Factors predictive of outcome in patients with breast cancer refractory to neoadjuvant chemotherapy.

PURPOSE: The purpose of this study was to determine the clinical, pathological, and treatment factors that are predictive of local-regional recurrence and overall survival for patients with breast cancer that is refractory to neoadjuvant chemotherapy. PATIENTS AND METHODS: This study analyzed the data of the 177 breast cancer patients treated on our institutional protocols who had less than a partial response to neoadjuvant chemotherapy. The initial clinical stage of disease was II in 27%, III in 69%, and IV (supraclavicular lymph node involvement) in 4%. Surgery was performed in 94% of the patients, and 77% of these patients also received adjuvant chemotherapy. RESULTS: After a median follow-up of 5.2 years, 106 patients experienced disease recurrence, with 98 of these having distant metastases and 45 having local-regional recurrence. The 5- and 10-year overall survivals for the entire group were 56% and 33%, respectively. The factors that were independently associated with a statistically significant poorer overall survival in a Cox regression analysis were pathologically involved lymph nodes after surgery, estrogen receptor-negative disease, and progressive disease during neoadjuvant chemotherapy. The 5-year overall survival for patients with pathologically negative lymph nodes ranged from 84% (estrogen receptor-positive disease) to 75% (estrogen re-ceptor-negative disease), compared with rates for patients with pathologically positive lymph nodes of 66% (estrogen receptor-positive disease) and 40% (estrogen receptor-negative disease). The 5-year survival of patients with progressive disease was only 19%. The 5- and 10-year local-regional recurrence rates for the 177 patients were 27% and 34%, respectively. Significant factors on Cox analysis that predicted for local-regional recurrence were four or more pathologically involved lymph nodes and estrogen receptor-negative disease. For the 105 patients treated with surgery and postoperative radiation therapy, the 10-year local-regional recurrence rates for the subgroups with 0, 1, or 2 of these factors were 12%, 25%, and 44%, respectively. CONCLUSIONS: For patients with a poor response to neoadjuvant chemotherapy, conventional treatments achieve reasonable outcomes in those with lymph node-negative disease or estrogen receptor-positive disease. However, more active systemic and local therapies are needed for patients with estrogen receptor-negative disease and positive lymph nodes and for those with clinical evidence of progressive disease during neoadjuvant chemotherapy.

Monoclonal antibodies in the treatment of metastatic carcinoma to the liver: updated report of a pilot study including leukapheresis.

Twenty-two patients who had failed conventional treatment for advanced colorectal carcinoma metastatic to the liver were entered in this study. Survival from the date the hepatic disease was documented and ranged from 3 to 62 months, with an average of 20 months. Notably, 8 of the 22, or 36%, lived 24 months or more. Four patients, or 18%, survived 3 to 5 years after diagnosis of hepatic metastasis.

The changing national policy system: complexity, Medicare, and implications for aging groups.

Changes in congressional processes, health agendas, and competitive positions of physician and hospital groups in the 1980s have produced important setbacks for such group interests within Medicare. Though united and successful in opposing Carter's 1977-79 hospital cost-containment proposals, these groups were subjected to severe new limits on hospital reimbursements under the 1982 budget reconciliation act. Thereafter, problems in protecting their interests continued or increased. Disagreements among hospital groups (e.g., the American Hospital Association and the former Federation of American Hospitals) surfaced over the Prospective Payment System introduced in 1983. In 1984, Congress instituted a freeze on physicians' Medicare fees despite AMA opposition. This projected narrow self-interest, thus decreasing the AMA's credibility. Further cost restrictions were imposed in 1985-86 budget acts. The problems of these organizations indicate that if aging groups are to protect their own stake in Medicare in the new political context, they must be particularly concerned with unity, credibility, and long-term perspectives.

Acetaminophen and analogs as cosubstrates and inhibitors of prostaglandin H synthase.

