Robert Taub | Columbia University (original) (raw)

Papers by Robert Taub

Annals of surgical oncology, 2017

The prognosis for patients with diffuse malignant peritoneal mesothelioma has dramatically improv... more The prognosis for patients with diffuse malignant peritoneal mesothelioma has dramatically improved with cytoreductive surgery and intraperitoneal chemotherapy. Little is known about disease recurrence after treatment. We analyzed the time to and predictors of recurrence in a large cohort of optimally treated patients. We examined 113 patients completing a two-stage cytoreduction and intraperitoneal chemotherapy protocol. All patients achieved optimal surgical resection with completeness of cytoreduction (CC) score ≤ 1 and were divided into two groups based on absence (Group A) or presence (Group B) of gross disease at the outset of the second operation. Predictors of disease recurrence and recurrence-free survival (RFS) were determined using Cox proportional hazard regression modeling, and estimates were obtained by using the Kaplan-Meier method. Forty-six percent of patients had no gross evidence of disease at the second operation; the remaining 54% were cytoreduced to CC ≤ 1 (Gro...

Archives of pathology & laboratory medicine, 2018

Translational Lung Cancer Research, 2016

82 Background: From the moment of diagnosis, malignant mesothelioma (MM), decreases health-relate... more 82 Background: From the moment of diagnosis, malignant mesothelioma (MM), decreases health-related quality-of-life (QOL) in patients and their caregivers. In addition to symptoms of disease, aggressive treatments such as surgery, radiation, and chemotherapy can cause extreme side effects – specifically, chemotherapy is associated with chronic fatigue, unremitting nausea, vomiting, and systemic pain. These side effects of treatments can be burdensome enough to lead to noncompliance or outright refusal of continuation of care.[1] Data from 13 frequently cited QOL studies focus on chest pain and shortness of breath as the two chief symptoms of pleural mesothelioma. The largest QOL study to date enrolled 495 patients, evaluated MM using the LCSS (lung cancer symptom scale). Investigators reported MM’s most common symptoms as: fatigue (94%), dyspnea (89%), loss of appetite (86%), chest pain (85%), cough (75%), and hemoptysis (24%). In addition, mesothelioma has a number of emotional consequences. A study by the British Lung Foundation (BLF) reported significant impairment of emotional function and/or emotional state in patients with mesothelioma and their family members.[2] Methods: The platform for the support group was remote, consisting of both online and telephone domains. Participants would utilize both online and phone systems during sessions, held once a week for a total of 6 weeks. Sessions were guided and kept closed, available only to those affected by mesothelioma. Participants completed surveys after each support group. Session summaries and follow-up information were provided online after support meetings. Results: Using a 0-5 Likert Scale, consistent attendees reported support groups as very helpful (4). Irregular attendees had mixed feelings ranging from extremely helpful (5) to neutral (3). 80% of attendees participated in support groups prior to ours. Conclusions: Active participation in a guided and closed support group allowed participants to share their experiences and concerns about their diagnoses, comfortably – supporting transition beyond active-treatment. The online portion of the platform was helpful in assuaging common negative concerns.

Journal of clinical oncology : official journal of the American Society of Clinical Oncology, Nov 12, 2016

Palifosfamide is the active metabolite of ifosfamide and does not require prodrug activation, the... more Palifosfamide is the active metabolite of ifosfamide and does not require prodrug activation, thereby avoiding the generation of toxic metabolites. The PICASSO III trial compared doxorubicin plus palifosfamide with doxorubicin plus placebo in patients who had received no prior systemic therapy for metastatic soft tissue sarcoma. Patients were randomly assigned 1:1 to receive doxorubicin 75 mg/m(2) intravenously day 1 plus palifosfamide 150 mg/m(2)/d intravenously days 1 to 3 or doxorubicin plus placebo once every 21 days for up to six cycles. The primary end point was progression-free survival (PFS) by independent radiologic review. In all, 447 patients were randomly assigned to receive doxorubicin plus palifosfamide (n = 226) or doxorubicin plus placebo (n = 221). Median PFS was 6.0 months for doxorubicin plus palifosfamide and 5.2 months for doxorubicin plus placebo (hazard ratio, 0.86; 95% CI, 0.68 to 1.08; P = .19). Median overall survival was 15.9 months for doxorubicin plus pa...

