Impact of low- or moderate-risk gonadotoxic chemotherapy prior to testicular tissue freezing on spermatogonia quantity in human (pre)pubertal testicular tissue.

STUDY QUESTION: What is the impact of low- or moderate-risk gonadotoxic chemotherapy received prior to testicular tissue freezing (TTF), and of the cancer itself, on spermatogonia quantity in testicular tissue from (pre)pubertal boys? SUMMARY ANSWER: Vincristine, when associated with alkylating agents, has an additional adverse effect on spermatogonia quantity, while carboplatin has no individual contribution to spermatogonia quantity, in testicular tissue of (pre)pubertal boys, when compared to patients who have received non-alkylating chemotherapy. WHAT IS KNOWN ALREADY: The improved survival rates after cancer treatment necessitate the inclusion of fertility preservation procedures as part of the comprehensive care for patients, taking into consideration their age. Sperm cryopreservation is an established procedure in post-pubertal males while the TTF proposed for (pre)pubertal boys remains experimental. Several studies exploring testicular tissue of (pre)pubertal boys after TTF have examined the tubular fertility index (TFI, percentage of seminiferous tubule cross-sections containing spermatogonia) and the number of spermatogonia per seminiferous tubule cross-section (S/T). All studies have demonstrated that TFI and S/T always decrease after the introduction of chemotherapeutic agents, especially those which carry high gonadotoxic risks such as alkylating agents. STUDY DESIGN, SIZE, DURATION: Testicular tissue samples from 79 (pre)pubertal boys diagnosed with cancer (from 6 months to 16 years of age) were cryopreserved between May 2009 and June 2014. Their medical diagnoses and previous chemotherapy exposures were recorded. We examined histological sections of (pre)pubertal testicular tissue to elucidate whether the chemotherapy or the primary diagnosis affects mainly TFI and S/T. PARTICIPANTS/MATERIALS, SETTING, METHODS: (Pre)pubertal boys with cancer diagnosis who had been offered TTF prior to conditioning treatment for hematopoietic stem cell transplantation were included in the study. All the patients had previously received chemotherapy with low- or moderate-risk for future fertility. We have selected patients for whom the information on the chemotherapy received was complete. The quantity of spermatogonia and quality of testicular tissue were assessed by both morphological and immunohistochemical analyses. MAIN RESULTS AND THE ROLE OF CHANCE: A significant reduction in the number of spermatogonia was observed in boys treated with alkylating agents. The mean S/T values in boys exposed to alkylating agents were significantly lower compared to boys exposed to non-alkylating agents (P = 0.018). In contrast, no difference was observed for patients treated with carboplatin as the sole administered alkylating agent compared to the group of patients exposed to non-alkylating agents. We observed an increase of S/T with age in the group of patients who did not receive any alkylating agent and a decrease of S/T with age when patients received alkylating agents included in the cyclophosphamide equivalent dose (CED) formula (r = 0.6166, P = 0.0434; r = -0.3759, P = 0.0036, respectively). The TFI and S/T decreased further in the group of patients who received vincristine in combination with alkylating agents (decrease of 22.4%, P = 0.0049 and P < 0.0001, respectively), but in this group the CED was also increased significantly (P < 0.0001). Multivariate analysis, after CED adjustment, showed the persistence of a decrease in TFI correlated with vincristine administration (P = 0.02). LIMITATIONS, REASONS FOR CAUTION: This is a descriptive study of testicular tissues obtained from (pre)pubertal boys who were at risk of infertility. The study population is quite heterogeneous, with a small number of patients in each sub-group. Our results are based on comparisons between patients receiving alkylating agents compared to patients receiving non-alkylating agents rather than chemotherapy-naive patients. The French national guidelines for fertility preservation in cancer patients recommend TTF before highly gonadotoxic treatment. Therefore, all the patients had received low- or moderate-risk gonadotoxic chemotherapy before TTF. Access to testicular tissue samples from chemotherapy-naive patients with comparable histological types of cancer was not possible. The functionality of spermatogonia and somatic cells could not be tested by transplantation or in vitro maturation due to limited sample sizes. WIDER IMPLICATIONS OF THE FINDINGS: This study summarizes the spermatogonial quantity of (pre)pubertal boys prior to TTF. We confirmed a negative correlation between the cumulative exposure to alkylating agents and spermatogonial quantity. In addition, the synergistic use of vincristine in combination with alkylating agents showed a cumulative deleterious effect on the TFI. For patients for whom fertility preservation is indicated, TTF should be proposed for chemotherapy with a predicted CED above 4000 mg/m2. However, the data obtained from vincristine and carboplatin use should be confirmed in a subsequent study including more patients. STUDY FUNDING/COMPETING INTEREST(S): This study had financial support from a French national research grant PHRC No. 2008/071/HP obtained by the French Institute of Cancer and the French Healthcare Organization. The sponsors played no role in the study. The authors declare no conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.

