nab-Paclitaxel plus carboplatin or gemcitabine versus gemcitabine plus carboplatin as first-line treatment of patients with triple-negative metastatic breast cancer: results from the tnAcity trial.

Background: Metastatic triple-negative breast cancer (mTNBC) has a poor prognosis and aggressive clinical course. tnAcity evaluated the efficacy and safety of first-line nab-paclitaxel plus carboplatin (nab-P/C), nab-paclitaxel plus gemcitabine (nab-P/G), and gemcitabine plus carboplatin (G/C) in patients with mTNBC. Patients and methods: Patients with pathologically confirmed mTNBC and no prior chemotherapy for metastatic BC received (1 : 1 : 1) nab-P 125 mg/m2 plus C AUC 2, nab-P 125 mg/m2 plus G 1000 mg/m2, or G 1000 mg/m2 plus C AUC 2, all on days 1, 8 q3w. Phase II primary end point: investigator-assessed progression-free survival (PFS); secondary end points included overall response rate (ORR), overall survival (OS), percentage of patients initiating cycle 6 with doublet therapy, and safety. Results: In total, 191 patients were enrolled (nab-P/C, n = 64; nab-P/G, n = 61; G/C, n = 66). PFS was significantly longer with nab-P/C versus nab-P/G [median, 8.3 versus 5.5 months; hazard ratio (HR), 0.59 [95% CI, 0.38-0.92]; P = 0.02] or G/C (median, 8.3 versus 6.0 months; HR, 0.58 [95% CI, 0.37-0.90]; P = 0.02). OS was numerically longer with nab-P/C versus nab-P/G (median, 16.8 versus 12.1 months; HR, 0.73 [95% CI, 0.47-1.13]; P = 0.16) or G/C (median, 16.8 versus 12.6 months; HR, 0.80 [95% CI, 0.52-1.22]; P = 0.29). ORR was 73%, 39%, and 44%, respectively. In the nab-P/C, nab-P/G, and G/C groups, 64%, 56%, and 50% of patients initiated cycle 6 with a doublet. Grade ≥3 adverse events were mainly hematologic. Conclusions: First-line nab-P/C was active in mTNBC and resulted in a significantly longer PFS and improved risk/benefit profile versus nab-P/G or G/C.

Phase 2 study of neoadjuvant treatment with NOV-002 in combination with doxorubicin and cyclophosphamide followed by docetaxel in patients with HER-2 negative clinical stage II-IIIc breast cancer.

NOV-002 (a formulation of disodium glutathione disulfide) modulates signaling pathways involved in tumor cell proliferation and metastasis and enhances anti-tumor immune responsiveness in tumor models. The addition of NOV-002 to chemotherapy has been shown to increase anti-tumor efficacy in animal models and some early phase oncology trials. We evaluated the clinical effects of NOV-002 in primary breast cancer, whether adding NOV-002 to standard preoperative chemotherapy increased pathologic complete response rates (pCR) at surgery, and determined whether NOV-002 mitigated hematologic toxicities of chemotherapy and whether levels of myeloid derived suppressor cells (MDSC) were predictive of response. Forty-one women with newly diagnosed stages II-IIIc HER-2 negative breast cancer received doxorubicin-cyclophosphamide followed by docetaxel (AC â†’ T) every 3 weeks and concurrent daily NOV-002 injections. The trial was powered to detect a doubling of pCR rate from 16 to 32% with NOV-002 plus AC â†’ T (α = 0.05, ß = 80%). Weekly complete blood counts were obtained as well as circulating MDSC levels on day 1 of each cycle were quantified. Of 39 patients with 40 evaluable tumors, 15 achieved a pCR (38%), meeting the primary endpoint of the trial. Concurrent NOV-002 resulted in pCR rates for AC â†’ T chemotherapy higher than previously reported. Patients with lower levels of circulating MDSCs at baseline and on the last cycle of chemotherapy had significantly higher probability of a pCR (P = 0.02). Further evaluation of NOV-002 in a randomized study is warranted.

