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The 3-year overall survival (OS) rate of patients with previously treated or untreated stage III or IV melanoma has by now reached 63% using ipilimumab and nivolumab therapy. However, immune-related adverse events (irAEs) of grade 3 or 4 occurred in 59% of patients leading to discontinuation of therapy in 24.5% of patients and one death. Therapy with checkpoint inhibitors could be safer and more effective in combination with hyperthermia and fever inducing therapies. We conducted a retrospective analysis to test the safety and efficacy of a new combination immune therapy in 131 unselected stage IV solid cancer patients with 23 different histological types of cancer who exhausted all conventional treatments. Treatment consisted of locoregional- and whole-body hyperthermia, individually dose adapted interleukin 2 (IL-2) combined with low-dose ipilimumab (0.3 mg/kg) plus nivolumab (0.5 mg/kg). The objective response rate (ORR) was 31.3%, progression-free survival (PFS) was 10 months, survival probabilities at 6 months was 86.7% (95% CI, 81.0–92.8%), at 9 months was 73.5% (95% CI, 66.2–81.7%), at 12 months was 66.5% (95% CI, 58.6–75.4%), while at 24 months survival was 36.6% (95% CI:28.2%; 47.3%). irAEs of World Health Organization (WHO) Toxicity Scale grade 1, 2, 3, and 4 were observed in 23.66%, 16.03%, 6.11%, and 2.29% of patients, respectively. Our results suggest that the irAEs profile of the combined treatment is safer than that of the established protocols without compromising efficacy. [ABSTRACT FROM AUTHOR]

Background:Biomarkers predictive of pathological complete response (pCR) to neoadjuvant chemotherapy (NACT) of breast cancer are urgently needed.Methods:Using a training/validation approach for detection of predictive biomarkers in HER2-negative breast cancer, pre-therapeutic core biopsies from four independent cohorts were investigated: Gene array data were analysed in fresh frozen samples of two cohorts (n=86 and n=55). Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was performed in formalin-fixed, paraffin-embedded (FFPE) samples from two neoadjuvant phase III trials (GeparTrio, n=212, and GeparQuattro, n=383).Results:A strong predictive capacity of thymosin beta 15 (TMSB15A) gene expression was evident in both fresh frozen cohorts (P<0.0001; P<0.0042). In the GeparTrio FFPE training cohort, a significant linear correlation between TMSB15A expression and pCR was apparent in triple-negative breast cancer (TNBC) (n=61, P=0.040). A cutoff point was then defined that divided TNBC into a low and a high expression group (pCR rate 16.0% vs 47.2%). Both linear correlation of TMSB15A mRNA levels (P=0.017) and the pre-defined cutoff point were validated in 134 TNBC from GeparQuattro (pCR rate 36.8% vs 17.0%, P=0.020). No significant predictive capacity was observed in luminal carcinomas from GeparTrio and GeparQuattro.Conclusion:In TNBC, TMSB15A gene expression analysis might help to select patients with a high chance for pCR after NACT. [ABSTRACT FROM AUTHOR]

Background: An earlier published series of neoadjuvant radiochemotherapy (NRT-CHX) in locally advanced noninflammatory breast cancer (LABC) has now been updated with a follow-up of more than 15 years. Long-term outcome data and predictive factors for pathologic complete response (pCR) were analyzed.Patients and Methods: During 1991-1998, 315 LABC patients (cT1-cT4/cN0-N1) were treated with NRT-CHX. Preoperative radiotherapy (RT) consisted of external beam radiation therapy (EBRT) of 50 Gy (5 × 2 Gy/week) to the breast and the supra-/infraclavicular lymph nodes combined with an electron boost in 214 cases afterwards or-in case of breast conservation-a 10-Gy interstitial boost with (192)Ir afterloading before EBRT. Chemotherapy was administered prior to RT in 192 patients, and concomitantly in 113; 10 patients received no chemotherapy. The update of all follow-up ended in November 2011. Age, tumor grade, nodal status, hormone receptor status, simultaneous vs. sequential CHX, and the time interval between end of RT and surgery were examined in multivariate terms with pCR and overall survival as end point.Results: The total pCR rate after neoadjuvant RT-CHX reached 29.2%, with LABC breast conservation becoming possible in 50.8% of cases. In initially node-positive cases (cN+), a complete nodal response (pN0) after NRT-CHX was observed in 56% (89/159). The multivariate analysis revealed that a longer time interval to surgery increased the probability for a pCR (HR 1.17 [95% CI 1.05-1.31], p < 0.01). However, in large tumors (T3-T4) a significantly reduced pCR rate (HR 0.89 [95% CI 0.80-0.99], p = 0.03) was obtained. Importantly, pCR was the strongest prognostic factor for long-term survival (HR 0.28 [95% CI 0.19-0.56], p < 0.001).Conclusion: pCR identifies patients with a significantly better prognosis for long-term survival. However, a long time interval to surgery (> 2 months) increases the probability of pCR after NRT-CHX. [ABSTRACT FROM AUTHOR]

