Sacituzumab govitecan in previously treated hormone receptor-positive/HER2-negative metastatic breast cancer: final results from a phase I/II, single-arm, basket trial.

BACKGROUND: Trophoblast cell-surface antigen-2 (Trop-2) is expressed in epithelial cancers, including hormone receptor-positive (HR+) metastatic breast cancer (mBC). Sacituzumab govitecan (SG; Trodelvy®) is an antibody-drug conjugate composed of a humanized anti-Trop-2 monoclonal antibody coupled to SN-38 at a high drug-to-antibody ratio via a unique hydrolyzable linker that delivers SN-38 intracellularly and in the tumor microenvironment. SG was granted accelerated FDA approval for metastatic triple-negative BC treatment in April 2020. PATIENTS AND METHODS: We analyzed a prespecified subpopulation of patients with HR+/human epidermal growth factor receptor 2-negative (HER2-) HR+/HER2- mBC from the phase I/II, single-arm trial (NCT01631552), who received intravenous SG (10 mg/kg) and whose disease progressed on endocrine-based therapy and at least one prior chemotherapy for mBC. End points included objective response rate (ORR; RECIST version 1.1) assessed locally, duration of response (DOR), clinical benefit rate, progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Fifty-four women were enrolled between 13 February 2015 and 1 June 2017. Median (range) age was 54 (33-79) years and all received at least two prior lines of therapy for mBC. At data cut-off (1 March 2019), 12 patients were still alive. Key grade ≥3 treatment-related toxicities included neutropenia (50.0%), anemia (11.1%), and diarrhea (7.4%). Two patients discontinued treatment due to treatment-related adverse events. No treatment-related deaths occurred. At a median follow-up of 11.5 months, the ORR was 31.5% [95% confidence interval (CI), 19.5%-45.6%; 17 partial responses]; median DOR was 8.7 months (95% CI 3.7-12.7), median PFS was 5.5 months (95% CI 3.6-7.6), and median OS was 12 months (95% CI 9.0-18.2). CONCLUSIONS: SG shows encouraging activity in patients with pretreated HR+/HER2- mBC and a predictable, manageable safety profile. Further evaluation in a randomized phase III trial (TROPiCS-02) is ongoing (NCT03901339). TRIAL REGISTRATION: ClinicalTrials.gov NCT01631552; https://clinicaltrials.gov/ct2/show/NCT01631552.

Characterization of immune responses to anti-PD-1 mono and combination immunotherapy in hematopoietic humanized mice implanted with tumor xenografts.

BACKGROUND: The success of agents that reverse T-cell inhibitory signals, such as anti-PD-1/PD-L1 therapies, has reinvigorated cancer immunotherapy research. However, since only a minority of patients respond to single-agent therapies, methods to test the potential anti-tumor activity of rational combination therapies are still needed. Conventional murine xenograft models have been hampered by their immune-compromised status; thus, we developed a hematopoietic humanized mouse model, hu-CB-BRGS, and used it to study anti-tumor human immune responses to triple-negative breast cancer (TNBC) cell line and patient-derived colorectal cancer (CRC) xenografts (PDX). METHODS: BALB/c-Rag2nullIl2rγnullSIRPαNOD (BRGS) pups were humanized through transplantation of cord blood (CB)-derived CD34+ cells. Mice were evaluated for human chimerism in the blood and assigned into experimental untreated or nivolumab groups based on chimerism. TNBC cell lines or tumor tissue from established CRC PDX models were implanted into both flanks of humanized mice and treatments ensued once tumors reached a volume of ~150mm3. Tumors were measured twice weekly. At end of study, immune organs and tumors were collected for immunological assessment. RESULTS: Humanized PDX models were successfully established with a high frequency of tumor engraftment. Humanized mice treated with anti-PD-1 exhibited increased anti-tumor human T-cell responses coupled with decreased Treg and myeloid populations that correlated with tumor growth inhibition. Combination therapies with anti-PD-1 treatment in TNBC-bearing mice reduced tumor growth in multi-drug cohorts. Finally, as observed in human colorectal patients, anti-PD-1 therapy had a strong response to a microsatellite-high CRC PDX that correlated with a higher number of human CD8+ IFNγ+ T cells in the tumor. CONCLUSION: Hu-CB-BRGS mice represent an in vivo model to study immune checkpoint blockade to human tumors. The human immune system in the mice is inherently suppressed, similar to a tumor microenvironment, and thus allows growth of human tumors. However, the suppression can be released by anti-PD-1 therapies and inhibit tumor growth of some tumors. The model offers ample access to lymph and tumor cells for in-depth immunological analysis. The tumor growth inhibition correlates with increased CD8 IFNγ+ tumor infiltrating T cells. These hu-CB-BRGS mice provide a relevant preclinical animal model to facilitate prioritization of hypothesis-driven combination immunotherapies.