[Impact of a more stringent organization of intravitreal injection treatment on the number of treatments and examinations in routine practice]. / Auswirkungen einer stringenteren IVOM-Behandlungsorganisation auf die Anzahl der Behandlungen und Untersuchungen im Praxisalltag.

BACKGROUND: Results from recent studies show that less intravitreal injections are often performed in everyday practice than in controlled trials, which subsequently leads to worse treatment success. In this study we analyzed the introduction of a more stringent organization of treatment using workflow optimization and new IT systems and analyzed the effect on treatment continuity. MATERIAL AND METHODS: In the second quarter of 2019 a new medical practice management software and a software for automated injection planning were implemented. There was also a change of the treatment regimen from pro re nata (PRN) to treat and extend (T&E ). We analyzed the results of the patients regarding the frequency of injections and treatment controls three quarters before (Q3/2018-Q1/2019) and three quarters after the change (Q2/2019-Q4/2019). Treatment-naive and pretreated patients were analyzed. RESULTS: In group 1 (Q3/2018-Q1/2019) the average number of injections per quarter was 1.74 (SD = 0.4). Eyes of patients from group 2 (Q2/2019-Q4/2019) received on average 2.17 (SD = 0.3) injections. The number of check-ups per quarter was 1.71 (SD = 0.3) before the introduction, and thereafter 2.16 (SD = 0.3). There was a significant increase in the number of OCTs from 1.18 (SD = 0.2) to 1.98 (SD = 0.3). The visual acuity was stable in both groups. CONCLUSION: We were able to show that the introduction of the medical practice management software and the change of the regimen from PRN to T&E can achieve numbers of injections, check-ups and OCT similar to those in studies. A standardized procedure facilitates efficient treatment planning and enables a better patient management.

Evaluation of patient satisfaction with an ophthalmology video consultation during the COVID-19 pandemic.

BACKGROUND: We introduced a video consultation (VC) during the coronavirus (COVID-19) pandemic in an ophthalmology practice with eight doctors to ensure continuous ophthalmological care, infection prophylaxis and to compensate a decreased number of patient presentations. OBJECTIVE: Evaluation of the most common reasons for patient presentations in the VC, the proportion of re-presentations in the practice despite VC, practical challenges associated with the introduction of VC and patient satisfaction. MATERIAL AND METHODS: Patients with a recent acute visual deterioration and severe eye pain were excluded from the VC. The VC were carried out by a trained specialist in ophthalmology. A questionnaire with eight questions was completed after the VC appointment in order to evaluate the proportion of completed VC and patient satisfaction. RESULTS: We included 29 (13 male, Ø 52.6 years, 16 female, Ø 64.7 years) patients in this analysis. The VC could be performed with 68.97% of the participants who rated their overall experience with an average grade of 1.6 (1 very good to 6 insufficient) and all of them indicated that they would recommend the VC. Of presentations in VC 70% were related to the symptoms of the anterior eye segment. In 70% of the cases no re-presentations took place in the unit. CONCLUSION: Our study represents a significant practical application of VC for the management of non-urgent ocular conditions with maximum infection prophylaxis. The introduction of VC was severely limited by technological or user-related issues by the establishment of video connections. Patient satisfaction with VC was high to very high.

[Evaluation of patient satisfaction with an ophthalmology video consultation during the COVID-19 pandemic]. / Evaluierung der Patientenzufriedenheit mit einer augenärztlichen Videosprechstunde während der COVID-19-Pandemie.