Clinical Utility of Genomic Tests Evaluating Homologous Recombination Repair Deficiency (HRD) for Treatment Decisions in Early and Metastatic Breast Cancer.

Breast cancer is the most frequently occurring cancer worldwide. With its increasing incidence, it is a major public health problem, with many therapeutic challenges such as precision medicine for personalized treatment. Thanks to next-generation sequencing (NGS), progress in biomedical technologies, and the use of bioinformatics, it is now possible to identify specific molecular alterations in tumor cells-such as homologous recombination deficiencies (HRD)-enabling us to consider using DNA-damaging agents such as platinum salts or PARP inhibitors. Different approaches currently exist to analyze impairment of the homologous recombination pathway, e.g., the search for specific mutations in homologous recombination repair (HRR) genes, such as BRCA1/2; the use of genomic scars or mutational signatures; or the development of functional tests. Nevertheless, the role and value of these different tests in breast cancer treatment decisions remains to be clarified. In this review, we summarize current knowledge on the clinical utility of genomic tests, evaluating HRR deficiency for treatment decisions in early and metastatic breast cancer.

The anti-IgE monoclonal antibody omalizumab as adjuvant treatment in desensitization to carboplatin in patients with ovarian cancer.

•Ovarian cancer is the most lethal among gynecological cancers.•Carboplatin-based chemotherapy identifies as the main systemic treatment for ovarian cancer patients.•Almost one every three patients treated with carboplatin experiences hypersensitivity reactions.•Patients may experience breakthrough reactions during drug desensitization.•Omalizumab represents a promising new treatment to overcome carboplatin hypersensitivity.

Neoadjuvant Chemotherapy of Triple-Negative Breast Cancer: Evaluation of Early Clinical Response, Pathological Complete Response Rates, and Addition of Platinum Salts Benefit Based on Real-World Evidence.

Pathological complete response (pCR) achievement is undoubtedly the essential goal of neoadjuvant therapy for breast cancer, directly affecting survival endpoints. This retrospective study of 237 triple-negative breast cancer (TNBC) patients with a median follow-up of 36 months evaluated the role of adding platinum salts into standard neoadjuvant chemotherapy (NACT). After the initial four standard NACT cycles, early clinical response (ECR) was assessed and used to identify tumors and patients generally sensitive to NACT. BRCA1/2 mutation, smaller unifocal tumors, and Ki-67 ≥ 65% were independent predictors of ECR. The total pCR rate was 41%, the achievement of pCR was strongly associated with ECR (OR = 15.1, p < 0.001). According to multivariable analysis, the significant benefit of platinum NACT was observed in early responders ≥45 years, Ki-67 ≥ 65% and persisted lymph node involvement regardless of BRCA1/2 status. Early responders with pCR had a longer time to death (HR = 0.28, p < 0.001) and relapse (HR = 0.26, p < 0.001). The pCR was achieved in only 7% of non-responders. However, platinum salts favored non-responders' survival outcomes without statistical significance. Toxicity was significantly often observed in patients with platinum NACT (p = 0.003) but not for grade 3/4 (p = 0.155). These results based on real-world evidence point to the usability of ECR in NACT management, especially focusing on the benefit of platinum salts.

Hypersensitivity to platinum salts according to BRCA status in ovarian cancer: A retrospective analysis of clinical outcomes and systematic review of literature.