Mechanisms underlying transition from acute glomerular injury to late glomerular sclerosis in a rat model of nephrotic syndrome.

Functional and morphologic measurements were performed in Munich-Wistar rats after a single central venous injection of puromycin aminonucleoside (PA) or saline vehicle (sham). During phase I, PA rats exhibited overt nephrotic syndrome and impaired glomerular filtration, primarily due to a reduction in the glomerular capillary ultrafiltration coefficient. The morphologic counterpart of the latter consisted of effacement of glomerular epithelial cell foot processes and decrease in the number of filtration slit diaphragms. Administration of the angiotensin I converting enzyme inhibitor (CEI) enalapril to PA rats did not ameliorate glomerular dysfunction. During phase II, PA rats exhibited spontaneous resolution of proteinuria, impaired function, and morphologic abnormalities. However, PA rats now demonstrated marked glomerular capillary hypertension and continued, albeit lesser, reductions in the ultrafiltration coefficient. Concurrent CEI administration modestly lowered systemic arterial pressure, and normalized the glomerular capillary hydraulic pressure and ultrafiltration coefficient. Additional rats were studied during phase III, 70 wk after injection. In PA rats, prior glomerular hypertension was associated with development of recurrent proteinuria and extensive glomerular sclerosis, whereas concurrent CEI administration limited these parameters to values comparable to those in sham rats. Glomerular hypertension thus may explain the development of glomerular sclerosis and renal failure long after an episode of acute glomerular injury.

Palbociclib:CDK4/6 inhibition in the treatment of ER-positive breast cancer.

Maintaining cell-cycle control has become a mainstay in treatment for many cancers. Cell-cycle manipulation can be especially valuable in breast cancer tumor cells that will often express hormone receptors that are amenable to anti-hormone receptor-targeted therapies. Despite these treatments, patients often progress, leading to other targeted agents being investigated to help promote progression-free survival. Cyclin-dependent kinases (CDKs) have been identified as contributors in the process of cell division. Combining inhibitors of CDKs with traditional endocrine treatments has shown significant progression-free survival in patients with metastatic breast cancer. One such CDK inhibitor, palbociclib, has shown great promise in the treatment of hormone receptor-positive breast cancer. In this article we review the traditional hormonal treatments of breast cancer, how CDK inhibition is beneficial in the treatment of this disease, and the preclinical and clinical data supporting the use of this medication.

Nonoliguric acute renal failure.

Nonoliguric acute renal failure is being recognized more commonly as a frequent initial observation for azotemia. Use of automated biochemical monitoring, aminoglycoside antibiotic utilization, and administration of potent diuretics and mannitol in settings of oliguria all contribute to its increased incidence. There appears to be less morbidity and mortality in patients with nonoliguric acute renal failure, and diagnostic urinary indexes suggest less of an insult to renal function. This article reviews the available literature and explores the reasons for the increased frequency of recognition of nonoliguric acute renal failure. Another aim is to compare nonoliguric acute renal failure with the oliguric from because there are important differences to be recognized by the clinician.