BACKGROUND: We introduced a video consultation (VC) during the coronavirus (COVID-19) pandemic in an ophthalmology practice with eight doctors to ensure continuous ophthalmological care, infection prophylaxis and to compensate a decreased number of patient presentations. OBJECTIVE: Evaluation of the most common reasons for patient presentations in the VC, the proportion of re-presentations in the practice despite VC, practical challenges associated with the introduction of VC and patient satisfaction. MATERIAL AND METHODS: Patients with a recent acute visual deterioration and severe eye pain were excluded from the VC. The VC were carried out by a trained specialist in ophthalmology. A questionnaire with eight questions was completed after the VC appointment in order to evaluate the proportion of completed VC and patient satisfaction. RESULTS: We included 29 (13 male, Ø 52.6 years, 16 female, Ø 64.7 years) patients in this analysis. The VC could be performed with 68.97% of the participants who rated their overall experience with an average grade of 1.6 (1 very good to 6 insufficient) and all of them indicated that they would recommend the VC. Of presentations in VC 70% were related to the symptoms of the anterior eye segment. In 70% of the cases no re-presentations took place in the unit. CONCLUSION: Our study represents a significant practical application of VC for the management of non-urgent ocular conditions with maximum infection prophylaxis. The introduction of VC was severely limited by technological or user-related issues by the establishment of video connections. Patient satisfaction with VC was high to very high.

Structure of the novel membrane-coating material in proton-secreting epithelial cells and identification as an H+ATPase.

Specialized proton-secreting cells known collectively as mitochondria-rich cells are found in a variety of transporting epithelia, including the kidney collecting duct (intercalated cells) and toad and turtle urinary bladders. These cells contain a population of characteristic tubulovesicles that are believed to be involved in the shuttling of proton pumps (H+ATPase) to and from the plasma membrane. These transporting vesicles have a dense, studlike material coating the cytoplasmic face of their limiting membranes and similar studs are also found beneath parts of the plasma membrane. We have recently shown that this membrane coat does not contain clathrin. The present study was performed to determine the structure of this coat in rapidly frozen and freeze-dried tissue, and to determine whether the coat contains a major membrane protein transported by these vesicles, a proton pumping H+ATPase. The structure of the coat was examined in proton-secreting, mitochondria-rich cells from toad urinary bladder epithelium by rapidly freezing portions of apical membrane and associated cytoplasm that were sheared away from the remainder of the cell using polylysine-coated coverslips. Regions of the underside of these apical membranes as large as 0.2 micron2 were decorated by studlike projections that were arranged into regular hexagonal arrays. Individual studs had a diameter of 9.5 nm and appeared to be composed of multiple subunits arranged around a central depression, possibly representing a channel. The studs had a density of approximately 16,800 per micron2 of membrane. Similar arrays of studs were also found on vesicles trapped in the residual band of cytoplasm that remained attached to the underside of the plasma membrane, but none were seen in adjacent granular cells. To determine whether these arrays of studs contained H+ATPase molecules, we examined a preparation of affinity-purified bovine medullary H+ATPase, using the same technique, after incorporation of the protein eluted from a monoclonal antibody affinity column into phospholipid liposomes. The affinity-purified protein was shown to be capable of ATP-dependent acidification. In such preparations, large paracrystalline arrays of studs identical in appearance to those seen in situ were found. The dimensions of the studs as well as the number per square micrometer of membrane were identical to those of toad bladder mitochondria-rich cells: 9.5 nm in diameter, 16,770 per micron2 of membrane.(ABSTRACT TRUNCATED AT 400 WORDS)

Apical endosomes isolated from kidney collecting duct principal cells lack subunits of the proton pumping ATPase.

