Prognostic impact of translocation t(11;14) and of other cytogenetic abnormalities in patients with AL amyloidosis in the era of contemporary therapies.

OBJECTIVES: Translocation t(11;14) is the most common cytogenetic abnormality in patients with systemic AL amyloidosis with prognostic and therapeutic relevance, which has not been clearly defined in the most recent therapeutic era. METHODS: We assessed its prognostic role in 146 newly-diagnosed patients who received novel agent-based treatment combinations. Event-free survival (EFS), a composite endpoint defined by hematological progression, start of a new treatment-line or death, and overall survival (OS) were the primary endpoints. RESULTS: Half of the patients had at least one FISH abnormality; 40% had t(11;14) which was inversely associated with other cytogenetic abnormalities. At 1, 3, and 6-month landmarks, hematologic response rates were numerically but not statistically higher in the non-t(11;14) group. Patients with t(11;14) were more frequently switched to second-line treatment within 12 months (p = .015). At median follow-up of 31.4 months, t(11;14) was associated with shorter EFS [17.1 (95% CI 3.2-10.6) vs. 27.2 months (95% CI 13.8-40.6), p = .021] and retained its prognostic significance in the multivariate model (HR:1.66, p = .029). The effect on OS was neutral, possibly due to the use of effective salvage therapies. CONCLUSIONS: Our data support the use of targeted therapies for patients with t(11;14) to avoid delays in the achievement of deep hematologic responses.

Pinnae and facial hypertrichosis induced by cetuximab.

INTRODUCTION: Anti-EGFR targeted anti-cancer treatment is associated with various skin adverse events. Cetuximab is often associated with acneiform papules and skin disorders. Hypertrichosis cited in face pinnae and eyelash trichomegaly are seldom described. CASE REPORT: A 72-year-old female cancer patient presented deteriorating facial-pinnae hypertrichosis and eyelash prolongation post cetuximab infusion. MANAGEMENT AND OUTCOME: Consecutive cetuximab administration led to exaggerating hairy skin side effects, fully alleviated when the drug was discontinued. DISCUSSION: To the best of our knowledge, this is the first reported case of an anti-EGFR-associated diffuse pinnae hypertrichosis presentation in a female patient in literature. This distinct entity can be easily diagnosed and manipulated with early drug withdrawal. An extensive review of relevant basic molecular research is provided to increase physicians' awareness.

Lichenoid drug eruption associated with imatinib mesylate therapy.

INTRODUCTION: Imatinib Mesylate (IM), a tyrosine kinase inhibitor, has been reported to cause several adverse reactions, most of them with cutaneous involvement. Non- Lichenoid IM associated skin reactions have been sufficiently- recorded. To our knowledge, Lichenoid Drug Eruption (LDE) is recorded in a minority of registries. CASE REPORT: To describe an LDE induced case by IM treatment. TREATMENT AND OUTCOME: Histological Confirmation and promptly dermatological consultation relieved successfully the cutaneous adverse event. DISCUSSION: Ongoing expansion of IM usage in a wide spectrum of new indications is more likely to make physicians experience such LDE cutaneous side effects more often. Hence, they should be highly suspicious to early detect these distinct histologic entities, handle these undesired complications and guarantee satisfactory immediate outcomes, avoiding frivolous IM dosage modifications.

Daratumumab-based therapy for patients with monoclonal gammopathy of renal significance.

Treatment of the plasma cell clone in monoclonal gammopathy of renal significance (MGRS) is necessary in order to reduce toxic immunoglobulin load to the kidneys and salvage renal function. There are limited data on the use of daratumumab in patients with MGRS. We summarize our experience with the use of daratumumab-based therapy in 25 MGRS patients, 12 of whom were previously untreated. The median follow-up of the cohort is 14 months. The best overall haematologic response in evaluable patients was complete response (CR) in five (22%), very good partial response (VGPR) in five (22%) and partial response (PR) in seven (30%) patients for an overall response rate of 74%. Two of five patients in CR and two patients with initially detectable clones, but non-measurable immunoglobulins, had undetectable minimal residual disease (MRD) with next-generation flow cytometry (NGF) after therapy. Haematologic response rate for previously untreated patients was 83% vs. 69% for previously treated and for daratumumab combinations it was 91% vs. 64%, and with CR/VGPR 82% vs. 29%, compared to daratumumab monotherapy. At six months, 12/22 (55%) patients not on dialysis achieved a reduction of proteinuria >30%, of at least 0·5 g/24 h, without an estimated glomerular filtration rate (eGFR) reduction. The toxicity was mild and predictable. In conclusion, daratumumab-based therapy is a new option for patients with MGRS.

Predictive tissue markers in testicular germ cell tumors: Immunohistochemical expression of MLH1 and REV-7 proteins.