Fractional excretion of sodium. Exceptions to its diagnostic value.

Determining the cause of acutely deteriorating renal function is a common problem in clinical nephrology. The fractional excretion of filtered sodium (FENa) has been demonstrated to be a reliably discriminating test between prerenal azotemia and acute tubular necrosis. However, with increasing clinical use of the FENa, numerous reports of low FENa (less than 1%) have appeared. The clinical settings of these reports include oliguric and nonoliguric acute tubular necrosis, urinary tract obstruction, acute glomerulonephritis, hepatorenal syndrome, renal allograft rejection, sepsis, and drug-related alterations in renal hemodynamics. One particular urinary index cannot be expected to reliably discriminate between prerenal azotemia and acute renal failure in all cases. The utility of the FENa test in the differential diagnosis of acute renal failure must be interpreted in conjunction with the patient's clinical course and the use of additional urinary and serum tests.

Cardiovascular outcomes in type 2 diabetes. A double-blind placebo-controlled study of bezafibrate: the St. Mary's, Ealing, Northwick Park Diabetes Cardiovascular Disease Prevention (SENDCAP) Study.

OBJECTIVE: To determine whether serum lipid intervention, in addition to conventional diabetes treatment, could alter cardiovascular outcomes in type 2 diabetes. RESEARCH DESIGN AND METHODS: There were 164 type 2 diabetic subjects (117 men, 47 women) without a history of clinical cardiovascular disease randomized to receive either bezafibrate or placebo daily on a double-blind basis in addition to routine diabetes treatment and followed prospectively for a minimum of 3 years. Serial biochemical and noninvasive vascular assessments, carotid and femoral artery B-mode ultrasound measurements, and those pertaining to coronary heart disease (CHD)--clinical history, the World Health Organization (WHO) cardiovascular questionnaire, and resting and exercise electrocardiogram (ECG)--were recorded. RESULTS: Bezafibrate treatment was associated with significantly greater reductions over 3 years in median serum triglyceride (-32 vs. 4%, P = 0.001), total cholesterol (-7 vs. -0.3%, P = 0.004), and total-to-HDL cholesterol ratio (-12 vs. -0.0%, P = 0.001), and an increase in HDL cholesterol (6 vs. -2%, P = 0.02) as compared with placebo. There was a trend toward a greater reduction of fibrinogen (-18 vs. -6%, P = 0.08) at 3 years. No significant differences between the two groups were found in the progress of ultrasonically measured arterial disease. In those treated with bezafibrate, there was a significant reduction (P = 0.01, log-rank test) in the combined incidence of Minnesota-coded probable ischemic change on the resting ECG and of documented myocardial infarction. CONCLUSIONS: Improving dyslipidemia in type 2 diabetic subjects had no effect on the progress of ultrasonically measured arterial disease, although the lower rate of "definite CHD events" in the treated group suggests that this might result in a reduction in the incidence of coronary heart disease.

Cholestyramine resin ameliorates chronic aminonucleoside nephrosis.

We chose to assess the role of cholesterol reduction in chronic aminonucleoside nephrosis by pharmacologically lowering serum cholesterol with cholestyramine. Two groups of rats were made nephrotic with a single intravenous dose of puromycin aminonucleoside (PA): one group (PA/resin) received 5% (w:w in diet) cholestyramine resin and the dietary control group (PA/cell) received 5% cellulose. Cholestyramine-treated rats demonstrated significant functional and histological protection. Recurrent proteinuria was significantly lower in PA/resin animals. Whole-kidney glomerular filtration rate in the PA/resin group was preserved at a level equivalent to normal age-matched control rats whereas the PA/cell group had a significantly lower value than did the normal animals. The extent of segmental glomerulosclerosis 24 wk after PA delivery was significantly lower in the PA/resin group. These results suggest a role for hyperlipidemia as one of the mechanisms involved in the pathogenesis of progressive glomerular disease.

