Neoadjuvant durvalumab improves survival in early triple-negative breast cancer independent of pathological complete response.

BACKGROUND: Addition of immune checkpoint inhibitors to neoadjuvant chemotherapy (NACT) is a promising strategy in early breast cancer, but the optimal duration of therapy is currently unknown. In the GeparNuevo (NCT02685059) trial, addition of durvalumab to NACT as previously reported led to a moderate increase in pathological complete response (pCR) rate by an absolute 9% (P = 0.287). PATIENTS AND METHODS: Patients with cT1b-cT4a-d triple-negative breast cancer (TNBC) received durvalumab 1.5 g or placebo every 4 weeks added to nab-paclitaxel 125 mg/m2 weekly for 12 weeks, followed by durvalumab/placebo every 4 weeks plus epirubicin/cyclophosphamide every 2 weeks followed by surgery. Durvalumab was not continued after surgery. The primary objective was pCR. Secondary endpoints included invasive disease-free survival (iDFS), distant disease-free survival (DDFS) and overall survival (OS). RESULTS: A total of 174 patients were randomised between June 2016 and October 2017. After a median follow-up of 43.7 months, 34 events had occurred. Despite a non-significant increase in the pCR rate, significant differences were observed for 3-year iDFS, DDFS and OS: iDFS was 85.6% with durvalumab versus 77.2% with placebo [hazard ratio (HR) 0.48, 95% confidence interval (CI) 0.24-0.97, stratified log-rank P = 0.036]; DDFS 91.7% versus 78.4% (HR 0.31, 95% CI 0.13-0.74, P = 0.005); OS 95.2% versus 83.5% (HR 0.24, 95% CI 0.08-0.72, P = 0.006). pCR patients had 3-year iDFS of 95.5% with durvalumab and 86.1% without (HR 0.22, 95% CI 0.05-1.06). In the non-pCR cohort 3-year iDFS was 76.3% versus 69.7% (HR 0.67, 95% CI 0.29-1.54). Multivariable analysis confirmed a durvalumab effect independent of the pCR effect. No new safety signals occurred. CONCLUSIONS: Durvalumab added to NACT in TNBC significantly improved survival despite a modest pCR increase and no adjuvant component of durvalumab. Additional studies are needed to clarify the optimal duration and sequence of checkpoint inhibitors in the treatment of early TNBC.

A randomised phase II study investigating durvalumab in addition to an anthracycline taxane-based neoadjuvant therapy in early triple-negative breast cancer: clinical results and biomarker analysis of GeparNuevo study.

BACKGROUND: Combining immune-checkpoint inhibitors with chemotherapy yielded an increased response rates in patients with metastatic triple-negative breast cancer (TNBC). Therefore, we evaluated the addition of durvalumab to standard neoadjuvant chemotherapy (NACT) in primary TNBC. PATIENTS AND METHODS: GeparNuevo is a randomised phase II double-blind placebo-controlled study randomising patients with TNBC to durvalumab or placebo given every 4 weeks in addition to nab-paclitaxel followed by standard EC. In the window-phase durvalumab/placebo alone was given 2 weeks before start of nab-paclitaxel. Randomisation was stratified by stromal tumour-infiltrating lymphocyte (sTILs). Patients with primary cT1b-cT4a-d disease, centrally confirmed TNBC and sTILs were included. Primary objective was pathological complete response (pCR) (ypT0 ypN0). RESULTS: A total of 174 patients were randomised, 117 participated in the window-phase. Median age was 49.5 years (range 23-76); 47 patients (27%) were younger than 40 years; 113 (65%) had stage ≥IIA disease, 25 (14%) high sTILs, 138 of 158 (87%) were PD-L1-positive. pCR rate with durvalumab was 53.4% (95% CI 42.5% to 61.4%) versus placebo 44.2% (95% CI 33.5% to 55.3%; unadjusted continuity corrected χ2P = 0.287), corresponding to OR = 1.45 (95% CI 0.80-2.63, unadjusted Wald P = 0.224). Durvalumab effect was seen only in the window cohort (pCR 61.0% versus 41.4%, OR = 2.22, 95% CI 1.06-4.64, P = 0.035; interaction P = 0.048). In both arms, significantly increased pCR (P < 0.01) were observed with higher sTILs. There was a trend for increased pCR rates in PD-L1-positive tumours, which was significant for PD-L1-tumour cell in durvalumab (P = 0.045) and for PD-L1-immune cell in placebo arm (P = 0.040). The most common immune-related adverse events were thyroid dysfunction any grade in 47%. CONCLUSIONS: Our results suggest that the addition of durvalumab to anthracycline-/taxane-based NACT increases pCR rate particularly in patients treated with durvalumab alone before start of chemotherapy. TRIAL REGISTRATION: ClinicalTrials.gov number: NCT02685059.