Prognostic models that predict the clinical course of a breast cancer patient are important in oncology. We propose an approach to constructing such models based on fractional polynomials in which useful transformations of the continuous factors are determined. The idea may be applied with all types of regression model, including Cox regression, the method of choice for survival-time data. We analyse a prospective study of node-positive breast cancer. Seven standard prognostic factors -- age, menopausal status, tumour size, tumour grade, number of positive lymph nodes, progesterone and oestrogen receptor concentrations -- were investigated in 686 patients, of whom 299 had an event for recurrence-free survival and 171 died. We determine a final model with transformations of prognostic factors and compare it with the more traditional approaches using categorized variables or assuming a straight line relationship. We conclude that analysis using fractional polynomials can extract important prognostic information which the traditional approaches may miss. [ABSTRACT FROM AUTHOR]

Human renal cell carcinoma (HRCC) reportedly contains low levels of estrogen- and progestin-binding components of unproven receptor nature. Well-defined glucocorticoid receptors and low titers of androgen receptors are present in some HRCCs. From recent reports on endocrine therapy of advanced HRCC it may be concluded that only 5/305 (1.6%) patients show complete remission. The overall rate of partial remissions is less than 7%. Hormone/antihormone-induced disease stabilization of short duration is not uncommon. Patients with M HRCC seem to experience no benefit from adjuvant endocrine therapy. No clearly proven correlation between the presence of cytoplasmic binding components for estrogens and progestins and response to endocrine therapy has been published. Responses to endocrine therapy may be due to the receptor nonmediated direct effects of high-dose hormone and antihormone therapy. Pain relief induced by high-dose MPA has been shown to be independent of the endocrine responsiveness of the tumors. No correlation between receptor status and relapse rate in nephrectomized M HRCC patients has been observed. [ABSTRACT FROM AUTHOR]

As with normal human liver, both focal nodular hyperplasia (FNH) of the liver and a hepatocellular carcinoma were found to contain low levels of high affinity estrogen-binding components. In low-salt sucrose gradients the estrogen binders sedimented at 4S and 8S. Specificity studies indicated a requirement for estrogenic hormones. Progestin-binding studies using labeled and unlabeled ORG 2058 revealed high levels of specific binding in FNH and normal liver cytosol, whereas only insignificant amounts of ORG 2058 binding was found in the hepatocellular carcinoma. As judged by the high apparent dissociation constant (4-14×10 mol/l) of the ORG 2058 - binder complex, the apparent lack of 8S binding in low-salt sucrose gradients and the atypical ligand specificity, the progestin receptor nature of these binding entities is unlikely. In contrast, normal liver, FNH, and the hepatocellular carcinoma were found to contain significant quantities of glucocorticoid receptors. [ABSTRACT FROM AUTHOR]

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Cytosolic oestrogen receptors were measured in bovine and rat vas deferens of immature and mature animals. The bindings in the mature animals of both species were similar and specific. Furthermore, our physicochemical studies suggest characteristics identical to those obtained for oestrogen receptors in other target tissues. Our receptor measurements on the calf and the immature rat reveal significantly lower binding capacities than those obtaoned in the mature animals. [ABSTRACT FROM AUTHOR]