Hyperlipidemia of nephrosis: pathophysiologic role in progressive glomerular disease.

During the past few years, the increasing speculation that the hyperlipidemia of nephrosis may be one of several pathogenic mechanisms involved in the progression of initial glomerular injury to glomerulosclerosis has generated many clinical and experimental investigations. This discussion reviews pertinent studies that address two major issues. First, the underlying pathophysiologic mechanisms involved in the development of the hyperlipidemia of nephrosis are explored. Second, this article examines recent studies that investigate how this secondary hyperlipidemia may further aggravate initial glomerular injury and contribute to a progressive glomerulopathy, primarily mediated through alterations in monocyte/macrophage function.

Nifedipine-induced renal dysfunction. Alterations in renal hemodynamics.

Nifedipine caused acute, reversible deterioration in renal function in four patients with chronic renal insufficiency. The absence of hypotension, clinical course, benign urinary sediments, and normal results of renal ultrasound examinations excluded acute tubular necrosis, pyelonephritis, interstitial nephritis, obstructive uropathy, and acute glomerulonephritis. It is postulated that this slow calcium channel blocker produced deleterious intrarenal hemodynamic alterations in the setting of moderate to severe renal functional impairment. Nifedipine may alter renal function by blocking calcium entry into renal vascular smooth muscle, thereby reducing the efficacy of vasoconstrictor hormones in regulation of renal blood flow and glomerular filtration rate. An alternative explanation is that nifedipine may inhibit the compensatory synthesis of vasodilatory prostaglandin E2 analogous to the clinical observation of acute deterioration in renal function by nonsteroidal anti-inflammatory drugs in patients with pre-existing renal insufficiency. These observations suggest that clinicians should monitor renal function closely and exercise caution when administering nifedipine to patients with underlying renal insufficiency.

Progressive albuminuria and glomerulosclerosis in a rat model of chronic renal allograft rejection.

A significant proportion of renal allografts fail within several months or years after transplantation, primarily because of chronic rejection. The etiology and pathophysiology of this condition remain unclear. We studied the renal function, morphology, and immunohistology, in parallel, among F344-to-Lewis allografts (n = 23) and isografts (n = 13) over the course of 24 weeks. Only an initial 10-day course of CsA (5 mg/kg/day) was given to both groups to prevent acute rejection. Hypertension did not develop, although awake systolic blood pressure was significantly higher in allografts at the end of the study. Significant differences in urine albumin excretion (UalbV) between isografts and allografts were evident as early as 4 weeks after engraftment but rose dramatically by 20 weeks (3.3 +/- 0.7 vs. 21.2 +/- 3.7 mg/day, respectively, P < .001). This pattern continued until the conclusion of the study (5.0 +/- 1.1 vs. 53.5 +/- 7.6 mg/day, P < .001). Serum creatinine values were only significantly elevated in allografts at 16 weeks, which temporally corresponded to the dramatic increase in UalbV. However, renal blood flow and glomerular filtration rate, measured by paraaminohippurate and inulin clearances, respectively, were significantly lower in allografted organs, at 24 weeks. The frequency of glomerulosclerosis lesions was significantly increased in allografted kidneys at 24 weeks and correlated with UalbV values. Glomerular localization of mononuclear leukocyte subsets were equivalent between allografts and isografts; however, the numbers of interstitial macrophages, CD8+, and pan-T-cells were all significantly greater in allografts at 24 weeks. The infiltration of significantly greater numbers of macrophages and lymphocytes into the tubulointerstitium of the allograft group suggests a mononuclear leukocyte effector cell mediation of the progressive glomerular abnormalities in this model of chronic renal allograft rejection in the rat.

The role of macrophages and reactive oxygen species in experimental hydronephrosis.