Endocytic vesicles that are involved in the vasopressin-stimulated recycling of water channels to and from the apical membrane of kidney collecting duct principal cells were isolated from rat renal papilla by differential and Percoll density gradient centrifugation. Fluorescence quenching measurements showed that the isolated vesicles maintained a high, HgCl2-sensitive water permeability, consistent with the presence of vasopressin-sensitive water channels. They did not, however, exhibit ATP-dependent luminal acidification, nor any N-ethylmaleimide-sensitive ATPase activity, properties that are characteristic of most acidic endosomal compartments. Western blotting with specific antibodies showed that the 31- and 70-kD cytoplasmically oriented subunits of the vacuolar proton pump were not detectable in these apical endosomes from the papilla, whereas they were present in endosomes prepared in parallel from the cortex. In contrast, the 56-kD subunit of the proton pump was abundant in papillary endosomes, and was localized at the apical pole of principal cells by immunocytochemistry. Finally, an antibody that recognizes the 16-kD transmembrane subunit of oat tonoplast ATPase cross-reacted with a distinct 16-kD band in cortical endosomes, but no 16-kD band was detectable in endosomes from the papilla. This antibody also recognized a 16-kD band in affinity-purified H+ ATPase preparations from bovine kidney medulla. Therefore, early endosomes derived from the apical plasma membrane of collecting duct principal cells fail to acidify because they lack functionally important subunits of a vacuolar-type proton pumping ATPase, including the 16-kD transmembrane domain that serves as the proton-conducting channel, and the 70-kD cytoplasmic subunit that contains the ATPase catalytic site. This specialized, non-acidic early endosomal compartment appears to be involved primarily in the hormonally induced recycling of water channels to and from the apical plasma membrane of vasopressin-sensitive cells in the kidney collecting duct.

Osteoclastic bone resorption by a polarized vacuolar proton pump.

Bone resorption depends on the formation, by osteoclasts, of an acidic extracellular compartment wherein matrix is degraded. The mechanism by which osteoclasts transport protons into that resorptive microenvironment was identified by means of adenosine triphosphate-dependent weak base accumulation in isolated osteoclast membrane vesicles, which exhibited substrate and inhibition properties characteristic of the vacuolar, electrogenic H+-transporting adenosine triphosphatase (H+-ATPase). Identify of the proton pump was confirmed by immunoblot of osteoclast membrane proteins probed with antibody to vacuolar H+-ATPase isolated from bovine kidney. The osteoclast's H+-ATPase was immunocytochemically localized to the cell-bone attachment site. Immunoelectron microscopy showed that the H+-ATPase was present in the ruffled membrane, the resorptive organ of the cell.

Lack of acidification in Mycobacterium phagosomes produced by exclusion of the vesicular proton-ATPase.

The success of Mycobacterium species as pathogens depends on their ability to maintain an infection inside the phagocytic vacuole of the macrophage. Although the bacteria are reported to modulate maturation of their intracellular vacuoles, the nature of such modifications is unknown. In this study, vacuoles formed around Mycobacterium avium failed to acidify below pH 6.3 to 6.5. Immunoelectron microscopy of infected macrophages and immunoblotting of isolated phagosomes showed that Mycobacterium vacuoles acquire the lysosomal membrane protein LAMP-1, but not the vesicular proton-adenosine triphosphatase (ATPase) responsible for phagosomal acidification. This suggests either a selective inhibition of fusion with proton-ATPase-containing vesicles or a rapid removal of the complex from Mycobacterium phagosomes.

Patients retrieved to intensive care via a dedicated retrieval service do not have increased hospital mortality compared with propensity-matched controls.

This study was performed to estimate the effect of the retrieval process on mortality for patients admitted to a mixed adult intensive care unit (ICU) compared with propensity-matched, non-retrieved controls. Patients retrieved to the Royal Adelaide Hospital (RAH) ICU between 2011 and 2015 were propensity-score matched for age, gender, Aboriginal and Torres Strait Islander status, Acute Physiology and Chronic Health Evaluation (APACHE) III score and diagnostic group with non-retrieved ICU patients to estimate the average treatment effect of retrieval on hospital mortality. Factors associated with mortality in those retrieved were assessed by multiple logistic regression. Retrieved patients comprised 1,597 (14%) of 11,641 index ICU admissions; this group were younger, mean (standard deviation) 53 (18.5) versus 59 (17.7) years, had higher APACHE III scores, 61 (30.3) versus 56 (27.5), were more likely to be Indigenous (5.1% versus 3.7%) and to have sustained trauma (34% versus 9%). The average treatment effect for retrieval on hospital mortality, risk difference (95% confidence interval), was -0.7% (-2.8% to 1.3%), P=0.50. Variables independently associated with hospital mortality in those retrieved included age, APACHE III score and diagnostic category. Time from retrieval team activation to arrival with the patient, rural location, radial distance from the RAH and population size at the retrieval location were not significantly associated with mortality. The hospital mortality for retrieved patients was not significantly different when compared with propensity-matched controls. Mortality in those retrieved was associated with increasing age, APACHE III score and diagnostic category; however, was independent of time from team activation to arrival with the patient.