BACKGROUND: Hypersensitivity reactions (HSRs) to platinum are an important issue in the treatment of patients (pts) with ovarian cancer (OC). Germline BRCA mutations have been proposed as a risk factor. We aimed at evaluating the incidence and severity of HSRs to platinum in OC pts. with known BRCA status. PATIENTS AND METHODS: We retrospectively analyzed 432 pts. from 5 Italian Centers. In addition, we performed a systematic review and meta-analysis of published series. RESULTS: Four hundred nine pts. received at least one prior platinum-based treatment line: 314 were BRCA wild type (77%) and 95 were BRCA mutated (23%). There was no statistical difference in exposure to platinum. Incidence of any grade HSRs was higher among BRCA mutated pts. [9% vs 18%, p = 0.019] and the time-to-HSRs curves show that the risk increases with the duration of platinum exposure, in BRCA mutated pts. more than in BRCA wild type. A multivariable analysis showed that harboring a germline BRCA mutation was related to a higher incidence of HSRs (HR: 1.84, 95% CI 1.00-3.99, p = 0.05) while having received pegylated liposomal doxorubicin (PLD) was related to a lower incidence of HSRs (HR: 0.03 95% CI 0.004-0.22, p = 0.001). The systematic review confirmed the higher incidence of HSRs in BRCA mutated pts., though heterogeneity among series was significant. CONCLUSIONS: In OC pts. with BRCA mutations, there is a significantly higher incidence of HSRs to carboplatin, not justified by longer drug exposure. On the other hand, PLD exerted a protective role in our series.

Neo-adjuvant therapy for triple-negative breast cancer: Insights from a network meta-analysis.

BACKGROUND: The best regimen of neo-adjuvant therapy for triple-negative breast cancer (TNBC) is unknown. Recent studies have shown promising data that adding carboplatin or pembrolizumab improves the rate of pathologic complete response (pCR) in TNBC. Therefore, we performed a network meta-analysis to define the overall, most effective, neo-adjuvant systemic therapy for TNBC. METHODS: We searched for studies comparing different neo-adjuvant regimens in patients with TNBC. We performed a network meta-analysis comparing the regimens using the random-effects model. We focused on anthracycline, bevacizumab, pembrolizumab, and platinum salts (Pl). All study regimens contained a taxane. We analyzed the rate of pCR (ypT0/is, N0), and the incidence of febrile neutropenia, grade 3-grade 4 thrombocytopenia, nausea/vomiting, and diarrhea. RESULTS: We identified a total of 13 randomized control trials for this analysis. We compared ten different classes of regimens. We found that regimens containing Pl were significantly superior to non-PI-containing regimens for the rate of pCR. Similarly, pembrolizumab-containing regimens were associated with significantly higher pCR rates. Regimens containing bevacizumab significantly increased the rate of pCR as well. However, it was equivocal as to whether the addition of Pl to pembrolizumab-containing regimen increases pCR rates. Adding anthracycline into the regimen did not show an improved rate of pCR. In the safety analysis, regimens containing Pl were associated with a significantly higher incidence of febrile neutropenia and grade 3-grade 4 thrombocytopenia. The regimen containing anthracycline plus bevacizumab plus Pl was associated with a higher risk of gastrointestinal adverse events. CONCLUSIONS: For TNBC, regimens containing bevacizumab, pembrolizumab, or Pl are most effective in terms of pCR rates, though it is unclear whether combining all these medications has the greatest efficacy. Additionally, the benefit of using anthracycline in the neo-adjuvant therapy regimen for TNBC is not apparent, which may warrant a further head-to-head comparison.

Allergy Evaluation of Hypersensitivity to Platinum Salts and Taxanes: A Six-Year Experience.

BACKGROUND: Hypersensitivity reactions (HSRs) to platinum salts (PS) and taxanes (TX) are a challenge to cancer management. Allergy evaluation based on skin tests (ST) and graded challenges can provide a diagnosis of an allergy to a suspected drug and indicate possible treatment with alternative same-class drugs. OBJECTIVE: This study aimed to estimate the negative predictive value of ST in the diagnosis of HSRs to TX and PS. METHODS: This multicenter study prospectively enrolled patients with a suspected HSR to PS and TX. ST were performed for chemotherapy, drugs of the same pharmacological class, and other agents (latex or cotreatments). For patients with negative ST, a graded challenge was performed by the cancer teams trained in allergy management. RESULTS: A total of 119 consecutive patients were included during a 6-year period. ST results were positive for 58% of the cohort: for TX in 7 patients and for PS in 62 patients. Other agents were responsible for 4.2% of cases. Skin cross-reactivity was 50% for TX and 30% for PS. A graded challenge was performed in 14 patients for TX and in 50 patients for PS. Negative predictive values (NPVs) for ST were 100% for TX and 92% for PS, with NPVs for individuals PS of 100% for cisplatin, 89% for oxaliplatin, and 87% for carboplatin. CONCLUSIONS: ST to PS or TX offered a high NPV, making allergy evaluation a key element in the management of patients with cancer. Graded challenges can be safely performed by oncology teams trained in anaphylaxis management.