Evaluation of psychosocial distress in patients treated in a community-based oncology group practice in Germany.

BACKGROUND: Systematic evaluation of psychosocial distress in oncology outpatients is an important issue. We assessed feasibility and benefit of standardized routine screening using the Distress Thermometer (DT) and Problem List (PL) in all patients of our community-based hematooncology group practice. PATIENTS AND METHODS: One thousand four hundred forty-six patients were screened between July 2008 and September 2008. Five hundred randomly selected patients were sent a feedback form. RESULTS: The average distress level was 4.7, with 37% indicating a distress level >5. Patients with nonmalignant diseases (81% autoimmune diseases or hereditary hemochromatosis) showed the highest distress level of 5.2. Most distressed were patients who just learned about relapse or metastases (6.4), patients receiving best supportive care (5.4) and patients receiving adjuvant antihormonal therapy (5.4). Ninety-seven percent of patients appreciated to speak to their doctor about their distress. Fifty-six percent felt better than usual after this consultation. CONCLUSION: DT and PL are feasible instruments to measure distress in hematooncology outpatients receiving routine care. DT and PL are able to improve doctor-patient communication and thus should be implemented in routine patient care. The study shows that distress is distributed differently between individuals, disease groups and treatment phases.

The impact of new treatment options for advanced colorectal cancer on routine care: results of a retrospective analysis of 206 consecutive patients treated in a community-based oncology group practice in Germany.

Due to necessary selection criteria, the results obtained in clinical trials may not reflect the actual impact of current treatment options for unselected general populations. We analysed the treatment modalities and the outcome in 206 consecutive patients with advanced colorectal cancer who started treatment between 1/1999 and 11/2004. The median age of this cohort was 66 years (range 30-87) and 39 patients (19%) were ≥ 75 years old. First-line treatment consisted of low-dose bolus 5-fluorouracil and folinic acid regimens in 68 patients (33%), weekly 24-h 5-fluorouracil infusion and folinic acid in 36 patients (17%), weekly 24-h 5-fluorouracil infusion plus oxaliplatin or irinotecan in 60 patients (29%), capecitabine regimens in 22 patients (11%), monotherapy with oxaliplatin or irinotecan in six patients (3%) and other regimens in 14 patients (7%). A total of 166 patients (81%) received a second-line treatment and third-line chemotherapy was given to 122/206 patients (59%). With a minimum follow-up of 18 months, the median survival of the cohort is 21 months (range 1-85) and 17 months (range 3-57) for patients ≥ 75 years. We conclude that the increased survival seen in prospective studies can be transferred to routine care for unselected patients with advanced colorectal cancer.

Follow-up Reality for Breast Cancer Patients - Standardised Survey of Patients and Physicians and Analysis of Treatment Data.