An electrogenic proton-translocating adenosine triphosphatase from bovine kidney medulla.

Urinary acidification in the mammalian collecting tubule is similar to that in the turtle bladder, an epithelium whose H+ secretion is due to a luminal proton-translocating ATPase. We isolated a fraction from bovine renal medulla, which contains ATP-dependent proton transport. H+ transport was found to be electrogenic in that its rate was reduced by a membrane potential. H+ transport activity was inhibited by N-ethyl maleimide and dicyclohexyl carbodiimide, but not by oligomycin or vanadate; its activity did not depend on the presence of potassium, differentiating this ATPase from the mitochondrial F0-F1 ATPase and the gastric H+-K+ ATPase. H+ transport activity had a specific substrate requirement for ATP, distinguishing this pump from the lysosomal H+ ATPase, which uses guanosine or inosine triphosphate as well. The distribution of this H+ pump on linear sucrose density gradient was different from that of markers of lysosomes and basolateral membranes. These results show that the kidney medulla contains an H+ -translocating ATPase different from mitochondrial, gastric, and lysosomal proton pumps, but similar to the turtle bladder ATPase.

Localization of a proton-pumping ATPase in rat kidney.

The distribution of vacuolar H+ATPase in rat kidney was examined by immunocytochemistry using affinity-purified antibodies against the 31-, 56-, and 70-kD subunits of the bovine kidney proton pump. Proximal convoluted tubules were labeled over apical plasma membrane invaginations, and in the initial part of the thin descending limb, apical and basolateral plasma membranes were moderately stained. Thick ascending limbs and distal convoluted tubules were apically stained although the intensity was greater in the distal convoluted tubule. Collecting duct principal cells were virtually unlabeled, but intercalated cells had intense staining with an apical, basolateral or diffuse pattern in the cortex, and exclusively apical staining in the medulla. These results (a) show the presence of an H+ATPase in the apical plasma membrane of the proximal tubule that may contribute to H+ transport in this segment; (b) provide direct evidence that the intercalated cell contains most of the H+ATPase detectable in the collecting duct, supporting its proposed role in H+ transport; (c) demonstrate that subpopulations of cortical intercalated cells have opposite polarities of an H+ATPase, consistent with the presence of both proton- and bicarbonate-secreting cells; and (d) suggest a role for the H+ATPase in acid/base regulation or H+ transport in segments other than the collecting duct and the proximal tubule.

Expression and distribution of renal vacuolar proton-translocating adenosine triphosphatase in response to chronic acid and alkali loads in the rat.

Renal hydrogen ion excretion increases with chronic acid loads and decreases with alkali loads. We examined the mechanism of adaptation by analyzing vacuolar proton-translocating adenosine triphosphatase (H+ ATPase) 31-kD subunit protein and mRNA levels, and immunocytochemical distribution in kidneys from rats subjected to acid or alkali loads for 1, 3, 5, 7, and 14 d. Acid- and alkali-loaded rats exhibited adaptive responses in acid excretion, but showed no significant changes in H+ ATPase protein or mRNA levels in either cortex or medulla. In contrast, there were profound adaptive changes in the immunocytochemical distribution of H+ ATPase in collecting duct intercalated cells. In the medulla, H+ ATPase staining in acid-loaded rats shifted from cytoplasmic vesicles to plasma membrane, whereas in alkali-loaded rats, cytoplasmic vesicle staining was enhanced, and staining of plasma membrane disappeared. In the cortical collecting tubule, acid loading increased the number of intercalated cells showing enhanced apical H+ ATPase staining and decreased the number of cells with basolateral or poorly polarized apical staining. The results indicate that both medulla and cortex participate in the adaptive response to acid and alkali loading by changing the steady-state distribution of H+ ATPase, employing mechanisms that do not necessitate postulating interconversion of intercalated cells with opposing polarities.

