) were given daily for 25 consecutive days. Rhinovirus colds developed in 6.3% of rIFN-beta ser recipients and 5.3% of placebo recipients. In each study, illness frequency and number of days with subjective colds did not differ between the groups. Recipients of nasal drops of rIFN-beta ser at either dosage did not differ in tolerance from placebo recipients. The lack of both prophylactic efficacy and nasal toxicity are in contrast to prior observations with nasal sprays of rIFN-alpha 2b.

Augmentation of acetaminophen analgesia by the antihistamine phenyltoloxamine.

A double-blind, placebo-controlled, parallel-group study was performed to compare the analgesic activity of the combination of 650 mg acetaminophen plus 60 mg phenyltoloxamine citrate with that of 650 mg acetaminophen alone. Two hundred female inpatients who had severe pain associated with a recent episiotomy procedure were randomly assigned to receive a single dose of one of the two active treatments or a placebo. Analgesia was assessed over a 6-hour period. Treatments were compared on the basis of standard subjective scales for pain intensity and relief, a number of derived variables based on these data and two global measures. For essentially all measures, the two active treatments were significantly superior to the placebo control. The combination was significantly superior to acetaminophen alone for all analgesic measures including SPID, TOTAL, and global ratings. The results of this study demonstrate that 60 mg phenyltoloxamine produces significant augmentation of the analgesic activity of 650 mg acetaminophen in postepisiotomy pain.