Breast Cancer in BRCA1/2 Mutation Carriers - Do We Treat It Differently? Focus on Systemic Therapy for BRCA1/2 Associated Breast Cancer.

Hereditary breast cancer syndrome is associated with a higher risk of developing breast cancer and accounts for 5-10% of all breast tumors. Is it possible that mutations in BRCA1/2 genes (which are involved in DNA repair genes) should be treated differently from sporadic breast cancer? In addition to anthracyclines, taxanes are effective against tumors with a BRCA2 mutation. A TNT trial showed that platinum derivatives have marked effects against metastatic breast cancer. Data from neoadjuvant trials testing efficacy in triple negative cancer confirm that neoadjuvant chemotherapy is more effective against sporadic tumors, whereas the effect of carboplatin is not statistically significant, as opposed to sporadic cancer. A new group of therapeutics, particularly for tumors with mutations in BRCA1/2 genes, is PARP inhibitors. These treatments were effective not only against triple negative tumors but also against luminal tumors. The author declares she has no potential confllcts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 5. 6. 2019 Accepted: 12. 6. 2019.

APE1 and NPM1 protect cancer cells from platinum compounds cytotoxicity and their expression pattern has a prognostic value in TNBC.

BACKGROUND: Triple negative breast cancer (TNBC) is a breast cancer subgroup characterized by a lack of hormone receptors' expression and no HER2 overexpression. These molecular features both drastically reduce treatment options and confer poor prognosis. Platinum (Pt)-salts are being investigated as a new therapeutic strategy. The base excision repair (BER) pathway is important for resistance to Pt-based therapies. Overexpression of APE1, a pivotal enzyme of the BER pathway, as well as the expression of NPM1, a functional regulator of APE1, are associated with poor outcome and resistance to Pt-based therapies. METHODS: We evaluated the role of NPM1, APE1 and altered NPM1/APE1 interaction in the response to Pt-salts treatment in different cell lines: APE1 knockout (KO) cells, NPM1 KO cells, cell line models having an altered APE1/NPM1 interaction and HCC70 and HCC1937 TNBC cell lines, having different levels of APE1/NPM1. We evaluated the TNBC cells response to new chemotherapeutic small molecules targeting the endonuclease activity of APE1 or the APE1/NPM1 interaction, in combination with Pt-salts treatments. Expression levels' correlation between APE1 and NPM1 and their impact on prognosis was analyzed in a cohort of TNBC patients through immunohistochemistry. Bioinformatics analysis, using TCGA datasets, was performed to predict a molecular signature of cancers based on APE1 and NPM1 expression. RESULTS: APE1 and NPM1, and their interaction as well, protect from the cytotoxicity induced by Pt-salts treatment. HCC1937 cells, having higher levels of APE1/NPM1 proteins, are more resistant to Pt-salts treatment compared to the HCC70 cells. A sensitization effect by APE1 inhibitors to Pt-compounds was observed. The association of NPM1/APE1 with cancer gene signatures highlighted alterations concerning cell-cycle dependent proteins. CONCLUSIONS: APE1 and NPM1 protect cancer cells from Pt-compounds cytotoxicity, suggesting a possible improvement of the activity of Pt-based therapy for TNBC, using the NPM1 and APE1 proteins as secondary therapeutic targets. Based on positive or negative correlation with APE1 and NPM1 gene expression levels, we finally propose several TNBC gene signatures that should deserve further attention for their potential impact on TNBC precision medicine approaches.

Platinum salts in the treatment of BRCA-associated breast cancer: A true targeted chemotherapy?