Introduction: Currently, about 360 000 breast cancer patients who could, after completion of their primary therapy, take advantage of follow-up options are living in Germany. Up to now very little is known about the extent to which the available options are used and as to how the follow-up reality is experienced and evaluated. Thus, an explorative examination among the patients and their physicians was undertaken. Patients and Methods: All patients who underwent surgery in a certified breast centre between 2007 and 2013 received a standardised questionnaire; at the same time the physicians responsible for the follow-up were invited to answer a standardised questionnaire. Results: 920 patients (response rate: 61 %) with a median age of 65 years (32-95) could be analysed. 99 % of the participants stated that they regularly attended follow-ups. The personal contact with the physician (mean value: 4.4) and the reassurance that the cancer disease had not recurred (mean value: 4.5) were described on a scale of 0 to 5 to be two of the most important factors of the follow-up. Deficits were expressed with regard to psychosocial care (70 %) and the perception and treatment of physical complaints (55 %). In addition, 105 physicians returned completed questionnaires (response rate: 12 %). For asymptomatic patients the physicians performed the following examinations most frequently: anamnesis (92 %), physical examination (87 %) as well as laboratory tests (63 %) and tumour marker determinations (40 %). Conclusion: On the whole it became clear that the vast majority of the patients took advantage of the follow-up options. From the patient's perspective the importance of the follow-up lies in contact to the physician and the comforting assurance that the breast cancer has not relapsed. Deficits are seen in the psychosocial care and the perception and treatment of physical impairments. Not recommended examinations were employed by a significant proportion of the surveyed physicians.

[Lymphomas: new therapeutic options]. / Lymphomverdacht. Wie gehen Sie vor, welche Chancen hat ihr Patient?

Malignant lymphomas are differentiated clinically, morphologically and molecular-biologically, into aggressive (formerly high-grade malignant) and indolent (formerly low-grade malignant) lymphomas. In the meantime, virtually all patients can be diagnosed and treated on an ambulatory basis. The introduction of the monoclonal antibody rituximab (R) in combination with chemotherapeutic agents, has led to the development of highly potent forms of chemoimmunotherapy. In the case of aggressive lymphomas, R-CHOP has been shown to be significantly superior to CHOP alone, both in elderly and younger patients. In stage III and IV indolent (follicular) lymphomas, rituximab/chemotherapy combinations achieve response rates in excess of 90%, and prolonged progression-free survival rates which, for the first time hold out hope of a cure. Monoclonal antibodies that can be coupled to radioisotopes open up new possibilities for potent radioimmunotherapy which look promising for effecting a cure or long-lasting palliation in additional proportion of the patients.

[Immunoglobulin substitution in patients with indolent non-Hodgkin's lymphoma]. / Immunglobulin-Substitution bei Patienten mit indolenten Non-Hodgkin-Lymphomen.

BACKGROUND: Infections are major complications in chronic lymphoproliferative disorders, among them indolent non-Hodgkin's lymphoma (iNHL) including chronic lymphocytic leukemia, follicular lymphoma and multiple myeloma.We report on a retrospective cohort analysis of outpatients with indolent non-Hodgkin's lymphoma who were treated in an oncology / hematology group practice and received intravenous polyvalent immunoglobulin G (IVIG) as supportive care. The aim was to describe the treated iNHL population, the course of therapy and the effects of IVIG administrations on the levels of immunoglobulin G (IgG), the incidence of infections and the survival time. PATIENTS AND METHOD: 57 patients with secondary iNHL antibody deficiencies (n = 46) or IgG subclass deficiencies (n = 11) who received IVIG substitution were included. Patients received median 11 IVIG doses with a mean dose of 28 g over a period of median 9.5 months. RESULTS: Mean IgG levels increased with IVIG substitution at about twice and then remained within the normal range. The incidence of infections decreased in 46 % of treated patients. Effects on survival could not be observed. Median overall survival was in the group of substituted patients 124 months (range 7-124), the control group had a median survival time of 96 months (range 3-129) (p = 0.537). CONCLUSION: IgG levels should be reviewed during IVIG substitution on a regular basis and dosage and intervals should be adjusted individually.

Perforation of urinary bladder by intrauterine device.

