Increased risks of solid tumors after older radiotherapy strategies for testicular cancer (TC) are well established. Few population-based studies, however, focus on solid cancer risk among survivors ...of TC managed with nonradiotherapy approaches. We quantified the site-specific risk of solid cancers among testicular nonseminoma patients treated in the modern era of cisplatin-based chemotherapy, without radiotherapy.
Standardized incidence ratios (SIRs) for solid tumors were calculated for 12,691 patients with testicular nonseminoma reported to the population-based Surveillance, Epidemiology, and End Results program (1980 to 2008) and treated initially with either chemotherapy (n = 6,013) or surgery (n = 6,678) without radiotherapy. Patients accrued 116,073 person-years of follow-up.
Two hundred ten second solid cancers were observed. No increased risk followed surgery alone (SIR, 0.93; 95% CI, 0.76 to 1.14; n = 99 solid cancers), whereas significantly increased 40% excesses (SIR, 1.43; 95% CI, 1.18 to 1.73; n = 111 solid cancers) occurred after chemotherapy. Increased risks of solid cancers after chemotherapy were observed in most follow-up periods (median latency, 12.5 years), including more than 20 years after treatment (SIR, 1.54; 95% CI, 0.96 to 2.33); significantly increased three- to seven-fold risks occurred for cancers of the kidney (SIR, 3.37; 95% CI, 1.79 to 5.77), thyroid (SIR, 4.40; 95% CI, 2.19 to 7.88), and soft tissue (SIR, 7.49; 95% CI, 3.59 to 13.78).
To our knowledge, this is the first large population-based series reporting significantly increased risks of solid cancers among patients with testicular nonseminoma treated in the modern era of cisplatin-based chemotherapy. Subsequent analytic studies should focus on the evaluation of dose-response relationships, types of solid cancers, latency patterns, and interactions with other possible factors, including genetic susceptibility.
Abstract Background The majority of testicular cancer (TC) patients are cured and expected to live for decades after treatment, such that knowledge about hypogonadism and fertility issues is ...particularly important for the group of testicular cancer survivors (TCSs). Hypogonadism and fertility issues are related to treatment intensity. Methods In order to give an overview about hypogonadism in testicular cancer survivors (TCSs) the literature was reviewed. Testicular dysfunction was defined as inadequate spermatogenesis, as reflected by increased levels of Follicle Stimulating Hormone (FSH) and reduced fertility and/with or without insufficient testosterone (T) production with or without compensatory increased Luteinizing Hormone (LH) levels. Findings Hypogonadism may lead to reduced sexual functioning and well-being, fertility problems, muscle weakness, loss of energy, and depression. Furthermore, hypogonadism also increases the risk of osteoporosis and is associated with the metabolic syndrome and cardiovascular disease (CVD). The hypothesized "Testicular Dysgenesis Syndrome" comprising low sperm counts, hypospadias, cryptorchidism, and finally TC, probably contributes to hypogonadism independent of applied TC treatment. Recently, an increased risk of accelerated hormonal ageing has been reported in TCSs in the very long term, i.e. 20 years after TC treatment.
Germ cell testicular cancer (TC) represents a malignancy with high cure rates. Since the introduction of cisplatin-based chemotherapy in the late 1970s, the 5-year survival rate has increased ...considerably, and it is currently above 95%. Because TC is usually diagnosed before the age of 40 years, these men can expect to live for another 40 to 50 years after being successfully treated. This success, however, is hampered by an increased risk of long-term and late effects of treatment. Secondary malignant neoplasms and cardiovascular disease represent the most common potentially life-threatening late effects, typically occurring more than 10 years after treatment. Other long-term effects include pulmonary toxicity, nephrotoxicity, neurotoxicity, decreased fertility, hypogonadism, and psychosocial problems. The incidence and time to onset of these various adverse effects vary according to treatment type and intensity. There is still little knowledge about underlying mechanisms and genetic susceptibility of the various adverse effects. Apart from treatment burden, it is not yet possible to identify patients who are at high risk for certain late effects after TC treatment. In this clinical review, we present the current status regarding different somatic and psychosocial long-term late effects after treatment for TC, based on Medline searches and our own research. Moreover, we postulate recommendations for general medical evaluations that should begin after treatment is completed and continue during follow-up.