Complete degradation of type X collagen requires the combined action of interstitial collagenase and osteoclast-derived cathepsin-B.

We have studied the degradation of type X collagen by metalloproteinases, cathepsin B, and osteoclast-derived lysates. We had previously shown (Welgus, H. G., C. J. Fliszar, J. L. Seltzer, T. M. Schmid, and J. J. Jeffrey. 1990. J. Biol. Chem. 265:13521-13527) that interstitial collagenase rapidly attacks the native 59-kD type X molecule at two sites, rendering a final product of 32 kD. This 32-kD fragment, however, has a Tm of 43 degrees C due to a very high amino acid content, and thus remains helical at physiologic core temperature. We now report that the 32-kD product resists any further attack by several matrix metalloproteinases including interstitial collagenase, 92-kD gelatinase, and matrilysin. However, this collagenase-generated fragment can be readily degraded to completion by cathepsin B at 37 degrees C and pH 4.4. Interestingly, even under acidic conditions, cathepsin B cannot effectively attack the whole 59-kD type X molecule at 37 degrees C, but only the 32-kD collagenase-generated fragment. Most importantly, the 32-kD fragment was also degraded at acid pH by cell lysates isolated from murine osteoclasts. Degradation of the 32-kD type X collagen fragment by osteoclast lysates exhibited the following properties: (a) cleavage occurred only at acidic pH (4.4) and not at neutral pH; (b) the cysteine proteinase inhibitors E64 and leupeptin completely blocked degradation; and (c) specific antibody to cathepsin B was able to inhibit much of the lysate-derived activity. Based upon these data, we postulate that during in vivo endochondral bone formation type X collagen is first degraded at neutral pH by interstitial collagenase secreted by resorbing cartilage-derived cells. The resulting 32-kD fragment is stable at core temperature and further degradation requires osteoclast-derived cathepsin B supplied by invading bone.

Requirement for phospholipase C-gamma1 enzymatic activity in growth factor-induced mitogenesis.

The cytoplasmic regions of the receptors for epidermal growth factor (EGF) and platelet-derived growth factor (PDGF) bind and activate phospholipase C-gamma1 (PLC-gamma1) and other signaling proteins in response to ligand binding outside the cell. Receptor binding by PLC-gamma1 is a function of its SH2 domains and is required for growth factor-induced cell cycle progression into the S phase. Microinjection into MDCK epithelial cells and NIH 3T3 fibroblasts of a polypeptide corresponding to the noncatalytic SH2-SH2-SH3 domains of PLC-gamma1 (PLC-gamma1 SH2-SH2-SH3) blocked growth factor-induced S-phase entry. Treatment of cells with diacylglycerol (DAG) or DAG and microinjected inositol-1,4,5-triphosphate (IP3), the products of activated PLC-gamma1, did not stimulate cellular DNA synthesis by themselves but did suppress the inhibitory effects of the PLC-gamma1 SH2-SH2-SH3 polypeptide but not the cell cycle block imposed by inhibition of the adapter protein Grb2 or p21 Ras. Two c-fos serum response element (SRE)-chloramphenicol acetyltransferase (CAT) reporter plasmids, a wild-type version, wtSRE-CAT, and a mutant, pm18, were used to investigate the function of PLC-gamma1 in EGF- and PDGF-induced mitogenesis. wtSRE-CAT responds to both protein kinase C (PKC)-dependent and -independent signals, while the mutant, pm18, responds only to PKC-independent signals. Microinjection of the dominant-negative PLC-gamma1 SH2-SH2-SH3 polypeptide greatly reduced the responses of wtSRE-CAT to EGF stimulation in MDCK cells and to PDGF stimulation in NIH 3T3 cells but had no effect on the responses of mutant pm18. These results indicate that in addition to Grb2-mediated activation of Ras, PLC-gamma1-mediated DAG production is required for EGF- and PDGF-induced S-phase entry and gene expression, possibly through activation of PKC.