Cancer Research, 1984

Thirty-one consecutive patients with chronic myelogenous leukemia were treated in the chronic pha... more Thirty-one consecutive patients with chronic myelogenous leukemia were treated in the chronic phase with immunotherapy in addition to chemotherapy. Immunotherapy consisted of Bacil lus Calmette-Guerin and allogeneic myeloblasts given by vacci nation, and chemotherapy comprised busulfan p.o. in most pa tients. No randomly allocated control group was designated, but patient characteristics appear to be typical of those of other published groups. Twenty-eight of 31 patients were followed from diagnosis to death, and the three remaining patients were followed for over 5 years. The median survival of the patients in our group was 37 months. There was a constant rate of decline in survival with time, with a mean annual death rate of 30% per year. Twentyfive of the 31 patients terminated in blast crisis. One of 21 patients achieved complete remission in blast crisis of myeloid or indeterminate type, and three of four patients achieved com plete remission for blast crisis of lymphoid type. The median survival, the rate of decline in survival, and the remission rate in blast crisis do not appear to differ from those of comparable groups of patients treated with chemotherapy alone.

Cancer Research, Sep 1, 1983

Cellular uptake and binding of daunomycin were studied using the digitized video fluorescence mic... more Cellular uptake and binding of daunomycin were studied using the digitized video fluorescence microscopy technique, in a sen sitive and a resistant subline of P388 leukemic ascites tumor cells. When a 60-min time course of uptake was monitored, the sensitive cells had a 4-fold greater uptake than did the resistant cells. When the cells were perfused with drug-free medium, identical exchangeable levels of the drug were lost from both sublines. The difference in drug uptake could be accounted for entirely on the basis of differences in a slowly exchanging drug fraction which probably represents bound intracellular drug. In glucose-free medium, uptake of daunomycin was accelerated by metabolic inhibition to a greater extent in resistant than in sen sitive cells. Furthermore, there was minimal decrease in the fluorescence when both sublines were perfused with drug-free medium. The addition of glucose to this medium induced a significant decrease in fluorescence in resistant but not in sen sitive cells. These data raise the possibility that decreased drug uptake in resistant cells associated with decreased slowly ex changing drug fraction may be associated with an inherent defect in drug binding which is reversed by inhibition of energy metab olism. Parallel in vitro and in vivo studies revealed the presence of uptake heterogeneity; both sensitive and resistant cells con tained subpopulations (20 to 30%) that have less or more fluo rescence than the predominant pattern. This observation dem onstrates the possible use of the digitized video fluorescence microscopy for recognizing subsets of cells with different drug susceptibility and to monitor the emergence of anthracyclineresistant cell populations.

Cancer Research, Jul 1, 1985

Because alterations in cell membrane sialoglycoconjugates can affect the behavior of neoplastic c... more Because alterations in cell membrane sialoglycoconjugates can affect the behavior of neoplastic cells, we investigated the effects of in vitro treatment with antimetabolites used in cancer therapy on the expression of membrane sialic acid in cultured HL-60 leukemic cells. In these studies, cells were incubated with Vibrio cholerae neuraminidase to remove surface sialic acid. Reappearance of membrane sialic acid during drug treatment was followed (a) by measuring changes in radioactive surface labeling of viable cells with sodium metaperiodate-sodium[3H]