Many real world problems involve fluid flow phenomena, typically be described by the Navier–Stokes equations. The Navier–Stokes equations are partial differential equations (PDEs) with highly ...nonlinear properties. Currently mostly used methods solve this differential equation by discretizing geometries. In the field of fluid mechanics the finite volume method (FVM) is widely used for numerical flow simulation, so-called computational fluid dynamics (CFD). Due to high computational costs and cumbersome generation of the discretization they are not widely used in real time applications. Our presented work focuses on advancing PDE-constrained deep learning frameworks for more real-world applications with irregular geometries without parameterization. We present a Deep Neural Network framework that generate surrogates for non-geometric boundaries by data free solely physics driven training, by minimizing the residuals of the governing PDEs (i.e., conservation laws) so that no computationally expensive CFD simulation data is needed. We named this method geometry aware physics informed neural network—GAPINN. The framework involves three network types. The first network reduces the dimensions of the irregular geometries to a latent representation. In this work we used a Variational-Auto-Encoder (VAE) for this task. We proposed the concept of using this latent representation in combination with spatial coordinates as input for PINNs. Using PINNs we showed that it is possible to train a surrogate model purely driven on the reduction of the residuals of the underlying PDE for irregular non-parametric geometries. Furthermore, we showed the way of designing a boundary constraining network (BCN) to hardly enforce boundary conditions during training of the PINN. We evaluated this concept on test cases in the fields of biofluidmechanics. The experiments comprise laminar flow (Re = 500) in irregular shaped vessels. The main highlight of the presented GAPINN is the use of PINNs on irregular non-parameterized geometries. Despite that we showed the usage of this framework for Navier Stokes equations, it should be feasible to adapt this framework for other problems described by PDEs.
To assess longitudinal long-term alterations of testosterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) in testicular cancer survivors (TCSs).
In all, 307 TCSs treated from ...1980 to 1994 provided blood samples after orchiectomy but before further treatment, at Survey I (SI; 1998-2002), and Survey II (SII; 2007-2008). Levels of sex hormones were categorized according to quartiles and reference range (2.5 and 97.5 percentiles) of 599 controls for each decadal age group. TCSs were categorized according to treatment: surgery, radiotherapy (RT), or chemotherapy (CT). The risk of higher (LH) or lower (testosterone) levels was assessed with χ(2) test (FSH) or ordinal logistic regression analysis and expressed as odds ratios (ORs) with 95% CIs.
Risk of lower testosterone and higher LH and FSH levels was significantly increased for TCSs at all time points after RT or CT. At SII, ORs were 3.3 (95% CI, 2.3 to 4.7) for lower testosterone categories and 5.2 (95% CI, 3.5 to 7.9) for RT and CT. ORs for increased LH and FSH were 4.4 (95% CI, 3.1 to 6.5) and 18.9 (95% CI, 11.0 to 32.6) for RT, respectively, and 3.6 (95% CI, 2.4 to 5.3) and 14.2 (95% CI, 8.3 to 24.4) for CT, respectively. The cumulative platinum dose was significantly associated with risk of higher LH levels at both surveys and higher FSH at SI. In total, half the TCSs had at least one of three sex hormone levels outside the reference range at SII.
Long-term TCSs are at risk of premature hormonal aging. Our findings may pertain to cancer survivors in general, underlining the importance of extended follow-up.
Cisplatin-induced neurotoxicity and ototoxicity (NTX) are important adverse effects after chemotherapy for testicular cancer (TC). Although serum platinum is measurable years after therapy, its ...impact on NTX has not been evaluated.
In all, 169 cisplatin-treated survivors of TC provided blood samples at Survey I and reported NTX during Survey I (1998-2002) and Survey II (2007-2008). Serum platinum was quantified by inductively coupled plasma mass spectrometry. Patient-reported outcomes were evaluated with the Scale for Chemotherapy-Induced Neurotoxicity (SCIN), regarding the extent of symptom bother as 0, "not at all"; 1, "a little"; 2, "quite a bit"; or 3, "very much." Summing the six symptom scores yielded a total SCIN score of 0 to 18. Categorizing total SCIN scores into quartiles yielded similar-sized groups with increasing symptoms. Multivariate ordinal logistic regression analyses evaluated associations between NTX and long-term serum platinum levels, adjusting for cisplatin dose, dosing schedule, and age.
At Survey I, a significant four- to five-fold association with total SCIN score emerged for the highest serum platinum quartile (odds ratio OR, 4.69; 95% CI, 1.82 to 12.08). Paresthesias and Raynaud's syndrome (hands and feet) showed significant two- to four-fold increased risks with the highest platinum quartile. At Survey II, total SCIN score remained significantly associated with the highest platinum quartile (OR, 4.28; 95% CI, 1.36 to 13.48). Paresthesias (hands and feet) and tinnitus showed significant three- to four-fold increased risks for the highest platinum quartile. Cumulative cisplatin dose was not associated with total SCIN score or individual SCIN symptoms in multivariate analyses.
Here we document a significant relationship between increasing levels of residual serum platinum and NTX severity after adjusting for initial cisplatin dose.