Toxicity profile differences of adjuvant docetaxel/cyclophosphamide (TC) between Asian and Caucasian breast cancer patients.

AIM: For early-stage breast cancer, four cycles of docetaxel and cyclophosphamide (TC) was proven superior to doxorubicin plus cyclophosphamide in the US Oncology 9375 trial. Given primary prophylactic antibiotics, 5% febrile neutropenia was recorded in a population comprising 75.5% Caucasians. Smaller trials and retrospective studies reviewing TC use in Asian patients did not produce similar incidence rates. This study aims to discover the variable hematological toxicities with TC use in Caucasian and Asian patients. METHODS: Breast cancer data was retrospectively reviewed for patients receiving adjuvant docetaxel 60-75 mg/m2 plus cyclophosphamide 600 mg/m2 from six countries (China, Hong Kong, Japan, Taiwan, Italy, and United States). Similar number of patients with relatively balanced baseline characteristics were chosen for analysis of hematological and nonhematological toxicities and survival data. RESULTS: From March 2004 to July 2013, data of 227 patients (127 Asians and 100 Caucasian) patients were analyzed for treatment-related toxicities. During the four cycles of TC, Asians had a significantly higher rate of grade ≥2 neutropenia than Caucasians (45.7% vs 6.0%; P <0.001) and significantly more grade ≥3 neutropenia events were documented (respectively 30.7% vs 4.0%, P <0.001). The prophylactic use of G-CSF was similar; 26.0% in Asians and 28.0% in Caucasian (P = 0.764). There were no differences in nonhematological toxicities. No significant difference in disease-free survival was observed between Asians and Caucasians (log-rank P = 0.910). CONCLUSIONS: Ethnic differences in toxicity profile exist between Asian and Caucasian patients given adjuvant TC. Over 30% Asians but less than 5% Caucasians experienced grade ≥3 neutropenia.

Diagnostic yield of active case finding for tuberculosis and HIV at the household level in slums in Haiti.

SETTING: Haiti has the highest burden of tuberculosis (TB) in the Americas, with an estimated prevalence of 254 per 100 000 population. The Haitian Group for the Study of Kaposi's Sarcoma and Opportunistic Infections (Groupe Haïtien d'Etude du Sarcome de Kaposi et des Infections Opportunistes, GHESKIO) conducted active case finding (ACF) for TB at the household level in nine slums in Port-au-Prince. OBJECTIVE: We report on the prevalence of undiagnosed TB detected through GHESKIO's ACF campaign. DESIGN: From 1 August 2014 to 31 July 2015, we conducted a retrospective cohort analysis using GHESKIO's ACF campaign data. All individuals who reported chronic cough (cough 2 weeks) were tested for TB at GHESKIO, and those aged 10 years were included in the analyses. RESULTS: Of 104 097 individuals screened in the community, 5598 (5%) reported chronic cough and satisfied the study inclusion criteria. A total of 1110 (20%) were diagnosed with active TB disease (prevalence of 1066/100 000). Of the 5472 (98%) patients tested for human immunodeficiency virus (HIV), 528 (10%) were HIV-positive; 143 (3%) patients were diagnosed with both diseases. CONCLUSION: Household-level screening for cough with TB and HIV testing for symptomatic patients was a high-yield strategy, leading to the detection of a prevalence of undiagnosed disease exceeding national estimates by more than four-fold for TB, and by five-fold for HIV.