Perforation of the uterus by an intrauterine device (IUD) is not an uncommon complication of this means of birth control. Comparatively, however, perforation of the bladder is uncommon, having been reported only seven times previously in the literature. This additional case is presented with review of the current literature and discussion of uterine and bladder perforation by an IUD.

Fatal transitional cell carcinoma of bladder in renal transplant recipient.

The risk of development of a malignancy as a consequence of long-term immunosuppression is well documented. Herein, we report the course of a renal allograft recipient in whom a fatal transitional cell carcinoma of the bladder developed eighteen years following transplantation.

Posterior urethral valves in siblings.

The etiology and incidence of posterior urethral valves is unknown. We report on a pair of non-twin siblings with identical pathology stemming from type I posterior urethral valves as well as discordance in a pair of monozygotic twins. Familial posterior urethral valves have been reported before in both twin and non-twin siblings. The occurrence of identical pathology in non-twin siblings suggests the possibility of an inherited trait as does its occurrence in identical twins. However, non-identical clinical manifestation is as common as is identical presentation in both groups. There are also instances of discordance in monozygotic twins suggesting the possibility of a random mutation. As such, we recommend urologic evaluation of the male siblings of affected patients with posterior urethral valves. Further prospective and retrospective analyses are needed to define the genetic etiology of valves.

Acute lobar nephronia of renal transplant allograft.

Acute lobar nephronia (acute focal bacterial nephritis) has recently been recognized as an infectious process of the kidney. It is a radiologic diagnosis characterized as a nonliquifiable inflammatory renal mass associated with signs and symptoms of bacterial pyelonephritis. We present the successful management of a renal allograft recipient who had radiologic evidence of acute lobar nephronia within the graft six weeks after placement of an internalized ureteral stent.

Secondary hyperparathyroidism. The role of surgery.

A retrospective analysis was undertaken to better define the clinical presentation and therapy of patients with secondary hyperparathyroidism and the timing of surgical removal of the parathyroid glands in secondary hyperparathyroidism. Sixty-eight patients with end-stage renal disease (ESRD) underwent 74 parathyroid procedures over a 10-year period. There were 38 per cent women and 62 per cent men in this population--the same proportion of men and women with ESRD. These proportions are reversed when compared with patients with primary hyperparathyroidism. The mean time between initiation of dialytic therapy and parathyroidectomy was 5.4 years. Preoperative mean serum calcium and phosphorus levels were 10.1 +/- 0.2 and 6.1 +/- 0.2 mg/dl, respectively. All patients were symptomatic and 60 per cent of the patients had at least two symptoms before surgery. Renal osteodystrophy was the most common symptom (74%), whereas pruritus was noted in 65 per cent of this population. Patients underwent either subtotal (88%) or total (12%) parathyroidectomy with autotransplantation. Six patients required reoperation: five for recurrent disease (2 to 5 years after the initial surgery) and one for persistent disease. All patients were symptomatically improved after the surgery. Complications included the following: transient hoarseness (7%), hypocalcemia requiring calcium, and/or vitamin D therapy (32%) for 6 months after surgery. This analysis demonstrates that although the initial therapy of secondary hyperparathyroidism is medical, surgical therapy should be instituted before multiple symptoms develop in the ESRD population.

Identification of a gene frequently mutated in prostate tumors.