Germline pathogenic mutations in breast cancer (BC) susceptibility genes (gBRCA1/2) are the most frequent inherited alterations in BC and are involved in the homologous recombination pathway, the principal mechanism of DNA double strand break repair. Platinum salts which act as DNA cross-linking agents are therefore more likely to be active in BRCA-deficient tumors. Women with gBRCA-associated tumors, particularly with triple negative BC, receiving neoadjuvant platinum containing regimens achieved higher pCR rates as compared to wild-type BC. However in two large randomized trials the addition of carboplatin significantly increased pCR rate only in wild-type tumors. On the contrary, the randomized TNT trial showed a significant benefit for carboplatin vs docetaxel in terms of response rate and PFS specifically in patients with advanced gBRCA -associated tumors. Biomarkers of sensitivity to DNA damaging agents beyond gBRCA mutations predicting activity of platinum salts have been proposed and should be validated prospectively.

Targeting homologous repair deficiency in breast and ovarian cancers: Biological pathways, preclinical and clinical data.

Mutation or epigenetic silencing of homologous recombination (HR) repair genes is characteristic of a growing proportion of triple-negative breast cancers (TNBCs) and high-grade serous ovarian carcinomas. Defects in HR lead to genome instability, allowing cells to acquire the multiple genetic alterations essential for cancer development. However, this deficiency can also be exploited by using DNA damaging agents or by targeting compensatory repair pathways. A noteworthy example is treatment of TNBC and epithelial ovarian cancer harboring BRCA1/2 germline mutations using platinum salts and/or PARP inhibitors. Dramatic responses to PARP inhibitors may support a wider use in the HR-deficient population beyond those with mutated germline BRCA1 and 2. In this review, we discuss HR deficiency hallmarks as predictive biomarkers for platinum salt and PARP inhibitor sensitivity for selecting patients affected by TNBC or epithelial ovarian cancer who could benefit from these therapeutic options.

Retrospective study of hypersensitivity reactions to chemotherapeutic agents in a thoracic oncology service.

WHAT IS KNOWN AND OBJECTIVE: With the increasing use of cancer chemotherapy agents, hypersensitivity reactions are commonly encountered. The allergic clinical symptoms are variable and unpredictable. The aim of this study was to identify the characteristics of hypersensitivity reactions and to assess the value of skin tests for platinum salts and pemetrexed in the treatment of patients with non-small cell lung cancers or malignant pleural mesothelioma. METHODS: A single-centre retrospective study was performed for 2 years. Patients treated with the drugs of interest for an advanced or metastatic non-small cell lung cancers or malignant pleural mesothelioma and who experienced hypersensitivity reactions symptoms were eligible for this study. Clinical symptoms of hypersensitivity reactions, population characteristics and administered chemotherapy regimens were identified. RESULTS: The hypersensitivity reactions frequency was rare (1.2%) and concerned 17 patients in our study. Typical clinical features of immediate hypersensitivity reactions associated with treatment were observed for nine patients (anaphylactic reactions for three cases, angioedema and hypotension associated with asthenia and heat in one case, respectively, and other cutaneous symptoms in the remaining four cases). Skin tests were positive in three patients, but only for platinum salts. The outcome after reintroduction of a negatively tested platinum salt allowed us to calculate a negative predictive value for platinum salt skin tests of 100%. For pemetrexed, skin tests were negative for all patients. WHAT IS NEW AND CONCLUSION: Skin tests could be used to diagnose hypersensitivity reactions with platinum salts or to evaluate the possibility of cross-reactions between two platinum salts. A negative skin test may predict with reasonable reliability the absence of future hypersensitivity reactions in case of reintroduction of drug infusion. Because the IgE-mediated mechanism has never been demonstrated for pemetrexed, skin tests are not valid and have no diagnostic value for this molecule. Because hypersensitivity reactions are potentially fatal adverse events, we recommend that patients who experience a hypersensitivity reactions onset should be monitored closely and clinicians must be aware of hypersensitivity reaction signs.

[Hypersensitivity to platinum salts and taxanes: The value of skin tests and tolerance induction procedures]. / Hypersensibilité aux sels de platine et aux taxanes : intérêt des tests cutanés et des inductions de tolérance.