Cancer Research, Sep 15, 1991

Four well defined multidrug-resistant cell lines and their drug-sensitive counterparts were exami... more Four well defined multidrug-resistant cell lines and their drug-sensitive counterparts were examined for intracellular distribution of daunorubicin (DNR) by laser-assisted confocal fluorescence microscopy: P-glycoprotein-negative III,-60/AR cells, and P-glycoprotein-positive P388/ADR, KBV-1, and MCF-7/ADR cells. Both drug sensitive cell lines (HL-60/S, P388/S, KB3-1, and MCF-7/ S) and drug-resistant cell lines (HL-60/AR, P388/ADR, KBV-1, and MCF-7/ADR) exposed to DNR showed a similar rapid distribution of drug from the plasma membrane to the perinuclear region within the first 2 min. From 2-10 min, the drug sensitive HL-60/S, P388/S, and MCF-7/S cells redistributed drug to the nucleus and to the cytoplasm in a diffuse pattern. In contrast, drug-resistant HL-60/AR, P388/ADR, and MCF-7/ADR redistributed DNR from the perinuclear region into vesicles distinct from nuclear structures, thereby assuming a "punctate" pattern. This latter redistribution could be inhibited by glucose deprivation (in dicating energy dependence), or by lowering the temperature of the medium below 18Â°C. The differences in distribution between sensitive and resistant cells did not appear to be a function of intracellular DNR content, nor the result of drug cytotoxicity. Drug-sensitive KB3-1 and-resistant KBV-1 cells did not fully follow this pattern in that they demonstrated an intracellular DNR distribution intermediate between HL-60/S and HL-60/AR cells with both "punctate" and nuclear/cytoplasmic uptake sometimes in the same cell. These data indicate that the intracellular distribution of DNR is an important deter minant of drug resistance regardless of the overexpression of P-glycoprotein. The intracellular movement of drug requires the presence of glucose and a temperature above 18Â°C, implicating energy-dependent processes and vesicle fusion in the distribution process. This intracellular transport of DNR away from the nucleus in multidrug-resistant cells may protect putative cell targets such as DNA against drug toxicity.

Cancer Research, Mar 1, 1987

We studied the intracellular distribution of drugs within anthracyclinesensitive and-resistant ce... more We studied the intracellular distribution of drugs within anthracyclinesensitive and-resistant cells by computer-assisted digitized video fluores cence microscopy. We found that the antitumor antibiotic, daunorubicin, distributes differently in anthracycline-sensitive and-resistant human leukemia cells (HL-60). Verapamil and other agents known to circumvent resistance in pleiotropic drug-resistant cell lines were able to change the pattern of distribution of daunorubicin in the anthracycline-resistant HL-60 cells back to the distribution found in anthracycline-sensitive HL-60 cells. To investigate the biochemical basis for this effect, we studied the distribution of daunorubicin and doxorubicin in a hydrophobic/hydrophilic (membrane/cytoplasmic) environment using the two-compartment cell-free system of Folch. Our results demonstrate that various unrelated drugs known to overcome resistance will also change the distribution of the anthracyclines in the hydrophobic/hydrophilic compartments. Our data allow the hypothesis that various unrelated agents known to circumvent resistance may act by altering the hydrophobic/hydrophilic solubility of anthracyclines in the resistant cell.

Gene, 1997

HRS/SRp40/SFRS5 (HRS) is an SR (serine-arginine-rich) protein which regulates both alternative sp... more HRS/SRp40/SFRS5 (HRS) is an SR (serine-arginine-rich) protein which regulates both alternative splicing and basal splicing. HRS mRNA contains several transcripts, including HRS-SF and HRS-LF which have different temporal patterns of expression in proliferating liver. As previously reported, HRS-SF mRNA encodes the SR splicing factor. However, the identity of HRS-LF remained unknown. Here, we cloned and characterized the mouse HRS gene, partial human HRS gene, and several cDNAs derived from HRS-LF mRNA. The mouse HRS gene spans 5050 bp and contains eight exons and seven introns. HRS-LF mRNA contains a 1.2 kb insert within the SF mRNA with stop codons in all three reading frames. A comparison of HRS-LF and the HRS gene revealed that HRS-LF mRNA is an intron-retaining product which contains intron 5. At most, HRS-LF encodes a truncated HRS protein with one RNA binding domain. Interestingly, intron 5 demonstrates 90% identity between the mouse and human HRS genes, implying that intron 5 might play an important role in regulating HRS gene splicing or expression.