The prognostic significance of age at testicular cancer (TC) diagnosis, socioeconomic status (SES), race, and marital status on TC-specific mortality is not well-characterized. In a cancer that is so ...curable, it is important to identify any influence that confers an increased risk of TC-specific mortality.
Using multivariate cause-specific Cox regression models that accounted for competing risks, hazard ratios (HRs) were calculated for 10-year TC-specific mortality among 27,948 patients with TC reported to the Surveillance, Epidemiology and End Results program (1978 to 2006). Independent predictors were age at diagnosis, SES, race, marital status, extent of disease (EOD), calendar year of diagnosis, radiotherapy, and retroperitoneal lymph node dissection (RPLND).
Compared with younger patients, diagnostic age 40+ was associated with increased mortality (seminoma, HR, 2.00, P < .001; nonseminoma, HR, 2.09; P < .001; most evident in metastatic disease, HR, 8.62; P < .001; HR, 6.35; P < .001, respectively). Unmarried men had two-to three-fold excess mortality compared to married men (HR, 2.97; P < .001; HR, 1.54; P < .001, respectively). Among nonseminoma patients, decreasing SES (P trend < .001) and nonwhite race (HR, 2.11; P < .001) increased mortality. Diagnosis after 1987 resulted in reduced mortality compared to earlier calendar years (HR, 0.58; P = .001; HR, 0.74; P = .001, respectively). Lack of RPLND was associated with seven-fold increase in death (P < .001).
TC-specific mortality is doubled among US patients diagnosed with seminoma or nonseminoma after age 40, even when initial treatment and EOD are taken into account. Among men with nonseminoma, nonwhite race and lower SES also significantly increase TC-specific mortality. Additional research is needed, enabling the development of interventional strategies and preventive approaches, as applicable.
Abstract Testicular cancer (TC) is the most common solid organ malignancy among young men at their peak of family life, education, and career. The exceptionally high cure rates are hampered by an ...increased risk of several treatment-related toxicities that may emerge several years after treatment. In this article, we review the current knowledge regarding pulmonary and cardiovascular toxicity in long-term survivors of TC. Bleomycin pulmonary toxicity is associated with the cumulative bleomycin dose, renal function, age and smoking status and can be avoided by a careful patient evaluation before chemotherapy. Lung function assessments are not routinely recommended for detecting bleomycin pulmonary toxicity. Long-term decreased pulmonary function may also be related to other chemotherapy agents such as cisplatin. Cardiovascular disease represents one of the most serious late effects of cytotoxic treatment in TC survivors and typically appears several years to decades after treatment. The increased risk for cardiovascular disease is probably mediated by a direct vascular damage from cytotoxic treatment that may stimulate the endothelium, possibly ultimately inducing the atherosclerotic process, as well as an indirect cytotoxic effect by increasing the levels of cardiovascular risk factors. Follow-up of these cancer survivors should include recommendations for maintaining a healthy lifestyle to reduce the risk of future cardiovascular events and to avoid declining pulmonary function.
Cisplatin, a cornerstone of combination chemotherapy in the treatment of testicular cancer, induces hearing impairment with considerable interindividual variations. These differences might be a ...result of functional polymorphisms in cisplatin-detoxifying enzymes like glutathione S-transferases (GSTs).
We identified 173 cisplatin-treated testicular cancer survivors (TCSs) who had participated in a long-term survey that included audiometric testing and lymphocyte sampling. The hearing decibel thresholds at 4,000 Hz were categorized into leveled scales by normative decibel percentiles. Known functional polymorphisms (positive or negative) in GSTT1 and GSTM1 and codon 105 A/G (Ile/Val) in GSTP1 were analyzed by multiplex polymerase chain reaction, followed by restriction enzyme cutting, and separated by gel electrophoresis.
The risk of having an inferior audiometric result was more than four times higher in TCSs with 105Ile/105Ile-GSTP1 or 105Val/105Ile-GSTP1 compared with 105Val/105Val-GSTP1 (odds ratio OR = 4.21; 95% CI, 1.99 to 8.88; P < .001 when modeled by ordinal logistic regression OLR). GSTM1 positivity was detrimental for hearing ability. Two combined genotypes were associated with hearing ability. The presence of pattern 1 (GSTT1 positive, GSTM1 positive, and 105Ile/105Ile-GSTP1) was associated with hearing impairment (OR = 2.76; 95% CI, 1.35 to 5.64; P = .005, OLR). TCSs with pattern 2 (GSTT1 positive, GSTM1 positive, and 105Val/105Val-GSTP1) had better hearing ability than TCSs without this pattern (OR = 5.35; 95% CI, 2.25 to 12.76; P < .001, OLR).
The presence of both alleles of 105Val-GSTP1 offered protection against cisplatin-induced hearing impairment. Two genotype patterns with good and poor protection against cisplatin-induced ototoxicity were identified.
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