Previous studies have shown that acetaminophen (APAP) is converted by prostaglandin H synthase (PGHS) to both one-electron oxidized products and the two-electron oxidized product, N-acetyl-p-benzoquinone imine (NAPQI). The present study further characterizes this reaction and shows that relatively low concentrations (20-200 microM) of APAP stimulate PGHS activity in ram seminal vesicle microsomes, whereas high concentrations (greater than 10 mM) inhibit the conversion of arachidonic acid (AA) to 15-hydroperoxy-9,11-peroxidoprosta-5,13-dienoic acid (PGG2). Stimulatory and inhibitory activities apparently involve the reduction of oxidized complexes of PGHS, and stimulatory and inhibitory activities roughly correlate with the electrochemical half-wave oxidation potentials of a series of hydroxyacetanilides. Using APAP as a probe, it was found that at low concentrations, APAP is converted in a cooxidation reaction with arachidonic acid to a dimer, 4'4"'-dihydroxy-3', 3"'-biacetanilide (bi-APAP), and other polymeric products. Moreover, an electrophilic metabolite of acetaminophen, NAPQI, was detected directly and also detected indirectly by its reaction with glutathione (GSH) to form 3'-(S-glutathionyl)acetaminophen (GS-APAP). The formation of all products was inhibited by indomethacin and the reductants, ascorbic acid and butylated hydroxyanisole (BHA). However, in the presence of GSH, ascorbic acid only partially inhibited the formation of GS-APAP while almost completely inhibiting the formation of bi-APAP. The same products of APAP (bi-APAP and NAPQI) were formed by PGHS and hydrogen peroxide in reactions that were not inhibited by indomethacin. At high concentrations of APAP that inhibit PGHS, the formation of products in the presence of arachidonic acid but not H2O2 was inhibited. These findings are generally consistent with a mechanism of acetaminophen oxidation by PGHS that involves common intermediate enzyme forms for both cyclooxygenase- and hydroperoxidase-catalyzed reactions. At least one of the intermediate complexes is reduced by relatively low concentrations of APAP and stimulates PGHS, whereas another intermediate complex is reduced by APAP at higher concentrations to inhibit the enzyme.

Steady-state analysis of ion fluxes in Necturus gall-bladder epithelial cells.

1. The steady-state fluxes of Na, K and Cl ions have been measured in Necturus gall-bladder epithelium by a technique that involves labelling the cells with tracer ions from the mucosal bath only, whilst the serosa is kept at low specific activity. After removing tracer, the efflux is followed into the serosal bath, revealing two exponential components. 2. The time constant of the fast component lies between 0.03 and 0.04 s-1 and corresponds to that of the extracellular space. The slow component closely matches the cellular efflux, with constants which lie between 0.14 and 0.46 X 10(-2) s-1. 3. Full unstirred-layer calculations have been performed to determine the specific activities in the mucosal solution, the cell and the corium (subepithelium). These involved measuring the diffusion coefficients of Na and Cl in the isolated corium: they are restricted by factors of 0.17 and 0.11. 4. The partial flux equations for this double-membrane system have been solved to obtain the cellular fluxes for all three ions. The results indicate that: (i) the net transcellular Na flux is 190 pmol cm-2 s-1, equivalent to the transepithelial salt flux during fluid secretion; (ii) the net transcellular K flux is effectively zero because this ion recirculates across the serosal membrane; (iii) the net transcellular Cl flux is 27 pmol cm-2 s-1, or 15% of the net transepithelial salt flux. 5. The permeability of the paracellular pathway to Cl is 1.65 X 10(-5) cm s-1 and the available driving forces will allow a maximum net electrodiffusive Cl transport of 10% through the shunt pathway. 6. 1:1 coupling of Na and Cl net fluxes at the mucosal membrane of this epithelium cannot be present, and processes other than simple electrodiffussion are required to effect net Cl transport by another route. 7. The serosal fluxes of K and Cl do not obey the flux-ratio equation. A component of these fluxes must be present which is neither active (pumped) nor passive (electrodiffusive and independent). If they are symmetrical in the steady state then the ratio of these exchange fluxes lies between 2:1 and 3:1 depending upon the size of the pump flux. They support the view that a mode of coupled K and Cl transport may be operating at the basolateral membrane of these cells.

Transcellular sodium fluxes and pump activity in Necturus gall-bladder epithelial cells.