We have examinedthe role of CMP-NeuAc:GalÂ£I-3GalNAc-R o(2- 3)-sialyltransferase in fresh leukemi... more We have examinedthe role of CMP-NeuAc:GalÂ£I-3GalNAc-R o(2- 3)-sialyltransferase in fresh leukemia cells and leukemia-derived cell lines. Enzyme activity in normal granulocytes using Gal$l-3GalNAca- o-nitrophenyl as substrate was 1.5 Â± 0.7 nmol/mg/h whereas activity in morphologically mature granulocytes from 6 patients with chronic mye- logenous leukemia (CML) was 4.2 Â±1.6 nmol/mg/h (/' < 0.05). Myelo blasts from 5 patients with CML

Transplantation, 1974

ABSTRACT

Cancer Biology & Therapy, 2016

Malignant mesothelioma (MM) is an aggressive tumor arising from mesothelial linings of the serosa... more Malignant mesothelioma (MM) is an aggressive tumor arising from mesothelial linings of the serosal cavities. Pleural space is the most common site, accounting for about 80% of cases, while peritoneum makes up the majority of the remaining 20%. While histologically similar, tumors from these sites are epidemiologically and clinically distinct and their attribution to asbestos exposure differs. We compared DNA array-based findings from 48 epithelioid peritoneal MMs and 41 epithelioid pleural MMs to identify similarities and differences in copy number alterations (CNAs). Losses in 3p (BAP1 gene), 9p (CDKN2A) and 22q (NF2) were seen in tumors from both tumor sites, although CDKN2A and NF2 losses were seen at a higher rate in pleural disease (p<0.01). Overall, regions of copy number gain were more common in peritoneal MM, whereas losses were more common in pleural MM, with regions of loss containing known tumor suppressor genes and regions of gain encompassing genes encoding receptor tyrosine kinase pathway members. Cases with known asbestos causation (n D 32) were compared with those linked to radiation exposure (n D 9). Deletions in 6q, 14q, 17p and 22q, and gain of 17q were seen in asbestosassociated but not radiation-related cases. As reported in post-radiation sarcoma, gains outnumbered losses in radiation-associated MM. The patterns of genomic imbalances suggest overlapping and distinct molecular pathways in MM of the pleura and peritoneum, and that differences in causation (i.e., asbestos vs. radiation) may account for some of these site-dependent differences

Cancer Research, Aug 1, 1985

An anthracycline-resistant subline of HL-60 promyelocytic leu kemia cells (HL-60/AR) has been iso... more An anthracycline-resistant subline of HL-60 promyelocytic leu kemia cells (HL-60/AR) has been isolated in vitro by subculturing in progressively higher concentrations of Adriamycin. The resis tant cells are capable of sustaining continuous growth in 10~6 M Adriamycin which is more than 50 times the 50% inhibitory dose for the parent line. HL-60/AR expressed variable degrees of cross-resistance to daunorubicin, dihydroxyanthracenedione, vincristine, vinblastine, and actinomycin D, but it remained sen sitive to methotrexate and 1-0-D-arabinofuranosylcytosine.2 So dium dodecyl sulfate-polyacrylamide gel electrophoresis of glycoproteins of HL-60/AR revealed two prominent glycoproteins with molecular weights of 160,000 Â± 10,000 and 110,000 Â± 10,000 which were not detected in the sensitive cells. Cellular uptake and retention of daunorubicin was studied in the resistant and sensitive cells utilizing digitized video fluorescence micros copy. The sensitive cells accumulated more drug and showed at least 2-fold greater levels of brightness than the resistant cells. Studies of total intracellular accumulation, utilizing 10~6 M [14C]daunorubicin as a marker, showed a 1-h accumulation of 98 Â± 20 pmol/106 cells in HL-60/AR versus 255 Â±25 pmol/106 cells in HL-60. Exposure to nontoxic concentrations of the calcium channel blocker Verapamil (10~5 M)led to enhanced accumulation (175 Â±8 pmol/106 cells) and retention of the drug in HL-60/AR, resulting in increased cytotoxicity in HL-60/AR. These anthra cycline-resistant leukemic cells may serve as a valuable experi mental model in studying the phenomenon of multiple drug resistance as well as strategies to circumvent it in human myeloid leukemia.