AIM: The rate of hypersensitivity reactions to platinum salts (PS) and taxanes (TX) is on the increase. The aim of our study was to show the value of skin testing and efficacy of rapid drug desensitization. PATIENTS AND METHODS: This was a retrospective study conducted between January 2007 and February 2016 in patients consulting for immediate or delayed hypersensitivity to PS and TX. Skin prick tests (pT) and intradermal reaction tests (IDR) were performed according to the ENDA/EAACI recommendations. We used a 12-step desensitization protocol for rapid drug desensitization. RESULTS: Among the 99 patients included (30 men, 69 women, age 60.4) PS were suspected in 86 cases and taxanes in 13 cases. Skin tests were positive in 25 patients (7 pT, 18 IDR), 23 for platinum salts and 2 for taxanes. Rapid drug desensitization was proposed in 50 patients and performed in 33 (30 PS and 3 TX), proved effective in 29 patients, with protocol adaptation being necessary in 7 cases, and was ineffective in 4 patients. The skin tests for the latter 4 patients were positive. Seventy-five percent of patients with positive skin tests to oxaliplatin presented hypersensitivity reactions during desensitization, i.e. twice as many as patients having negative skin tests. Two percent of patient for PS and 7% for TX had cross reactivity. CONCLUSION: This French study confirms the efficacy of the 12-step protocol that allows patients to receive chemotherapy after hypersensitivity reaction. Skin test permits the detection of cross-reactions but their practice must be considered based on the patient's history.

Neoadjuvant Therapy for Patients with Triple Negative Breast Cancer (TNBC).

BACKGROUND: Patients with triple negative breast cancer (TNBC) are characterized by an unfavorable prognosis particularly when not responding well to anthracycline-taxane chemotherapy. This is due to a more aggressive biology in some cases but most importantly to a lack of agents other than conventional chemotherapy. Hence, there is an urgent need to optimize therapy of patients with TNBC in order to improve prognosis. OBJECTIVE: The objective of this review is to present the current understanding of TNBC biology and give an insight of current therapeutic concepts in the neoadjuvant treatment setting. METHOD: Current literature has been selected based on a literature search and current therapeutic concepts are explained and commented on. RESULTS: Novel therapeutic concepts for patients with TNBC focus on a) chemotherapy optimization through alternate scheduling, dosing or alternative/additional chemotherapeutic agents, b) evaluation of novel targeted agents and c) identification of clinically relevant patient subgroups through prognostic/ predictive biomarkers to enable a more personalized treatment approach. Potential novel therapeutic targets include inhibition of Poly-A-Ribose-Polymerase (PARP), checkpoint inhibition and antiandrogenic agents. CONCLUSION: Treatment of TNBC is currently been optimized both through optimization of chemotherapy and introduction of novel targeted agents which should enhance treatment response rates in the future.

Comparative toxicities of 3 platinum-containing chemotherapy regimens in relapsed/refractory lymphoma patients.

Optimal salvage chemotherapy regimen for patients with relapsed or refractory Hodgkin and non-Hodgkin lymphoma remains unclear but often based on platinum regimens. This retrospective study assesses in real life the toxicities profiles of patients with relapsed or refractory lymphoma treated with DHA (dexamethasone, high dose aracytine cytarabine) plus platinum salt (dexamethasone-High dose aracytine (cis)platin (DHAP), dexamethasone-High dose aracytine carboplatin (DHAC), or dexamethasone-High dose aracytine Oxaliplatin (DHAOX)), from February 2007 to May 2013 in 2 French hospitals. Toxicities were recorded from medical files and assessed according to the National Cancer Institute Common Toxicity Criteria version 3.0. Potential risk factors of renal insufficiency were tested by univariate analyses. A total of 276 patients were treated: 168 with DHAP (60.9%), 79 with DHAOX (28.6%), and 29 with DHAC (10.5%). Rituximab was associated in 80.1% of patients (n = 221). Renal failure was reported in 97 patients, mainly with cisplatin regimen (86.6%) leading to 8.9% grade III to IV renal failure (P = .001). Renal insufficiency was reversible in most patients but remained persistent in 24, with all of them being treated with DHAP except 1. Cisplatin-based regimen (50.0% versus 12.0%, P < .05) and female (44.6% versus 29.7%, P < .05) appeared to be at higher risks of renal failure. Platinum cumulative dose is a significant risk factor of nephrotoxicity. Hematologic toxicity was more frequent with carboplatin and cisplatin with at least 1 event (all toxicity grade) respectively in 79.3% and 71.4% of patients treated (P < .005). Auditory toxicity was mainly reported with cisplatin (n = 19; 4 grade I-II and 15 grade III-IV). Oxaliplatin was implicated in 77.6% of neurotoxicity (n = 59), mainly moderate (grade I-II). In conclusion, DHAOX and DHAC regimens have more favorable toxicity profile than DHAP regimen. Their lack of renal toxicity makes them attractive regimens, which may be interesting for patients eligible for autologous stem cell transplantation. Nevertheless, these results have to be confirmed by the therapeutic efficacy of these 3 regimens.