Pamidronate reduces skeletal morbidity in women with advanced breast cancer and lytic bone lesions: a randomized, placebo-controlled trial. Protocol 18 Aredia Breast Cancer Study Group.

PURPOSE: To assess whether pamidronate can reduce the frequency of skeletal morbidity in women with lytic bone metastases from breast cancer treated with hormone therapy. PATIENTS AND METHODS: Three hundred seventy-two women with breast cancer who had at least one lytic bone lesion and who were receiving hormonal therapy were randomized to receive 90 mg of pamidronate or placebo as a 2-hour intravenous infusion given in double-blind fashion every 4 weeks for 24 cycles. Patients were evaluated for skeletal complications: pathologic fractures, spinal cord compression, irradiation of or surgery on bone, or hypercalcemia. The skeletal morbidity rate (the ratio of the number of skeletal complications to the time on trial) was the primary efficacy variable. Bone pain, use of analgesics, quality of life, performance status, bone tumor response, and biochemical parameters were also evaluated. RESULTS: One hundred eighty-two patients who received pamidronate and 189 who received placebo were assessable. The skeletal morbidity rate was significantly reduced at 12, 18, and 24 cycles in patients treated with 90 mg of pamidronate (P = .028, .023, and .008, respectively). At 24 cycles, the proportion of patients having had any skeletal complication was 56% in the pamidronate group and 67% in the placebo group (P = .027). The time to the first skeletal complication was longer for patients receiving pamidronate than for those given placebo (P = .049). There was no statistical difference in survival or in objective bone response rate. Pamidronate was well tolerated. CONCLUSION: Treatment with 90 mg of pamidronate as a 2-hour intravenous infusion every 4 weeks in addition to hormonal therapy significantly reduces skeletal morbidity from osteolytic metastases.

Optimal timing for collections of blood progenitor cells following induction chemotherapy and granulocyte-macrophage colony-stimulating factor for autologous transplantation in advanced breast cancer.

Circulating progenitor cells collected during periods of rapid hematopoietic reconstitution can be used successfully as hematopoietic support for super-dose chemotherapy. A major problem for collection of peripheral blood progenitor cells has been determination of optimal time to start leukapheresis and of the adequate amount of progenitor cells. This study has demonstrated that an induction chemotherapy with augmented dosage of CEF (cyclophosphamide, epirubicin, 5-fluorouracil) in conjunction with granulocyte-macrophage colony-stimulating factor (CM-CSF) successfully mobilized peripheral blood progenitor cells in 15 patients with metastatic breast cancer. By monitoring the granulocyte-macrophage colony-forming units (CFU-GM), erythrocyte burst-forming units (BFU-E), and CD34+ cells in peripheral blood daily after leukocyte nadir, we have identified an optimal 'window' in which concentrations of blood progenitor cells reached a maximum range. Although the time interval between chemotherapy and the time for maximum stimulation could vary from between 13 days to 19 days, maximum mobilization started consistently 2 days after the white blood cells (WBC) recovered to > 2.0 x 10(9)/l after nadir, and remained elevated for 4 to 5 days. A significant reduction of progenitor cells in peripheral blood and in the corresponding leukapheresis products was observed, however, from cycle 1 versus subsequent cycles (p < 0.0001), but there was no significant difference between cycles 2 and 3. When used as the sole source of hematopoietic support for super-dose chemotherapy with cyclophosphamide, mitoxantrone, and carboplatin, these progenitor cells induce rapid and sustained reconstitution in all patients. The median time from reinfusion to recovery of absolute neutrophil count (ANC) to > 0.5 x 10(9)/l was 13 days (range 9-18 days) and to an unmaintained platelet count of > 50 x 10(9)/l, 12 days (range 10-35 days). Autologous transplantation with stimulated blood progenitor cells can be an efficient alternative to bone marrow transplantation. With optimal timing for collections, as few as two leukapheresis procedures are required to obtain an adequate progenitor cell dose.