PURPOSE: Testicular Germ Cell Tumors (TGCTs) are the most frequent solid malignancies in young adult men. Regardless of differences in their cell of origin, all TGCTs are considered highly curable malignancies. However, approximately 3-5% of all TGCTs do not respond to platinum-based chemotherapies. The purpose of our paper is to investigate whether immunohistochemical expression of MLH1 and REV-7 can be used as predictive tissue markers for TGCTs. MATERIAL AND METHODS: The main demographic and clinicopathological characteristics of 64 male patients with TGCTs who underwent orchiectomy from 2007 to 2022 were retrospectively obtained from two large Oncology Clinics in Greece. Both patients with chemosensitive and chemoresistant disease were included. Immunohistochemical staining for MLH1 and REV-7 proteins was applied in specimens of these patients. RESULTS: 31 seminomas and 33 non-seminomas were included. 48 patients had chemosensitive disease, while 16 had chemoresistant disease. 53 specimens showed preserved MLH1 expression, while 11 specimens had lost MLH1 expression. Expression of MLH1 was only significantly associated with patients' age. 16 specimens showed positive REV-7 expression, while 48 specimens were REV-7 negative. Interestingly, 50% of patients with chemoresistant disease and 16,7% of patients with chemosensitive disease were REV-7 positive. This difference was statistically significant. Moreover, REV-7 positivity was significantly associated with chemoresistance, various clinicopathological parameters and patients' prognosis and survival. CONCLUSION: Loss of MLH1 expression was only found to be significantly associated with lower patients' age. Positive immunohistochemical REV-7 expression was significantly associated with various clinicopathological parameters, while it was also associated with significantly lower survival and greater hazard. REV-7 positive percentages were significantly higher in patients with chemoresistant disease. Our findings imply that immunohistochemical staining for REV-7 could potentially be used as a predictive tissue marker for TGCT tumors. Moreover, targeting of REV-7 protein, could represent a potential therapeutic strategy for chemoresistant TGCT cases. The implementation of well-designed studies on a larger scale is of utmost importance, in order to draw safer conclusions. Additional studies are needed so as to draw safer conclusions.

The Immunohistochemical Expression of REV-7 in Various Human Cancer Pathology Specimens: A Systematic Review.

The purpose of this systematic review is to summarize all existing evidence, regarding the immunohistochemical expression of REV-7 in different human cancer pathology specimens. Moreover, the association of REV-7 expression with disease severity (clinical course), patients' survival, prognosis, and response to various treatments, such as chemotherapy and irradiation, was investigated. Three databases (PubMed, Scopus, and Cochrane) were systematically screened, from inception to September 2, 2023, as suggested by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Only studies using immunohistochemical staining for REV-7 in paraffin-embedded cancer tissues were included. Nine studies met the inclusion criteria and were included in the final qualitative synthesis. All nine studies were retrospective and non-comparative ones. Selected studies reported immunohistochemical expression of REV-7 in different types of cancer, including testicular cancer, ovarian cancer, esophagus squamous cell carcinoma, prostate cancer, colorectal cancer, diffuse large B-cell lymphoma, breast cancer, lung cancer, and skin cancer. High REV-7 expression was associated with faster disease progression, resistance to available treatment options, and worse prognosis in the majority of included studies. These results indicate that immunohistochemical staining of REV-7 protein could potentially be used as a predictive tissue marker in certain cases. Promising results, arising from REV-7 inactivation experiments, render REV-7 targeting a potential therapeutic strategy for future cancer management, especially in the cases of chemoresistant or radioresistant disease.

Next generation flow cytometry for MRD detection in patients with AL amyloidosis.

The treatment of AL amyloidosis aims to eradicate the plasma cell clone and eliminate toxic free light chain production. Only in a minority of patients the plasma cell clone is completely eradicated; residual light chain production may still exist while clonal relapse may occur. We used sensitive next-generation flow cytometry (NGF) to detect minimal residual disease (MRD) in AL amyloidosis patients at complete haematologic response. MRD evaluation was feasible in 51 of 52 (98%) tested patients and at a median sensitivity of 2.3 × 10-6 MRD was undetectable in 23 (45%). An organ response occurred in 86% of MRDneg vs 77% in MRDpos; renal response in 15/17(88%) of MRDneg vs in 14/16(87.5%) of MRDpos and cardiac response in 10/10(100%) of MRDneg vs 11/15(73%) of MRDpos patients. After a median follow-up of 24 months post MRD testing, no MRDneg patient had a haematologic relapse vs 6/28(21%) MRDpos (p = .029). Pooling haematologic and organ progressions, 9 (32%) MRDpos patients had disease progression vs only 1 (4%) MRDneg patient (p = .026). In conclusion, MRD detection using NGF has profound clinical implications, so that AL patients with undetectable MRD have a very high probability of organ response and a very low probability of haematologic relapse.

Consolidation with a short course of daratumumab in patients with AL amyloidosis or light chain deposition disease.