Although prostate cancer is the second leading cause of cancer death for men in the United States, the genetics of tumor development are poorly understood. Several expressed sequence tagged genes (ESTs) that are expressed predominantly in the prostate have recently been identified, although their role in the development and maintenance of the prostate is unknown. Here, we demonstrate that the gene identified as UNIGENE cluster Hs. 104215, which codes for a message found predominantly in the prostate, may be important in tumor development. We name this gene PCan1 for Prostate Cancer gene 1. Northern blot experiments were performed using RNA isolated from tumor-derived cell lines and human prostate to determine the expression pattern of the gene. DNA sequencing was used to identify mutations that occurred in tumor tissue. By Northern blot analysis, this gene product was not detectable in LNCaP, DU 145, or PC-3 prostate cancer cell lines, although it was readily observed in RNA isolated from total prostate and from dissected central and peripheral regions of prostate. Sequence analysis of genomic DNA from LNCaP, DU 145, or PC-3 cells demonstrated a G/A polymorphism at position 193. Analysis of matched tumor-derived DNA and blood-derived DNA samples from 11 of 13 patients who had undergone a radical prostatectomy and who were homozygous for A in blood-derived DNA demonstrated mutation of position 193 in matched tumor samples resulting in G/A polymorphism. Sixteen additional patient samples were G/A polymorphic in both blood-derived DNA and tumor-derived DNA and two samples were GG in both blood-derived and tumor-derived DNA. Our results suggest that this gene may be a hot spot for mutation in prostate cancer, especially because our radiation hybrid mapping located this gene within a region identified in linkage mapping studies of affected families with prostate cancer. Loss of heterozygosity in prostate tumors has also been reported at the location of PCan1. Further studies to determine the functional role of this candidate tumor suppressor gene are warranted.

Hypospadias repair in elderly patients.

Although surgical repair of hypospadias has been performed for decades, some older men with this anomaly have never been treated or even referred. Age alone should not be a contraindication for surgery. Rather, the physician needs to consider the degree of urethral stricture and voiding impairment caused by the disorder and the extent those factors affect the patient's quality of life.

Augmentation of the bladder in preparation for renal transplantation.

Although loop urinary diversion has been used successfully with renal allograft recipients, the potential and real morbidity of these diversions has led us to avoid this type of reconstruction in favor of the reconstructed bladder (3). Many of our first patients had undergone reconstruction or undiversion prior to the establishment of renal insufficiency and had a variety of augmentations (two ileocecal and three sigmoid). One additional patient underwent ileal patch augmentation three years after transplantation. However, many patients are now being seen in preparation for renal transplantation who have urinary diversions or require reconstruction and have such poor renal reserve that renal replacement therapy is inevitable. It is this latter group of patients who have prompted us to define what is the most suitable form of reconstruction of the bladder when subsequent transplantation is planned. Many forms of reconstruction and undiversion are available and appear to be equally satisfactory in the management of patients with lower urinary tract dysfunction. However, patients who are to undergo renal transplantation subsequently should be given consideration regarding the technical feasibility of the transplant operation. Accordingly, we believe that simple augmentation of the sigmoid colon as described herein prevents dissection of either iliac fossa, which greatly facilitates implantation of the allograft. As there currently appears to be no superior segment of both the large and small intestine or configuration for augmentation, augmentation of the sigmoid colon is at least as effective as other modes of reconstruction and, therefore, should be strongly considered in this population of patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Renal cell carcinoma in a renal allograft successful treatment with 5 year follow-up.

Renal cell carcinoma (RCC) developing in a renal allograft either as a result of undetected presence within the donor organ or as a consequence of de novo development post transplantation is a rare event. The Cincinnati Transplant Tumor Registry has recorded 45 cases of RCC developing in a renal allograft. A case is presented of localized RCC developing in a renal allograft 10 years post transplant treated by partial nephrectomy with 5 years of disease-free follow-up.

Ventral preputial island flap technique for the repair of epispadias with or without exstrophy.

The preputial island flap technique introduced by Duckett for repair of severe hypospadias has met with much clinical popularity. We report the use of a modification of this technique for repair of epispadias in 3 boys with exstrophy of the bladder and in 1 with penile epispadias. The results have been excellent in 3 cases and good in 1. Minimum followup has been 18 months.

Modified cruciate incision for transabdominal radical nephrectomy.

Experience with multiple organ harvesting procedures as well as orthotopic liver transplantation has provided for excellent extensive upper abdominal surgical exposure. We report use of a modified cruciate incision for transabdominal radical nephrectomy.