A common feature to a number of immune and non-immune renal diseases of diverse etiology is the infiltration of the glomerular and tubulointerstitial compartments by infiltrating macrophages. This review will focus on experimental data supporting the role of the infiltrating renal macrophage as a mediator of interstitial fibrosis during the course of obstructive nephropathy as it pertains to the unilateral ureteral obstruction model in the rat. The mechanical disturbance resulting from complete ureteral obstruction causes tubular injury/dysfunction resulting in a florid pro-inflammatory and fibrogenic response. The central pathobiological theme drawn from data in this model is that macrophage-derived pro-inflammatory mediators, including fibrogenic cytokines and reactive oxygen species, represent pivotal links between the pro-inflammatory state of ureteral obstruction and the late development of interstitial fibrosis. We propose that increased intrarenal oxidant stress, owing to an overproduction of reactive oxygen species and dysregulated tubular antioxidant enzymes, can induce overexpression of fibrogenic cytokines and chemoattractants, as well as increased transcription and synthesis of extracellular matrix proteins, leading to tubular loss and fibrogenesis.

Mechanisms of interstitial fibrosis in obstructive nephropathy.

Numerous pathological processes are involved in the renal tubulointerstitial fibrogenic reaction that occurs after ureteral ligation. Central to these maladaptive events is a florid interstitial monocytic infiltration of the tubulointerstitium, which is preceded by a proximal tubular up-regulation of macrophage chemoattractants. Once within the peritubular and periglomerular space, these macrophages are capable of releasing a potent armamentarium of peptide growth factors. TGF-beta has been singled out as a pivotal growth factor mediating fibrogenesis owing to its multifaceted effects on fibroblasts, tubular cells, matrix metalloproteinases, and TIMPs. A growing body of experimental studies using the rat hydronephrosis model is now demonstrating that angiotensin II may, in addition to its well-known hemodynamic effect, also be pro-inflammatory and pro-fibrogenic.

Analogous pathobiologic mechanisms in glomerulosclerosis and atherosclerosis.

This paper attempts to further delineate the similar pathobiologic mechanisms involved in the atherosclerosis and glomerulosclerosis processes. In particular, recent experimental data in models of both processes have focused on the roles of hypercholesterolemia and the monocyte/macrophage in propagating these lesions. In a nonimmune toxic glomerulopathy, chronic aminonucleoside nephrosis, our laboratory has demonstrated an important role for the glomerular macrophage, which is increased in number in temporal association with the onset of albuminuria, in propagating initial glomerular injury to glomerulosclerosis. In addition, a superimposition of dietary hypercholesterolemia further augments this heightened glomerular macrophage number and activates systemic macrophages. These data suggest a synergistic role between the hypercholesterolemia of nephrosis and the surge in glomerular macrophage number following initial glomerular injury in establishing a cascade of intercellular events that culminates in glomerulosclerosis. The intriguing histologic and immunohistochemical similarities between the evolving fatty streak in the atherosclerotic vessel wall and the progressive glomerular lesion leading to glomerulosclerosis suggest analogous pathobiologic mechanisms.

Urinary parameters to assess renal function.

Acute suppression of renal function has a multitude of etiologies. This review discusses the pathophysiologic basis, usefulness, and limitations of the commonly utilized urinary function parameters as well as some miscellaneous tests to properly diagnose specific disorders.

Hemolytic uremic syndrome/thrombotic thrombocytopenic purpura (HUS/TTP) complicating adult Still's disease: remission induced with intravenous immunoglobulin G.

Coexistence of hemolytic uremic syndrome/thrombotic thrombocytopenic purpura (HUS/TTP) and adult Still's disease is extremely rare. We describe the case history of a 22-year-old young man who presented with evidence of a thrombotic microangiopathy complicated by dialysis-dependent renal failure, encephalopathy, and an ischemic retinopathy. The most important and novel feature of this case was the dramatic and sustained clinical remission of the TMA induced by intravenous immunoglobulin (IVIg) after failure of plasmapheresis and glucocorticoids to do so.