Medical surveillance and long-term prognosis of occupational allergy due to platinum salts.

PURPOSE: Medical surveillance of workers in precious metals refineries and catalyst production plants is well established in many countries as a measure to prevent occupational asthma due to platinum (Pt) salts. It was the aim of this study to evaluate the impact of medical surveillance and to define prognostic factors with an emphasis on exposure determinants. METHODS: As part of an observational longitudinal study, 96 workers from German precious metals refineries and catalyst production plants with Pt salt allergy underwent a second examination several years (median 67 months) after the initial diagnosis was made. RESULTS: When the second examination was conducted, 92 subjects (96 %) had already been transferred to jobs with very low or no exposure to Pt salts. The number of subjects with sensitization to Pt salt as assessed by skin prick test (SPTPt) decreased from 86 to 52 %, and there was a clear improvement for rhinitis, conjunctivitis and contact urticaria between both examinations. Although the number of subjects with asthma symptoms decreased significantly, at the second examination 74 subjects (77 %) continued to suffer from asthma and 51 subjects (53 %) received asthma medication. Airway obstruction or bronchial hyperresponsiveness persisted in 83 subjects (86 %). CONCLUSIONS: Secondary prevention in subjects with occupational exposure to Pt salts, as practiced for over 25 years in Germany could not avoid persistent asthma in the majority of cases, although improvements occurred. This study reveals the limitations of the concept that removal from exposure after the occurrence of respiratory symptoms may prevent chronic asthma. It is recommended that removal from exposure should be done immediately after the occurrence of a positive SPTPt, irrespective of symptoms.

Eosinophilic airway disease in a patient with a negative skin prick test, but a positive patch test with platinum salts--implications for medical surveillance.

We present the case of a 52-year-old woman with a topic dermatitis since adolescence who developed work-related hand eczema, cough and runny nose 12 years after she had started working as a laboratory technician at a precious metals refinery. While skin prick test with sodium hexachloroplatinate (SPTPt ) was negative, patch testing with ammonium tetrachloroplatinate was positive after 24, 48, 72, and 96 hr. Inhalation challenge with sodium hexachloroplatinate yielded cough, mild shortness of breath, and a maximal decrease of FEV1 of 8% from baseline 24 hr after the challenge. Significant increases of bronchial hyperresponsiveness, exhaled nitric monoxide and sputum eosinophils were documented after the challenge. We conclude that eosinophilic airway disease due to platinum salts may occur in SPTPt negative subjects. Both, patch testing and inhalation challenge with platinum salts should be considered in SPT negative subjects with occupational exposure to precious metal salts and work-related allergic symptoms.

New therapeutic perspectives in CCDC6 deficient lung cancer cells.

Non-small cell lung cancer (NSCLC) is the main cause of cancer-related death worldwide and new therapeutic strategies are urgently needed. In this study, we have characterized a panel of NSC lung cancer cell lines for the expression of coiled-coil-domain containing 6 (CCDC6), a tumor suppressor gene involved in apoptosis and DNA damage response. We show that low CCDC6 protein levels are associated with a weak response to DNA damage and a low number of Rad51 positive foci. Moreover, CCDC6 deficient lung cancer cells show defects in DNA repair via homologous recombination. In accordance with its role in the DNA damage response, CCDC6 attenuation confers resistance to cisplatinum, the current treatment of choice for NSCLC, but sensitizes the cells to olaparib, a small molecule inhibitor of the repair enzymes PARP1/2. Remarkably, the combination of the two drugs is more effective than each agent individually, as demonstrated by a combination index <1. Finally, CCDC6 is expressed at low levels in about 30% of the NSCL tumors we analyzed by TMA immunostaining. The weak CCDC6 protein staining is significatively correlated with the presence of lymph node metastasis (p ≤ 0.02) and negatively correlated to the disease free survival (p ≤ 0.01) and the overall survival (p ≤ 0.05). Collectively, the data indicate that CCDC6 levels provide valuable insight for OS. CCDC6 could represent a predictive biomarker of resistance to conventional single mode therapy and yield insight on tumor sensitivity to PARP inhibitors in NSCLC.