Anthracycline-sensitive (HL-60) and -resistant (HL-60/AR) cells, which do not overexpress the P-g... more Anthracycline-sensitive (HL-60) and -resistant (HL-60/AR) cells, which do not overexpress the P-glycoprotein, each transport and distribute daunorubicin (DNR) into distinct intracellular locations, as visualized by digitized video fluorescence microscopy. At pH 7.4, the fluorescence of DNR in HL-60 cells appears distributed diffusely in both the nucleus and cytoplasm. In contrast, HL-60/AR cells show much less fluorescence in the nucleus and cytoplasm; most of the fluorescence localizes first to the Golgi apparatus and is then gradually shifted to the lysosomes and/or mitochondria. In pharmacokinetic studies, HL-60/AR cells exposed to different extracellular concentrations of [14C]DNR consistently accumulated less radioactive drug than the parent HL-60 cells. Incubation of HL-60/AR cells with sodium azide and deoxyglucose blocked the efflux of [14C]DNR and also prevented the shift of DNR fluorescence from the Golgi apparatus to the lysosomes/mitochondria. The efflux and the intracellular shift of DNR could also be inhibited by lowering the temperature to 18 degrees C, which stops endosomal membrane fusion. When DNR was allowed to accumulate in HL-60 or HL-60/AR cells at pH 5 there was an increase in the proportion of drug fluorescence in the membranes of both HL-60 and HL-60/AR cells; a decrease in the amount of drug retained by HL-60, but not by HL-60/AR cells; and a decrease in the cytostatic effects of DNR on both HL-60 and HL-60/AR cells. These data suggest that DNR resistance is associated with a failure of DNR to pass through membranes and to bind to cytoplasmic and nuclear structures. Instead, most of the drug is taken up by the Golgi apparatus from which it is then shifted to the lysosomes or to mitochondria, or out of the cell.

Histopathology, 2015

The prognostic significance of histological subtyping of epithelioid pleural mesotheliomas has be... more The prognostic significance of histological subtyping of epithelioid pleural mesotheliomas has been recently reported, but similar data are lacking in peritoneal mesotheliomas. We investigated possible relationships between histological growth patterns of epithelioid peritoneal mesotheliomas, clinicopathologic features and patient outcome. 84 cases of chemotherapy-naive epithelioid peritoneal mesothelioma were classified into tubulopapillary, micropapillary, papillary, tubular, solid and trabecular growth patterns. Pathologic features such as depth of invasion, lymphocytic host response, mitotic count, nuclear grade, lymphovascular invasion, lymph node metastasis, and stromal desmoplasia were analyzed. The most common histological patterns were solid (n = 37, 44%), tubulopapillary (n = 24, 29%) and micropapillary (n = 11, 13%). The overall median survival was 36 months. Patients with solid mesothelioma had shorter overall survival (median, 29 months) compared to patients with tubulopapillary and micropapillary growth patterns (median, 51 months and 53 months, respectively; p=.053). A high mitotic index (&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;5 in 50 hpf) was found to be associated with poor survival (p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;.03). Moderate to severe lymphocytic host response was associated with longer median survival (p=.13) CONCLUSIONS: Our study highlights the prognostic importance of the solid growth pattern among diffuse epithelioid peritoneal mesotheliomas and reaffirms mitotic index as a predictor of overall survival. This article is protected by copyright. All rights reserved.