Ureteral obstruction as a complication of renal transplantation: a review.

Ureteral obstruction in a renal allograft, due to a variety of etiologies, is both a challenging diagnostic and therapeutic disorder. Since ureteral obstruction in a renal transplant recipient usually presents as azotemia, it must also be distinguished from acute rejection. Although ultrasound is non-invasive and readily available, the most definitive diagnostic tool is percutaneous nephrostomy tube placement with antegrade nephrostogram. A variety of therapeutic approaches are available to treat ureteral obstruction in a renal allograft. These procedures can be open (e.g., repeat ureteroneocystotomy) or utilize an endourological approach (e.g., transluminal ureteral dilatation). From an experimental standpoint, recent data in rodent models of experimental hydronephrosis demonstrate similar pathobiologic events in both the obstructed kidney and an allograft undergoing the chronic rejection process. To this end, investigation needs to be conducted to assess whether partial, unrecognized ureteral obstruction in an allograft hastens the development of chronic rejection. This would further underscore the importance of ureteral obstruction as a cause for not only acute azotemia in an allograft, but also chronic deterioration in renal transplant function.

Renal revascularization in patients on dialysis.

Five patients requiring dialysis for acute pulmonary edema and uremia from severe renal artery occlusive disease underwent surgical revascularization. Three patients with oliguria had excellent outcomes and remain dialysis-independent as long as twenty-four months following operation (mean serum creatinine 2.0 mg/dl). The two patients who were anuric both had technically successful operations but remained dialysis-dependent. Diagnostic evaluation of the azotemic patient suspected to have renal arterial occlusive disease should include a history and physical examination, urinalysis, renal ultrasound, and duplex scan of the renal arteries. In appropriate patients, arteriography should then be considered if other diagnoses appear unlikely. This algorithm may help identify those patients who might benefit from renal revascularization. It appears that oliguria rather than anuria and the angiographic demonstration of a patent distal vessel and nephrogram suggest a better functional outcome after revascularization. Unfortunately, the response to surgery cannot be reliably predicted and patient selection remains a challenge, but retrieval of renal function can be achieved in some cases even if patients are already being hemodialyzed.

[Indications and contraindications for surgery in coronary insufficiency]. / Indicazioni e controindicationi alla chirurgia dell'insufficienza coronarica

The indications to aortocoronary by-pass technique have during the last two years developed thanks to surgical, emodinamic and clinical exsperiences. The mortality of patients in whom surgery is limited electively to the intervention of aorto-coronary by-pass is at present around 4%. The principal indications to surgery are: a) existence of more than one coronary artery disease; b) a good diameter of the by-passing artery (more than 1 mm) corresponding to the site of the by-pass graft; c) a left ventricular telediastolic pressure lower than 20 mm of Hg; d) left ventricular function with ejection fraction not lesser than 0,40; e) absence of any associated severe and irreversible damages. The comparative data obtained recently from coronary patients medically and surgically treated would show at 4 years a survival rate higher than in those who underwent aorto-coronary by-pass.

Medullary thyroid cancer and pseudocirrhosis: case report and literature review.

Pseudocirrhosis is a rare form of liver disease that can cause clinical symptoms and radiographic signs of cirrhosis; however, its histologic features suggest a distinct pathologic process. In the setting of cancer, hepatic metastases and systemic chemotherapy are suspected causes of pseudocirrhosis. Here, we present a patient with medullary thyroid carcinoma metastatic to the liver who developed pseudocirrhosis while on maintenance sunitinib after receiving 5-fluorouracil, leucovorin, and oxaliplatin (folfox) in combination with sunitinib. Cirrhotic change in liver morphology was accompanied by diffusely infiltrative carcinomatous disease resembling the primary tumor. We discuss the diagnosis of pseudocirrhosis in this case and review the literature regarding pseudocirrhosis in cancer.