1. Transepithelial Na transport in Necturus was determined by measuring the rate of isotonic fluid flow. The rate at 20 degrees C was equivalent to 175 pmol cm-2 s-1. 2. Ouabain was effective in Necturus, binding to the Na pump in gall-bladder cells with a mean rate constant of 5.4 X 10(3) M-1 s-1. Measurement of the diffusive time constant of the free space for [3H]ouabain shows that the pump must be fully inhibited within 20 s when ouabain is applied to the serosa at 10(-3) M. 3. The serosal Na efflux from loaded cells was inhibited 36% by ouabain equal to a flux of 73 pmol cm-2 s-1. The remaining flux could not be attributed to either exchange diffusion or electrodiffusion induced by ouabain. 4. The transepithelial potential was 0.3 mV serosa positive. The short-circuit current measured was 6.33 +/- 1.9 microA cm-2, equal to a positive univalent ion flux of 65.6 pmol cm-2 s-1 or 38% of the net Na transfer. The current was inhibited within 1-5 min by 5 X 10(-5) M-amiloride. 5. Fluid secretion was immediately inhibited 34% by ouabain, equivalent to an isotonic transport of Na of 59.7 pmol cm-2 s-1. Thereafter it continued for at least an hour, sometimes declining slowly. Amiloride had little effect (13%). 6. The Na pump rate was measured by titrating the cell content with tracer Na at different times after ouabain treatment. The initial slope was equal to a rate of 61.6 pmol cm-2 s-1 or 35% of the net flux at time zero. 7. The Na pump rate has also been measured by recording the rise in cell Na activity with ion-specific micro-electrodes, and correcting for swelling effects. The Na pump rate was very similar to that estimated from the rise in tracer Na content, equal to 59.3 pmol cm-2 s-1 or 31.4% of the transepithelial rate. Examination of the same experiment in the literature shows a closely similar value, about one-third of that expected from fluid secretion or net flux measurements. 8. A scheme is proposed to explain the results, which requires a flow of NaCl through a parallel pathway of small Na content involving exchange en route with the cytoplasmic Na.

The effect of low external pH on properties of the paracellular pathway and junctional structure in isolated frog skin.

1. Undirectional and net fluxes of Na, Cl and mannitol were measured across the isolated short-circuited frog skin when the mucosal surface was bathed with Ringer solution at normal (7.4) or low (2.5) pH. When this solution was changed from normal to low pH, there was a marked increase in both influx and backflux of Cl and mannitol. Na backflux increased markedly but Na influx did not, resulting in a substantial decrease in net flux. 2. In open-circuit conditions at low pH both undirectional fluxes of Na increased and the potential across the skin dropped by a third. 3. The total conductance, Gt and the short-circuit current, Isc increased when the mucosal solution was changed from normal to low pH. The structural integrity of the 'tight junctions' in the epithelium was disrupted by the low pH treatment and at least 50% of the junctions examined showed a separation of the two, previously apposed, membranes. 4. It has been shown previously that when a low pH solution bathes the mucosal surface the total and shunt conductance increase; the present results demonstrate that under these conditions the short-circuit current no longer provides a good estimate of the net Na flux. We present calculations to show that protons can be the carriers for the extra charge transfer. 5. Using our values for net Na flux in open circuit and published values for the solute-linked volume flow, Jv, it could be shown that the osmolarity of the absorbate decreased at low pH.

Fluid reabsorption by Necturus proximal tubule perfused with solutions of normal and reduced osmolarity.

Fluid absorption in Necturus proximal tubule was studied when the kidneys were perfused with solutions of different osmolarities. The rate of fluid absorption was inversely proportional to the perfusion fluid osmolarity, while Na uptake remained constant. No difference was detected between the collected and injected luminal fluid, i.e. reabsorption was isotonic at normal and reduced osmolarities. The transtubular osmotic permeability remained fairly constant under the different perfusion osmolarities. Using our experimental results to test various models based on osmotic equilibration across the tubule wall we show that none of these provides an adequate mechanism for fluid absorption in this epithelium.

Chloride dependence of active sodium transport in frog skin: the role of intercellular spaces.

1. In agreement with previous observations the replacement of Cl by a nonpenetrating anion in the solution bathing either the outside or both sides of the frog skin causes a fall in the short-circuit current. 2. When Cl is replaced by a non-penetrating anion in the solution bathing the outside of the frog skin the Isc is still a correct measure of the net Na transport. 3. Under the same conditions both active and shunt paths seem to be affected since there is a decrease in Isc, Na influx, amiloride-dependent conductance, and initial Na uptake across the external barrier, together with a decrease in Cl-backfluxes and amiloride-independent conductance. There is also a decrease in water permeability and a reduction in size of the intercellular spaces. 4. The removal of Cl does not appear to affect the entry step of Na but may have an effect on the shunt path. This in turn may change the active Na transport.