Daratumumab has major and rapid activity in AL amyloidosis with favourable toxicity. We used as a consolidation a short course of daratumumab in 25 patients with AL amyloidosis or light chain deposition disease (LCDD), who had not achieved a haematologic complete response (hemCR) after standard therapy with bortezomib, cyclophosphamide and dexamethasone (VCD). We evaluated minimal residual disease (MRD) and changes in the bone marrow (BM) microenvironment before and after consolidation using next generation flow cytometry (NGF). At the time of consolidation, 21 patients were in very good partial response (VGPR) and four in partial response (PR); all had detectable MRD. One month after consolidation completion, 8 patients (32%) achieved a hemCR, of whom 5 (20%) became also MRD negative. In the BM, we observed significant changes in B-cell precursors, naïve B-cells, T-cells, CD27+ NK & NKT cells, mast cells and erythroblasts. After a median follow-up of 25 months, none of the patients in hemCR has relapsed and all have achieved an organ response; a haematologic relapse occurred in 6/17 patients that did not achieve hemCR. In conclusion, consolidation with a short course of daratumumab can improve depth of response in patients with AL amyloidosis or LCDD and significantly affects BM environment.

Timing and impact of a deep response in the outcome of patients with systemic light chain (AL) amyloidosis.

A rapid and deep haematologic response is fundamental in order to improve outcomes of patients with AL amyloidosis. We evaluated the impact of timing and depth of haematologic response at early time points (at 1 and 3 months from the start of therapy) in 227 consecutive previously untreated AL patients, who received bortezomib-based primary therapy. After 1 month of therapy, 30.5% had ≥VGPR, 28% PR and 36% no response (NR), with 11% having iFLC <20 mg/L and 15% dFLC <10 mg/L. Deep haematologic response at 1 month (either ≥VGPR or iFLC <20 mg/L or dFLC <10 mg/L), was associated with a high organ response rate. The survival of patients with ≥VGPR was significantly better than those with PR and NR at 1-month landmark (p < .001) but this benefit was mainly driven by those with iFLC <20 mg/L. The depth of haematologic response at 1 month was significant across all Mayo stages. At 3 months, 46% of the patients had not significantly improved the depth of their response but even patients that improved their response from an iFLC ≥20 mg/L at 1 month to iFLC <20 mg/L at 3 months still had inferior outcome to those with an early deep response. Thus, in patients with AL amyloidosis, a very rapid and deep response is crucial, especially for those at high risk, targeting very low FLC levels within the first month of therapy.

Carfilzomib-associated renal toxicity is common and unpredictable: a comprehensive analysis of 114 multiple myeloma patients.

Carfilzomib (CFZ) is a non-reversible proteasome inhibitor approved for the treatment of patients with relapsed and refractory myeloma (RRMM). Its use has been associated with cardiovascular toxicity but although recently a signal of clinically significant renal complications has also been identified, it is less extensively investigated. We analyzed data of 114 consecutive patients with RRMM who received CFZ-based regimens. Renal complications not related to MM progression were observed in 19 (17%) patients; thrombotic microangiopathy (TMA) was seen in 6 (5%) patients, albuminuria >1 gr/day in 7 patients (6%) and at least grade 3 acute kidney injury (AKI) which could not be otherwise explained in 6 patients (5%). A total of 15 patients discontinued CFZ and dosing was reinitiated at a lower level in one patient with AKI. Albuminuria was associated with focal segmental glomerulosclerosis in the renal biopsy (performed in a total of 6 patients). Renal complications during CFZ therapy are common, occur mostly early and are unpredictable. A potential effect of CFZ on the renal endothelium could be implicated in the pathogenesis of these complications and may also share common pathophysiology with cardiovascular effects of CFZ.

Dapagliflozin as a cause of acute tubular necrosis with heavy consequences: a case report.

A 50-year-old man with type II diabetes, hypertension and dyslipidemia, presented with non-oliguric acute kidney injury (AKI) and anemia. Renal biopsy showed acute tubular necrosis (ATN) with extensive cytoplasmic vacuolization and areas of tubulitis. These findings were ultimately attributed to dapagliflozin, which he started 3 months earlier due to poor glycemic control. ATN with similar microscopic findings has been described with larger doses of dapagliflozin in non-clinical trials. Our patient was started on dialysis and remained dialysis-dependent for 4 weeks while his renal function improved gradually thereafter. Sixteen months after initial presentation he is being followed as an outpatient with chronic kidney disease (CKD) stage 3a. Dapagliflozin belongs to a novel class of antidiabetic drugs for which clinical trials show great beneficial effects on cardiovascular outcomes and glycemic control and as with many new drugs, their safety profile is being constantly revised. We report the first biopsy-proven ATN caused by dapagliflozin. Great caution together with continuous monitoring of renal function is advised when implementing SGLT-2 inhibitors in clinical practice.